THE CHOICES FOR BREAST CANCER TREATMENT PowerPoint Presentation

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer.

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment.

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000.

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy?

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women.

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+)

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year.

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488.

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538.

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538.

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217.

Slide 29 -

THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137.

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250.

Slide 31 -

THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173.

Slide 32 -

THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5%

Slide 33 -

THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist.

Slide 34 -

THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes

Slide 36 -

THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit

Slide 39 -

THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years

Slide 40 -

THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI ASCO Technology Assessment 2004 Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen

Slide 44 -

THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI ASCO Technology Assessment 2004 Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen Total Cholesterol in BIG 1-98: Summary Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group

Slide 45 -

THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI ASCO Technology Assessment 2004 Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen Total Cholesterol in BIG 1-98: Summary Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group AIs and Bone NORMAL BONE OSTEOPOROTIC BONE VERTEBRAL COMPRESSION FRACTURE

Slide 46 -

THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI ASCO Technology Assessment 2004 Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen Total Cholesterol in BIG 1-98: Summary Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group AIs and Bone NORMAL BONE OSTEOPOROTIC BONE VERTEBRAL COMPRESSION FRACTURE Osteoporosis/Fractures Reported in Adjuvant AI Trials ATAC Trialists’ Group Lancet 2005;365:60; Thürlimann et al. www.ibcsg.org; Coombes et al. N Engl J Med 2004;350:1081; Jakesz et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 2); Goss et al. N Engl J Med 2003;349:1793. A T AC BIG 1–98 68 26 AN A L E T R O T A M T A M F r a c tu r e F r a c tu r e 11. 0 vs 7.7 5.8 vs 4.1 < 0.00 0 1 N I IES AR N O 31 28 E X E M AN A T A M T A M F r a c tu r e O s te o por os i s F r a c tu r e 3.1 vs 2.3 7.4 vs 5.7 2.4 vs 2.1 0.0 8 0.0 5 N I M A - 1 7 28 L E T R O Pl a c ebo F r a c tu r e O s te o por os i s 3.6 vs 2.9 5.8 vs 4.5 0.2 4 0.0 7 Mouridsen 0305 Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI ASCO Technology Assessment 2004 Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen Total Cholesterol in BIG 1-98: Summary Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group AIs and Bone NORMAL BONE OSTEOPOROTIC BONE VERTEBRAL COMPRESSION FRACTURE Osteoporosis/Fractures Reported in Adjuvant AI Trials ATAC Trialists’ Group Lancet 2005;365:60; Thürlimann et al. www.ibcsg.org; Coombes et al. N Engl J Med 2004;350:1081; Jakesz et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 2); Goss et al. N Engl J Med 2003;349:1793. A T AC BIG 1–98 68 26 AN A L E T R O T A M T A M F r a c tu r e F r a c tu r e 11. 0 vs 7.7 5.8 vs 4.1 < 0.00 0 1 N I IES AR N O 31 28 E X E M AN A T A M T A M F r a c tu r e O s te o por os i s F r a c tu r e 3.1 vs 2.3 7.4 vs 5.7 2.4 vs 2.1 0.0 8 0.0 5 N I M A - 1 7 28 L E T R O Pl a c ebo F r a c tu r e O s te o por os i s 3.6 vs 2.9 5.8 vs 4.5 0.2 4 0.0 7 Mouridsen 0305 Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P ATAC: Bone Fracture Adverse Events at Treatment Completion Analysis ATAC Trialists’ Group. SABCS 2004. Lancet 2005; 365: 60-62.

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI ASCO Technology Assessment 2004 Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen Total Cholesterol in BIG 1-98: Summary Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group AIs and Bone NORMAL BONE OSTEOPOROTIC BONE VERTEBRAL COMPRESSION FRACTURE Osteoporosis/Fractures Reported in Adjuvant AI Trials ATAC Trialists’ Group Lancet 2005;365:60; Thürlimann et al. www.ibcsg.org; Coombes et al. N Engl J Med 2004;350:1081; Jakesz et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 2); Goss et al. N Engl J Med 2003;349:1793. A T AC BIG 1–98 68 26 AN A L E T R O T A M T A M F r a c tu r e F r a c tu r e 11. 0 vs 7.7 5.8 vs 4.1 < 0.00 0 1 N I IES AR N O 31 28 E X E M AN A T A M T A M F r a c tu r e O s te o por os i s F r a c tu r e 3.1 vs 2.3 7.4 vs 5.7 2.4 vs 2.1 0.0 8 0.0 5 N I M A - 1 7 28 L E T R O Pl a c ebo F r a c tu r e O s te o por os i s 3.6 vs 2.9 5.8 vs 4.5 0.2 4 0.0 7 Mouridsen 0305 Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P ATAC: Bone Fracture Adverse Events at Treatment Completion Analysis ATAC Trialists’ Group. SABCS 2004. Lancet 2005; 365: 60-62. How Serious Is This Difference? No placebo arm What fracture rate might normally be observed in a similarly aged population? 12-25 # per 1000 patient years ATAC Tam: 13.44 # per 1000 pt years ATAC Arimidex: 21.55 # per 1000 pt years

Slide 49 -

THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI ASCO Technology Assessment 2004 Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen Total Cholesterol in BIG 1-98: Summary Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group AIs and Bone NORMAL BONE OSTEOPOROTIC BONE VERTEBRAL COMPRESSION FRACTURE Osteoporosis/Fractures Reported in Adjuvant AI Trials ATAC Trialists’ Group Lancet 2005;365:60; Thürlimann et al. www.ibcsg.org; Coombes et al. N Engl J Med 2004;350:1081; Jakesz et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 2); Goss et al. N Engl J Med 2003;349:1793. A T AC BIG 1–98 68 26 AN A L E T R O T A M T A M F r a c tu r e F r a c tu r e 11. 0 vs 7.7 5.8 vs 4.1 < 0.00 0 1 N I IES AR N O 31 28 E X E M AN A T A M T A M F r a c tu r e O s te o por os i s F r a c tu r e 3.1 vs 2.3 7.4 vs 5.7 2.4 vs 2.1 0.0 8 0.0 5 N I M A - 1 7 28 L E T R O Pl a c ebo F r a c tu r e O s te o por os i s 3.6 vs 2.9 5.8 vs 4.5 0.2 4 0.0 7 Mouridsen 0305 Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P ATAC: Bone Fracture Adverse Events at Treatment Completion Analysis ATAC Trialists’ Group. SABCS 2004. Lancet 2005; 365: 60-62. How Serious Is This Difference? No placebo arm What fracture rate might normally be observed in a similarly aged population? 12-25 # per 1000 patient years ATAC Tam: 13.44 # per 1000 pt years ATAC Arimidex: 21.55 # per 1000 pt years ATAC BMD Substudy No bisphosphonates allowed 2 years A => 4% loss in LS 3.2% loss in hip 2 years Tam => 1.9% gain in LS 1.2% gain in hip Considered small losses compared to the natural BMD loss that occurs in menopause Benefits of the drug outweigh this risk

Slide 50 -

THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI ASCO Technology Assessment 2004 Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen Total Cholesterol in BIG 1-98: Summary Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group AIs and Bone NORMAL BONE OSTEOPOROTIC BONE VERTEBRAL COMPRESSION FRACTURE Osteoporosis/Fractures Reported in Adjuvant AI Trials ATAC Trialists’ Group Lancet 2005;365:60; Thürlimann et al. www.ibcsg.org; Coombes et al. N Engl J Med 2004;350:1081; Jakesz et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 2); Goss et al. N Engl J Med 2003;349:1793. A T AC BIG 1–98 68 26 AN A L E T R O T A M T A M F r a c tu r e F r a c tu r e 11. 0 vs 7.7 5.8 vs 4.1 < 0.00 0 1 N I IES AR N O 31 28 E X E M AN A T A M T A M F r a c tu r e O s te o por os i s F r a c tu r e 3.1 vs 2.3 7.4 vs 5.7 2.4 vs 2.1 0.0 8 0.0 5 N I M A - 1 7 28 L E T R O Pl a c ebo F r a c tu r e O s te o por os i s 3.6 vs 2.9 5.8 vs 4.5 0.2 4 0.0 7 Mouridsen 0305 Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P ATAC: Bone Fracture Adverse Events at Treatment Completion Analysis ATAC Trialists’ Group. SABCS 2004. Lancet 2005; 365: 60-62. How Serious Is This Difference? No placebo arm What fracture rate might normally be observed in a similarly aged population? 12-25 # per 1000 patient years ATAC Tam: 13.44 # per 1000 pt years ATAC Arimidex: 21.55 # per 1000 pt years ATAC BMD Substudy No bisphosphonates allowed 2 years A => 4% loss in LS 3.2% loss in hip 2 years Tam => 1.9% gain in LS 1.2% gain in hip Considered small losses compared to the natural BMD loss that occurs in menopause Benefits of the drug outweigh this risk Patient Recommendations On AIs Stop smoking Reduce caffeine and alcohol intake Perform regular weight-bearing exercise Supplement with Calcium 1500mg/d and vitamin D 800 IU/d Never take estrogen Raloxifene is contraindicated

Slide 51 -

THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI ASCO Technology Assessment 2004 Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen Total Cholesterol in BIG 1-98: Summary Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group AIs and Bone NORMAL BONE OSTEOPOROTIC BONE VERTEBRAL COMPRESSION FRACTURE Osteoporosis/Fractures Reported in Adjuvant AI Trials ATAC Trialists’ Group Lancet 2005;365:60; Thürlimann et al. www.ibcsg.org; Coombes et al. N Engl J Med 2004;350:1081; Jakesz et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 2); Goss et al. N Engl J Med 2003;349:1793. A T AC BIG 1–98 68 26 AN A L E T R O T A M T A M F r a c tu r e F r a c tu r e 11. 0 vs 7.7 5.8 vs 4.1 < 0.00 0 1 N I IES AR N O 31 28 E X E M AN A T A M T A M F r a c tu r e O s te o por os i s F r a c tu r e 3.1 vs 2.3 7.4 vs 5.7 2.4 vs 2.1 0.0 8 0.0 5 N I M A - 1 7 28 L E T R O Pl a c ebo F r a c tu r e O s te o por os i s 3.6 vs 2.9 5.8 vs 4.5 0.2 4 0.0 7 Mouridsen 0305 Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P ATAC: Bone Fracture Adverse Events at Treatment Completion Analysis ATAC Trialists’ Group. SABCS 2004. Lancet 2005; 365: 60-62. How Serious Is This Difference? No placebo arm What fracture rate might normally be observed in a similarly aged population? 12-25 # per 1000 patient years ATAC Tam: 13.44 # per 1000 pt years ATAC Arimidex: 21.55 # per 1000 pt years ATAC BMD Substudy No bisphosphonates allowed 2 years A => 4% loss in LS 3.2% loss in hip 2 years Tam => 1.9% gain in LS 1.2% gain in hip Considered small losses compared to the natural BMD loss that occurs in menopause Benefits of the drug outweigh this risk Patient Recommendations On AIs Stop smoking Reduce caffeine and alcohol intake Perform regular weight-bearing exercise Supplement with Calcium 1500mg/d and vitamin D 800 IU/d Never take estrogen Raloxifene is contraindicated Patient Recommendations On AIs BMD performed at baseline and q12-18mos If patient has had an osteoporotic #, add a bisphosphonate right away If there is evidence of OP, add bisphosphonate right away If there is osteopenia, evaluate other RFs and consider bisphosphonate If follow-up BMD loss >3% LS or >5% FN, add a bisphosphonate

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI ASCO Technology Assessment 2004 Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen Total Cholesterol in BIG 1-98: Summary Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group AIs and Bone NORMAL BONE OSTEOPOROTIC BONE VERTEBRAL COMPRESSION FRACTURE Osteoporosis/Fractures Reported in Adjuvant AI Trials ATAC Trialists’ Group Lancet 2005;365:60; Thürlimann et al. www.ibcsg.org; Coombes et al. N Engl J Med 2004;350:1081; Jakesz et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 2); Goss et al. N Engl J Med 2003;349:1793. A T AC BIG 1–98 68 26 AN A L E T R O T A M T A M F r a c tu r e F r a c tu r e 11. 0 vs 7.7 5.8 vs 4.1 < 0.00 0 1 N I IES AR N O 31 28 E X E M AN A T A M T A M F r a c tu r e O s te o por os i s F r a c tu r e 3.1 vs 2.3 7.4 vs 5.7 2.4 vs 2.1 0.0 8 0.0 5 N I M A - 1 7 28 L E T R O Pl a c ebo F r a c tu r e O s te o por os i s 3.6 vs 2.9 5.8 vs 4.5 0.2 4 0.0 7 Mouridsen 0305 Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P ATAC: Bone Fracture Adverse Events at Treatment Completion Analysis ATAC Trialists’ Group. SABCS 2004. Lancet 2005; 365: 60-62. How Serious Is This Difference? No placebo arm What fracture rate might normally be observed in a similarly aged population? 12-25 # per 1000 patient years ATAC Tam: 13.44 # per 1000 pt years ATAC Arimidex: 21.55 # per 1000 pt years ATAC BMD Substudy No bisphosphonates allowed 2 years A => 4% loss in LS 3.2% loss in hip 2 years Tam => 1.9% gain in LS 1.2% gain in hip Considered small losses compared to the natural BMD loss that occurs in menopause Benefits of the drug outweigh this risk Patient Recommendations On AIs Stop smoking Reduce caffeine and alcohol intake Perform regular weight-bearing exercise Supplement with Calcium 1500mg/d and vitamin D 800 IU/d Never take estrogen Raloxifene is contraindicated Patient Recommendations On AIs BMD performed at baseline and q12-18mos If patient has had an osteoporotic #, add a bisphosphonate right away If there is evidence of OP, add bisphosphonate right away If there is osteopenia, evaluate other RFs and consider bisphosphonate If follow-up BMD loss >3% LS or >5% FN, add a bisphosphonate

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI ASCO Technology Assessment 2004 Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen Total Cholesterol in BIG 1-98: Summary Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group AIs and Bone NORMAL BONE OSTEOPOROTIC BONE VERTEBRAL COMPRESSION FRACTURE Osteoporosis/Fractures Reported in Adjuvant AI Trials ATAC Trialists’ Group Lancet 2005;365:60; Thürlimann et al. www.ibcsg.org; Coombes et al. N Engl J Med 2004;350:1081; Jakesz et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 2); Goss et al. N Engl J Med 2003;349:1793. A T AC BIG 1–98 68 26 AN A L E T R O T A M T A M F r a c tu r e F r a c tu r e 11. 0 vs 7.7 5.8 vs 4.1 < 0.00 0 1 N I IES AR N O 31 28 E X E M AN A T A M T A M F r a c tu r e O s te o por os i s F r a c tu r e 3.1 vs 2.3 7.4 vs 5.7 2.4 vs 2.1 0.0 8 0.0 5 N I M A - 1 7 28 L E T R O Pl a c ebo F r a c tu r e O s te o por os i s 3.6 vs 2.9 5.8 vs 4.5 0.2 4 0.0 7 Mouridsen 0305 Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P ATAC: Bone Fracture Adverse Events at Treatment Completion Analysis ATAC Trialists’ Group. SABCS 2004. Lancet 2005; 365: 60-62. How Serious Is This Difference? No placebo arm What fracture rate might normally be observed in a similarly aged population? 12-25 # per 1000 patient years ATAC Tam: 13.44 # per 1000 pt years ATAC Arimidex: 21.55 # per 1000 pt years ATAC BMD Substudy No bisphosphonates allowed 2 years A => 4% loss in LS 3.2% loss in hip 2 years Tam => 1.9% gain in LS 1.2% gain in hip Considered small losses compared to the natural BMD loss that occurs in menopause Benefits of the drug outweigh this risk Patient Recommendations On AIs Stop smoking Reduce caffeine and alcohol intake Perform regular weight-bearing exercise Supplement with Calcium 1500mg/d and vitamin D 800 IU/d Never take estrogen Raloxifene is contraindicated Patient Recommendations On AIs BMD performed at baseline and q12-18mos If patient has had an osteoporotic #, add a bisphosphonate right away If there is evidence of OP, add bisphosphonate right away If there is osteopenia, evaluate other RFs and consider bisphosphonate If follow-up BMD loss >3% LS or >5% FN, add a bisphosphonate Case No. 2 Continues 4 years later she reports profound fatigue x 2 mos Drops in to office to see her SCC, complaining of fatigue, wants to set up an appointment with oncologist SCC notes she is in rapid AFib and sends her to ER Cardiologist diagnoses her with anthracycline-induced cardiomyopathy requiring medical management

Slide 54 -

THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI ASCO Technology Assessment 2004 Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen Total Cholesterol in BIG 1-98: Summary Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group AIs and Bone NORMAL BONE OSTEOPOROTIC BONE VERTEBRAL COMPRESSION FRACTURE Osteoporosis/Fractures Reported in Adjuvant AI Trials ATAC Trialists’ Group Lancet 2005;365:60; Thürlimann et al. www.ibcsg.org; Coombes et al. N Engl J Med 2004;350:1081; Jakesz et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 2); Goss et al. N Engl J Med 2003;349:1793. A T AC BIG 1–98 68 26 AN A L E T R O T A M T A M F r a c tu r e F r a c tu r e 11. 0 vs 7.7 5.8 vs 4.1 < 0.00 0 1 N I IES AR N O 31 28 E X E M AN A T A M T A M F r a c tu r e O s te o por os i s F r a c tu r e 3.1 vs 2.3 7.4 vs 5.7 2.4 vs 2.1 0.0 8 0.0 5 N I M A - 1 7 28 L E T R O Pl a c ebo F r a c tu r e O s te o por os i s 3.6 vs 2.9 5.8 vs 4.5 0.2 4 0.0 7 Mouridsen 0305 Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P ATAC: Bone Fracture Adverse Events at Treatment Completion Analysis ATAC Trialists’ Group. SABCS 2004. Lancet 2005; 365: 60-62. How Serious Is This Difference? No placebo arm What fracture rate might normally be observed in a similarly aged population? 12-25 # per 1000 patient years ATAC Tam: 13.44 # per 1000 pt years ATAC Arimidex: 21.55 # per 1000 pt years ATAC BMD Substudy No bisphosphonates allowed 2 years A => 4% loss in LS 3.2% loss in hip 2 years Tam => 1.9% gain in LS 1.2% gain in hip Considered small losses compared to the natural BMD loss that occurs in menopause Benefits of the drug outweigh this risk Patient Recommendations On AIs Stop smoking Reduce caffeine and alcohol intake Perform regular weight-bearing exercise Supplement with Calcium 1500mg/d and vitamin D 800 IU/d Never take estrogen Raloxifene is contraindicated Patient Recommendations On AIs BMD performed at baseline and q12-18mos If patient has had an osteoporotic #, add a bisphosphonate right away If there is evidence of OP, add bisphosphonate right away If there is osteopenia, evaluate other RFs and consider bisphosphonate If follow-up BMD loss >3% LS or >5% FN, add a bisphosphonate Case No. 2 Continues 4 years later she reports profound fatigue x 2 mos Drops in to office to see her SCC, complaining of fatigue, wants to set up an appointment with oncologist SCC notes she is in rapid AFib and sends her to ER Cardiologist diagnoses her with anthracycline-induced cardiomyopathy requiring medical management Chemotherapy Related Cardiotoxocity Anthracyclines Daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone Toxicity effects Acute (during administration) Arrhythmias, pericarditis-myocarditis Early (Several days to mos following) CHF with peak at 3 mos after last dose Late (years to decades following) CHF may develop up to 10-12 yrs after last anthracycline dose

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI ASCO Technology Assessment 2004 Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen Total Cholesterol in BIG 1-98: Summary Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group AIs and Bone NORMAL BONE OSTEOPOROTIC BONE VERTEBRAL COMPRESSION FRACTURE Osteoporosis/Fractures Reported in Adjuvant AI Trials ATAC Trialists’ Group Lancet 2005;365:60; Thürlimann et al. www.ibcsg.org; Coombes et al. N Engl J Med 2004;350:1081; Jakesz et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 2); Goss et al. N Engl J Med 2003;349:1793. A T AC BIG 1–98 68 26 AN A L E T R O T A M T A M F r a c tu r e F r a c tu r e 11. 0 vs 7.7 5.8 vs 4.1 < 0.00 0 1 N I IES AR N O 31 28 E X E M AN A T A M T A M F r a c tu r e O s te o por os i s F r a c tu r e 3.1 vs 2.3 7.4 vs 5.7 2.4 vs 2.1 0.0 8 0.0 5 N I M A - 1 7 28 L E T R O Pl a c ebo F r a c tu r e O s te o por os i s 3.6 vs 2.9 5.8 vs 4.5 0.2 4 0.0 7 Mouridsen 0305 Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P ATAC: Bone Fracture Adverse Events at Treatment Completion Analysis ATAC Trialists’ Group. SABCS 2004. Lancet 2005; 365: 60-62. How Serious Is This Difference? No placebo arm What fracture rate might normally be observed in a similarly aged population? 12-25 # per 1000 patient years ATAC Tam: 13.44 # per 1000 pt years ATAC Arimidex: 21.55 # per 1000 pt years ATAC BMD Substudy No bisphosphonates allowed 2 years A => 4% loss in LS 3.2% loss in hip 2 years Tam => 1.9% gain in LS 1.2% gain in hip Considered small losses compared to the natural BMD loss that occurs in menopause Benefits of the drug outweigh this risk Patient Recommendations On AIs Stop smoking Reduce caffeine and alcohol intake Perform regular weight-bearing exercise Supplement with Calcium 1500mg/d and vitamin D 800 IU/d Never take estrogen Raloxifene is contraindicated Patient Recommendations On AIs BMD performed at baseline and q12-18mos If patient has had an osteoporotic #, add a bisphosphonate right away If there is evidence of OP, add bisphosphonate right away If there is osteopenia, evaluate other RFs and consider bisphosphonate If follow-up BMD loss >3% LS or >5% FN, add a bisphosphonate Case No. 2 Continues 4 years later she reports profound fatigue x 2 mos Drops in to office to see her SCC, complaining of fatigue, wants to set up an appointment with oncologist SCC notes she is in rapid AFib and sends her to ER Cardiologist diagnoses her with anthracycline-induced cardiomyopathy requiring medical management Chemotherapy Related Cardiotoxocity Anthracyclines Daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone Toxicity effects Acute (during administration) Arrhythmias, pericarditis-myocarditis Early (Several days to mos following) CHF with peak at 3 mos after last dose Late (years to decades following) CHF may develop up to 10-12 yrs after last anthracycline dose Cardiac Toxicity – Anthracyclines Risk factors for the development of anthracycline cardiac toxicity Cumulative dose – strongest risk factor Age Prior irradiation Concomitant administration of other agents Previous history of cardiac disease

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI ASCO Technology Assessment 2004 Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen Total Cholesterol in BIG 1-98: Summary Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group AIs and Bone NORMAL BONE OSTEOPOROTIC BONE VERTEBRAL COMPRESSION FRACTURE Osteoporosis/Fractures Reported in Adjuvant AI Trials ATAC Trialists’ Group Lancet 2005;365:60; Thürlimann et al. www.ibcsg.org; Coombes et al. N Engl J Med 2004;350:1081; Jakesz et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 2); Goss et al. N Engl J Med 2003;349:1793. A T AC BIG 1–98 68 26 AN A L E T R O T A M T A M F r a c tu r e F r a c tu r e 11. 0 vs 7.7 5.8 vs 4.1 < 0.00 0 1 N I IES AR N O 31 28 E X E M AN A T A M T A M F r a c tu r e O s te o por os i s F r a c tu r e 3.1 vs 2.3 7.4 vs 5.7 2.4 vs 2.1 0.0 8 0.0 5 N I M A - 1 7 28 L E T R O Pl a c ebo F r a c tu r e O s te o por os i s 3.6 vs 2.9 5.8 vs 4.5 0.2 4 0.0 7 Mouridsen 0305 Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P ATAC: Bone Fracture Adverse Events at Treatment Completion Analysis ATAC Trialists’ Group. SABCS 2004. Lancet 2005; 365: 60-62. How Serious Is This Difference? No placebo arm What fracture rate might normally be observed in a similarly aged population? 12-25 # per 1000 patient years ATAC Tam: 13.44 # per 1000 pt years ATAC Arimidex: 21.55 # per 1000 pt years ATAC BMD Substudy No bisphosphonates allowed 2 years A => 4% loss in LS 3.2% loss in hip 2 years Tam => 1.9% gain in LS 1.2% gain in hip Considered small losses compared to the natural BMD loss that occurs in menopause Benefits of the drug outweigh this risk Patient Recommendations On AIs Stop smoking Reduce caffeine and alcohol intake Perform regular weight-bearing exercise Supplement with Calcium 1500mg/d and vitamin D 800 IU/d Never take estrogen Raloxifene is contraindicated Patient Recommendations On AIs BMD performed at baseline and q12-18mos If patient has had an osteoporotic #, add a bisphosphonate right away If there is evidence of OP, add bisphosphonate right away If there is osteopenia, evaluate other RFs and consider bisphosphonate If follow-up BMD loss >3% LS or >5% FN, add a bisphosphonate Case No. 2 Continues 4 years later she reports profound fatigue x 2 mos Drops in to office to see her SCC, complaining of fatigue, wants to set up an appointment with oncologist SCC notes she is in rapid AFib and sends her to ER Cardiologist diagnoses her with anthracycline-induced cardiomyopathy requiring medical management Chemotherapy Related Cardiotoxocity Anthracyclines Daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone Toxicity effects Acute (during administration) Arrhythmias, pericarditis-myocarditis Early (Several days to mos following) CHF with peak at 3 mos after last dose Late (years to decades following) CHF may develop up to 10-12 yrs after last anthracycline dose Cardiac Toxicity – Anthracyclines Risk factors for the development of anthracycline cardiac toxicity Cumulative dose – strongest risk factor Age Prior irradiation Concomitant administration of other agents Previous history of cardiac disease Conclusions Key advances in the management of breast cancer have been made in the last few years Adjuvant treatment is individualized to possibly include chemotherapy, hormone therapy and trastuzumab New treatments are intensive and may result in long-term health concerns Evidence-based, informative discussion to review risks and benefits for each patient is of critical importance

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI ASCO Technology Assessment 2004 Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen Total Cholesterol in BIG 1-98: Summary Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group AIs and Bone NORMAL BONE OSTEOPOROTIC BONE VERTEBRAL COMPRESSION FRACTURE Osteoporosis/Fractures Reported in Adjuvant AI Trials ATAC Trialists’ Group Lancet 2005;365:60; Thürlimann et al. www.ibcsg.org; Coombes et al. N Engl J Med 2004;350:1081; Jakesz et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 2); Goss et al. N Engl J Med 2003;349:1793. A T AC BIG 1–98 68 26 AN A L E T R O T A M T A M F r a c tu r e F r a c tu r e 11. 0 vs 7.7 5.8 vs 4.1 < 0.00 0 1 N I IES AR N O 31 28 E X E M AN A T A M T A M F r a c tu r e O s te o por os i s F r a c tu r e 3.1 vs 2.3 7.4 vs 5.7 2.4 vs 2.1 0.0 8 0.0 5 N I M A - 1 7 28 L E T R O Pl a c ebo F r a c tu r e O s te o por os i s 3.6 vs 2.9 5.8 vs 4.5 0.2 4 0.0 7 Mouridsen 0305 Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P ATAC: Bone Fracture Adverse Events at Treatment Completion Analysis ATAC Trialists’ Group. SABCS 2004. Lancet 2005; 365: 60-62. How Serious Is This Difference? No placebo arm What fracture rate might normally be observed in a similarly aged population? 12-25 # per 1000 patient years ATAC Tam: 13.44 # per 1000 pt years ATAC Arimidex: 21.55 # per 1000 pt years ATAC BMD Substudy No bisphosphonates allowed 2 years A => 4% loss in LS 3.2% loss in hip 2 years Tam => 1.9% gain in LS 1.2% gain in hip Considered small losses compared to the natural BMD loss that occurs in menopause Benefits of the drug outweigh this risk Patient Recommendations On AIs Stop smoking Reduce caffeine and alcohol intake Perform regular weight-bearing exercise Supplement with Calcium 1500mg/d and vitamin D 800 IU/d Never take estrogen Raloxifene is contraindicated Patient Recommendations On AIs BMD performed at baseline and q12-18mos If patient has had an osteoporotic #, add a bisphosphonate right away If there is evidence of OP, add bisphosphonate right away If there is osteopenia, evaluate other RFs and consider bisphosphonate If follow-up BMD loss >3% LS or >5% FN, add a bisphosphonate Case No. 2 Continues 4 years later she reports profound fatigue x 2 mos Drops in to office to see her SCC, complaining of fatigue, wants to set up an appointment with oncologist SCC notes she is in rapid AFib and sends her to ER Cardiologist diagnoses her with anthracycline-induced cardiomyopathy requiring medical management Chemotherapy Related Cardiotoxocity Anthracyclines Daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone Toxicity effects Acute (during administration) Arrhythmias, pericarditis-myocarditis Early (Several days to mos following) CHF with peak at 3 mos after last dose Late (years to decades following) CHF may develop up to 10-12 yrs after last anthracycline dose Cardiac Toxicity – Anthracyclines Risk factors for the development of anthracycline cardiac toxicity Cumulative dose – strongest risk factor Age Prior irradiation Concomitant administration of other agents Previous history of cardiac disease Conclusions Key advances in the management of breast cancer have been made in the last few years Adjuvant treatment is individualized to possibly include chemotherapy, hormone therapy and trastuzumab New treatments are intensive and may result in long-term health concerns Evidence-based, informative discussion to review risks and benefits for each patient is of critical importance

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THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI ASCO Technology Assessment 2004 Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen Total Cholesterol in BIG 1-98: Summary Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group AIs and Bone NORMAL BONE OSTEOPOROTIC BONE VERTEBRAL COMPRESSION FRACTURE Osteoporosis/Fractures Reported in Adjuvant AI Trials ATAC Trialists’ Group Lancet 2005;365:60; Thürlimann et al. www.ibcsg.org; Coombes et al. N Engl J Med 2004;350:1081; Jakesz et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 2); Goss et al. N Engl J Med 2003;349:1793. A T AC BIG 1–98 68 26 AN A L E T R O T A M T A M F r a c tu r e F r a c tu r e 11. 0 vs 7.7 5.8 vs 4.1 < 0.00 0 1 N I IES AR N O 31 28 E X E M AN A T A M T A M F r a c tu r e O s te o por os i s F r a c tu r e 3.1 vs 2.3 7.4 vs 5.7 2.4 vs 2.1 0.0 8 0.0 5 N I M A - 1 7 28 L E T R O Pl a c ebo F r a c tu r e O s te o por os i s 3.6 vs 2.9 5.8 vs 4.5 0.2 4 0.0 7 Mouridsen 0305 Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P ATAC: Bone Fracture Adverse Events at Treatment Completion Analysis ATAC Trialists’ Group. SABCS 2004. Lancet 2005; 365: 60-62. How Serious Is This Difference? No placebo arm What fracture rate might normally be observed in a similarly aged population? 12-25 # per 1000 patient years ATAC Tam: 13.44 # per 1000 pt years ATAC Arimidex: 21.55 # per 1000 pt years ATAC BMD Substudy No bisphosphonates allowed 2 years A => 4% loss in LS 3.2% loss in hip 2 years Tam => 1.9% gain in LS 1.2% gain in hip Considered small losses compared to the natural BMD loss that occurs in menopause Benefits of the drug outweigh this risk Patient Recommendations On AIs Stop smoking Reduce caffeine and alcohol intake Perform regular weight-bearing exercise Supplement with Calcium 1500mg/d and vitamin D 800 IU/d Never take estrogen Raloxifene is contraindicated Patient Recommendations On AIs BMD performed at baseline and q12-18mos If patient has had an osteoporotic #, add a bisphosphonate right away If there is evidence of OP, add bisphosphonate right away If there is osteopenia, evaluate other RFs and consider bisphosphonate If follow-up BMD loss >3% LS or >5% FN, add a bisphosphonate Case No. 2 Continues 4 years later she reports profound fatigue x 2 mos Drops in to office to see her SCC, complaining of fatigue, wants to set up an appointment with oncologist SCC notes she is in rapid AFib and sends her to ER Cardiologist diagnoses her with anthracycline-induced cardiomyopathy requiring medical management Chemotherapy Related Cardiotoxocity Anthracyclines Daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone Toxicity effects Acute (during administration) Arrhythmias, pericarditis-myocarditis Early (Several days to mos following) CHF with peak at 3 mos after last dose Late (years to decades following) CHF may develop up to 10-12 yrs after last anthracycline dose Cardiac Toxicity – Anthracyclines Risk factors for the development of anthracycline cardiac toxicity Cumulative dose – strongest risk factor Age Prior irradiation Concomitant administration of other agents Previous history of cardiac disease Conclusions Key advances in the management of breast cancer have been made in the last few years Adjuvant treatment is individualized to possibly include chemotherapy, hormone therapy and trastuzumab New treatments are intensive and may result in long-term health concerns Evidence-based, informative discussion to review risks and benefits for each patient is of critical importance

Slide 59 -

THE CHOICES FOR BREAST CANCER TREATMENT Nadia Califaretti MD FRCPC Medical Oncologist GRRCC No conflicts of interest Goal To review current information on making an informed decision about adjuvant treatment of early stage breast cancer. Objectives Case-based approach to evaluating the diagnosis and individualizing treatment. Understand the rationale for treatment. Review the three main treatment options: chemotherapy, endocrine therapy, trastuzumab. Review current standard chemotherapy protocols. Interpret survival data. Interpret morbidity data. To review health issues after cancer treatment. Mortality Rates in Patients With Breast Cancer Aged 50 to 69 Years 0 Year 105 90 75 60 45 30 15 1950 1960 1970 1980 1990 2000 Annual death rateper 100,000 women UK USA Reprinted with permission from Elsevier Science. Lancet 2000. Early Stage Breast Cancer Many women are cured with surgery alone Some women will have a systemic relapse All systemic relapses lead to death Medical oncologist’s role is to assess the risk of relapse/death for an individual woman and make recommendations on how to reduce this risk Decision: Adjuvant Therapy An agent that is active in the metastatic setting Targets microscopic metastatic disease Should be effective on minimal foci Given “blind”: no information on the efficacy for the individual patient Ideally should improve DFS and OS Early Breast Cancer Treatment Schema SURGERY Adjuvant Chemotherapy Adjuvant Radiation +/- Endocrine Tx Adjuvant Trastuzumab Case No. 1 45-year-old female patient, healthy and preMP R breast lumpectomy, SLNB and axillary dissection 6 weeks ago Pathology 2.5 cm size Tumour Grade II/III ER 80%, PR 80% Lymph nodes 3/12 involved HER 2 neu overexpression - positive Case No. 1 - Chemotherapy What is her recurrence risk over 10 years? Without any further treatment? With chemotherapy? What is her risk of dying from breast cancer within 10 years? Without any further treatment? With chemotherapy? Chemotherapy for PreMP BC First generation protocols: AC x 4 Second generation protocols: AC-Taxol, FEC-100 Third generation protocols: Dose dense AC-Taxol, CEF Citron, M. L. et al. J Clin Oncol; 21:1431-1439 2003 (A) Disease-free survival by dose density 4 yr DFS 82% vs 75% (B) Overall survival by dose density Severe neutropenia less frequent on DD regimen with filgrastim. CALGB 9741 Trial: Dose Dense vs Standard Dose AC-Taxol MA.21 Relapse-Free Survival: All Patients P = 0.001 (stratified) CEF EC-T AC-T CEF EC/T AC/T 701701702 451441405 125101113 2 yr 4 yr MA.21 Results: RFS * Adjusted for Stratification Case No. 1: Recurrence Risk (10 yr)Benefit from Chemotherapy 57.6% 29.6% Percentage of patients (%) None G3 G1 G2 Case No. 1: Survival Benefit from Chemotherapy(Alive in 10 years) 65.2% 82.4% Percentage of patients (%) None G1 G2 G3 Case No. 1 – Endocrine Therapy After her 3rd cycle of CEF, the patient stops having menstrual periods. Upon completion of CEF, she is offered Tamoxifen as endocrine therapy. At the discussion of hormonal therapy she brings in her Google search for Femara (Letrozole), which is superior to tamoxifen in postMP women. MA.5 Incidence Of CRA (ER+) EBCTCG (meta-analysis) Tamoxifen is an anti-estrogen 37,000 women in 55 trials of tam vs nil 70% had HR+ tumours, most PM For ER+ pre/postMP pts 5 years of tam results in 47% relative reduction in recurrence risk at 10y 26% relative reduction in mortality risk 47% reduction in contralateral ca risk Tamoxifen: Improvement in Disease-Free Survival Reprinted from The Lancet, vol 351, Early Breast Cancer Trialists’ Collaborative Group, 1451, 1998,with permission from Elsevier Science. Years 100 % Recurrence-free 90 80 60 40 20 0 5 10+ 0 Node -ve: 14.9% SD 1.4: 2P<0.00001 Node +ve: 15.2% SD 2.5: 2P<0.00001 Node -ve Node +ve 87.4 79.2 74.9 75.6 64.3 59.7 58.3 44.5 70 50 30 10 Absolute Recurrence Reduction Tamoxifen (~5 y) Placebo Placebo Tamoxifen (~5 y) Recurrence as First Event Aromatase Inhibitors selectively block peripheral conversion of androstenedione to estrone occurs in ovary, adipose tissue, skin, muscle, liver, cancer cell net result: inhibition of circulating estradiol in serum in PM women only eg: anastrozole (Arimidex), letrozole (Femara) – nonsteroidal eg. Exemestane (Aromasin) – steroidal Estrogen biosynthesis Cancer cell Nucleus Inhibition ofEstrogen-Dependent Growth Case No. 1 - Trastuzumab Upon completion of chemotherapy, MUGA scan reports EF 59%. Her cancer was HER2neu overexpression + Patient advised to consider Herceptin (trastuzumab) q3weeks for one year. ErbB2 (HER2/neu) Overexpression ErbB2 is a human epidermal growth factor receptor encoded by the ErbB2 gene ErbB2 is amplified in approximately 20% to 25% of metastatic breast cancers Adverse prognostic factor Confers resistance to some chemotherapy or hormone therapy Confers aggressive form of disease with significantly shortened disease-free survival and overall survival Breast Cancer. In: DeVita VT, et al. Cancer: Principles and Practice of Oncology. 7th ed. LWW; 1994:1399-1488. ErbB Receptor Tyrosine Kinase System The ErbB system includes four growth factor receptors and their numerous ligands Important in human growth and development Active in proliferating cells, inactive in quiescent cells 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB Receptor Tyrosine Kinases Four receptors: ErbB-1 (EGFR, HER-1) ErbB-2 (HER-2/neu) ErbB-3 (HER-3) ErbB-4 (HER-4) ErbB-1 ErbB-2 ErbB-3 ErbB-4 2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538. ErbB-2 or HER-2/neu Because of a unique ECD conformation, does not bind to ligands, but is primed to dimerize Usually does not homodimerize Heterodimerization with other ErbB receptors is necessary for activation . Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression Gene amplification results in overexpression of normal receptors Receptors spontaneously homodimerize Drives tumour growth 2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110. 3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137. Rationale for Inhibiting ErbB Receptors ErbB receptor inhibition may suppress cell growth, enhance cell death, and improve response to other cancer therapy in some tumors Inhibiting ErbB receptors may more selectively target cancer cells and spare normal cells, thereby reducing unwanted side effects of therapy 1. Baselga J. Oncologist. 2002;7(Suppl 4):2-8. 2. Nicholson R, et al. Eur J Cancer. 2001a;37(Suppl 4):S9-S15. 3. Nicholson R, et al. Endocr Relat Cancer. 2001b;8:175-182. 4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 5. Woodburn J. Pharmacol Ther. 1999;82:241-250. Monoclonal Antibodies Trastuzumab is humanized monoclonal antibody against EC domain of the HER-2 protein Mechanism of action: Inhibit TK activation Induce receptor endocytosis and degradation Induce immune-mediated cytotoxicity 1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217. 3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35. 4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173. Results of Adjuvant Trastuzumab Trials NEJM 2005: HERA Trial and NSABP B-31/NCCTG N9831 Trial: 1 year of adjuvant Herceptin after chemotherapy reduces the risk of a breast cancer recurrence by 50% Brief median followup of 1-2 years SEs: hypersensitivity with first infusion CHF 5% Case No. 1 Continues After 10 treatments of Herceptin, her MUGA reveals EF 45% (baseline 59%) Patient advised to stop Herceptin Even though patient is asymptomatic, referral is made to cardiologist Medical management and close follow-up by cardiologist. Trastuzumab And Cardiotoxicity erbB2 plays a critical role in the developing embryonic heart (gene deletion=mouse death) In adult heart, erbB2 modifies cardiac response to stress Two-hit model: erbB2 deficient heart is more susceptible to cardiotoxic effects of other stressors (eg. Anthracycline chemo)  increased loss of cardiac myocytes Case No. 2 56 year old healthy postMP patient Left lumpectomy and axillary dissection 4 weeks ago Pathology 2.5cm invasive ductal ca nos Grade II/III 0/12 LN involved ER pos 90%, PR pos 90% HER2neu overexpression neg Case No. 2 - Chemotherapy Pt wants to be aggressive with treatment, but is frightened by the concept of chemotherapy Risk of relapse at 10years is 35% Chemo options are reviewed Case No. 2 Continues First generation protocols AC 7% benefit Second generation protocols AC-Taxol, FEC-100 12% benefit Third generation protocols Dose dense AC-Taxol, FEC-D 16% benefit Case No. 2 – Endocrine Therapy Baseline MUGA EF 55% AC administered q 3 weeks x 4 cycles without serious effects After chemo completed she starts adjuvant letrozole 2.5mg po od for planned 5 years Early (Upfront) Adjuvant Trials 0-5 years Surgery TAM EXEM ANASTRO + TAM TAM ANASTRO LETRO TAM R R R TAM LETRO LETRO TAM ATAC TEAM BIG1-98 DFS: Reduction of Event Rate in the Adjuvant Setting EBCTCG,Lancet 1998;351:1451; ATAC Trialists Group, Lancet 2004; Dec 08; Thürlimann et al. ASCO 2005; Coombes et al., N Engl J Med 2004;350:1080, Jakesz et al.,Lancet 2005;366:455, Goss PE et al., JNCI 2005; 97:1262 Review: Mouridsen HT, January 2005 20 Relative Effect of AIs on Post MP Recurrences at 5 Years 38% recurrences with no adjuvant treatment (EBCTCG) 47% risk reduction with Tamoxifen Further 26% risk reduction with AI ASCO Technology Assessment 2004 Optimal adjuvant hormonal therapy for a PM woman with receptor + cancer INCLUDES an AI as initial therapy OR after treatment with tamoxifen Total Cholesterol in BIG 1-98: Summary Serum cholesterol decreased by ~ 12% in the tamoxifen group and was fairly stable in the letrozole group AIs and Bone NORMAL BONE OSTEOPOROTIC BONE VERTEBRAL COMPRESSION FRACTURE Osteoporosis/Fractures Reported in Adjuvant AI Trials ATAC Trialists’ Group Lancet 2005;365:60; Thürlimann et al. www.ibcsg.org; Coombes et al. N Engl J Med 2004;350:1081; Jakesz et al. Breast Cancer Res Treatm 2004;88:S7(Abstract 2); Goss et al. N Engl J Med 2003;349:1793. A T AC BIG 1–98 68 26 AN A L E T R O T A M T A M F r a c tu r e F r a c tu r e 11. 0 vs 7.7 5.8 vs 4.1 < 0.00 0 1 N I IES AR N O 31 28 E X E M AN A T A M T A M F r a c tu r e O s te o por os i s F r a c tu r e 3.1 vs 2.3 7.4 vs 5.7 2.4 vs 2.1 0.0 8 0.0 5 N I M A - 1 7 28 L E T R O Pl a c ebo F r a c tu r e O s te o por os i s 3.6 vs 2.9 5.8 vs 4.5 0.2 4 0.0 7 Mouridsen 0305 Study FU(MO) AI Ref.Drug Event AI vs Ref.(%) P ATAC: Bone Fracture Adverse Events at Treatment Completion Analysis ATAC Trialists’ Group. SABCS 2004. Lancet 2005; 365: 60-62. How Serious Is This Difference? No placebo arm What fracture rate might normally be observed in a similarly aged population? 12-25 # per 1000 patient years ATAC Tam: 13.44 # per 1000 pt years ATAC Arimidex: 21.55 # per 1000 pt years ATAC BMD Substudy No bisphosphonates allowed 2 years A => 4% loss in LS 3.2% loss in hip 2 years Tam => 1.9% gain in LS 1.2% gain in hip Considered small losses compared to the natural BMD loss that occurs in menopause Benefits of the drug outweigh this risk Patient Recommendations On AIs Stop smoking Reduce caffeine and alcohol intake Perform regular weight-bearing exercise Supplement with Calcium 1500mg/d and vitamin D 800 IU/d Never take estrogen Raloxifene is contraindicated Patient Recommendations On AIs BMD performed at baseline and q12-18mos If patient has had an osteoporotic #, add a bisphosphonate right away If there is evidence of OP, add bisphosphonate right away If there is osteopenia, evaluate other RFs and consider bisphosphonate If follow-up BMD loss >3% LS or >5% FN, add a bisphosphonate Case No. 2 Continues 4 years later she reports profound fatigue x 2 mos Drops in to office to see her SCC, complaining of fatigue, wants to set up an appointment with oncologist SCC notes she is in rapid AFib and sends her to ER Cardiologist diagnoses her with anthracycline-induced cardiomyopathy requiring medical management Chemotherapy Related Cardiotoxocity Anthracyclines Daunorubicin, doxorubicin, idarubicin, epirubicin, and mitoxantrone Toxicity effects Acute (during administration) Arrhythmias, pericarditis-myocarditis Early (Several days to mos following) CHF with peak at 3 mos after last dose Late (years to decades following) CHF may develop up to 10-12 yrs after last anthracycline dose Cardiac Toxicity – Anthracyclines Risk factors for the development of anthracycline cardiac toxicity Cumulative dose – strongest risk factor Age Prior irradiation Concomitant administration of other agents Previous history of cardiac disease Conclusions Key advances in the management of breast cancer have been made in the last few years Adjuvant treatment is individualized to possibly include chemotherapy, hormone therapy and trastuzumab New treatments are intensive and may result in long-term health concerns Evidence-based, informative discussion to review risks and benefits for each patient is of critical importance Thank you for your attention