Operable Breast Cancer PowerPoint Presentation

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بسم الله الرحمن الرحيم

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PRIMARY BREAST CANCER ESMO CLINICAL RECOMMENDATIONS FOR DIAGNOSIS,TREATMENT & FOLLOW UP

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incidence In 2006 the estimated age-adjusted annual incidence of breast cancer in the European Union (25 countries) was 110.3/100 000 and the mortality 25.0/100 000. The mortality rate has decreased especially in younger age groups because of earlier detection and improved treatment. However, breast cancer is still the leading cause of cancer-related deaths in European women.

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Diagnosis

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The diagnosis is based on the triad of clinical, radiological and pathological examinations. Clinical examination includes bi-manual palpation of the breasts and local regional lymph nodes.

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Radiological examinations include bilateral mammography of the breasts and ultrasound of the breasts and local regional lymph nodes. MRI of the breasts is not a routine procedure, but may be considered in cases involving diagnostic challenges arising, for example, because of dense breast tissue or positive axillary lymph node status with occult primary tumor in the breast

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Pathological diagnosis should be based on core needle biopsy obtained by manual, or preferably by ultrasound or stereotactic guidance. A core needle biopsy, or if that is not possible, at least a fine needle aspiration indicating carcinoma should be obtained before any surgical operations.

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Final pathological diagnosis should be made according to the World Health Organization classification and the tumor–node–metastasis (TNM) (International Union Against Cancer and American Joint Committee on Cancer, sixth edition 2002) staging system analyzing all tissue removed.

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Staging and risk assessment

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In case of preoperative systemic treatment, a full clinical staging should be carried out at the outset. In case of primary surgery, pathologic TNM staging based on hematoxylin–eosin staining, description of histologic type, standardized grading and evaluation of resection margins should be reported.

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Determination of estrogen receptor (ER) and progesterone receptor (PgR) status is mandatory, preferably by immunohistochemistry [III, B]. Reports of immunohistochemical results for ER and PgR should include the percentage of ER-and PgR-positive cells.

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Hormone receptors are no longer included among the prognostic factors but are the most relevant predictive factor for the choice of treatment.

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Immunohistochemical determination of HER2 receptor expression should be carried out at the same time for treatment planning.

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When semiquantitative results of immunohistochemistry are ambiguous (++), in situ hybridization (FISH or CISH) to determine HER2 gene amplification should be carried out. It is possible to directly carry out a gene amplification study (FISH or CISH) and not carry out the HER2 immunohistochemistry at all.

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staging and risk assessment

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Routine staging examinations include physical examination, full blood counts, routine chemistry including liver enzymes, alkaline phosphatase, calcium and assessment of menopausal status. This staging is needed for all patients and it can be acceptable for patients with small clinical tumors (T1) and without palpable nodes.

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For all other cases and in particular for candidates to preoperative treatment, the conduct of additional investigations should be considered prior rather that after surgery.

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In patients with higher risk (pathological N2 with four or more positive axillary nodes or T4 tumors or with laboratory signs or clinical signs or symptoms suspicious for the presence of metastases) : Chest X-ray, Abdominal ultrasound Isotopic bone scan are appropriate [III, B].

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Postoperatively the pathologist's report should include: 1-number of tumors in the tissue removed, 2-the maximum diameter of the largest tumor (T), 3- histologic type and 4- grade of the tumor, 5- evaluation of the resection margins including the minimum margin in millimetres and its anatomical direction;

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6-total number of removed lymph nodes, 7- number of positive lymph nodes, 8- extent of metastases in the lymph nodes (ITC, micrometastatic, metastatic), i.e. N-status

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The report should also include: 9- immunohistochemical evaluation of ER and PgR using a standardized assessment methodology, 10- immunohistochemical evaluation of HER2 receptor expression. HER2 gene amplification status may be determined directly from all tumors using in situ hybridization (FISH or CISH) or only from tumors with an ambiguous (2+) immunohistochemistry. Vascular and lymphovascular invasion should also be reported.

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Treatment decisions are based: Primarily on endocrine responsiveness of the tumor. Secondarily on risk of recurrence.

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Definition of risk categories for patients with operated breast cancer

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Risk stratification: has been revised and currently includes three risk groups: Low Intermediate High risk Vascular invasion has been described as an important prognostic factor, particularly in node-negative disease.

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Treatment Plan

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Treatment planning should be done by a multidisciplinary team including : A surgical, A medical A radiation oncologist. A pathologist in order to integrate local and systemic therapies as well as their sequence [III, B].

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The possibility of hereditary cancer should be explored and counseling of relatives should be considered [IV, D] .

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local therapy :non-invasive carcinoma Intraductal carcinoma (ductal carcinoma in situ, DCIS) may be treated with breast-conserving surgery (BCS) providing healthy tissue margins can be reached. There is no general consensus on what is regarded as a safe (negative) margin. However, margins >10 mm are adequate and margins <1 mm are inadequate.

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Adjuvant breast irradiation after BCS decreases the risk of local recurrence but has no effect on survival However, in some patients with low-risk DCIS (tumor size <10 mm, low/intermediate nuclear grade, adequate surgical margins), the risk of local recurrence following excision only is so low that omitting radiation may be an option.

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Especially in ER-positive DCIS tamoxifen may be considered following BCS (with or without adjuvant radiation)

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Total mastectomy with clear margins in DCIS is curative, and radiation therapy is not recommended. In this group of patients tamoxifen may also be considered as a risk reduction therapy to decrease the risk of contralateral breast cancer

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When ductal carcinoma in situ (DCIS) is treated by breast-conserving surgery, all subgroups of patients benefit from adjuvant radiation (I, A). Adjuvant tamoxifen should be considered in women with ER-positive DCIS (II, B), while its use in patients with ER-negative disease may be detrimental.

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Lobular carcinoma in situ (LCIS) is a risk factor for future development of invasive cancer. It should be completely resected.

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Local Therapy: 2- Invasive Carcinoma

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Operable breast cancer :is initially treated by surgery, using breast-conserving surgery or mastectomy, both in combination with axillary dissection or a sentinel node biopsy.

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Contraindications to BCS include : *Multicentric tumors, *Large tumors (>3–4 cm) in small breasts especially when no neo-adjuvant therapy is planned, * Positive margins after resection, *Inflammatory breast cancer and *Patient's own wish.

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Sentinel node biopsy

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Clinical Recommendations Sentinel node biopsy should not be carried out: In case of palpable axillary nodes, T3 or T4 tumors, Multicentric tumors Prior axillary surgery Large biopsies After breast reconstruction or implantation of a prosthesis During pregnancy or lactation After neo-adjuvant systemic treatment outside of clinical trials.

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-Breast radiotherapy is strongly recommended after breast-conserving surgery [I, A]. -Postmastectomy radiotherapy has been recommended for patients: With four or more positive axillary nodes . Is suggested for all T3 tumors .

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-Post-mastectomy radiotherapy may also be considered in cases of at least T1 tumor with 1–3 positive axillary lymph nodes, particularly if young, -and in cases of T2 or greater medially located tumors which show signs of biological aggressiveness (receptor-negative, grade 3, HER2-positive, high proliferation activity, e.g. Ki-67).

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Postoperative Radiotherapy reduces the risk of local recurrence by two-thirds and has a beneficial effect on survivaL

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In patients >70 years of age who have receptor-positive invasive breast cancer with maximum stage pT1N0 and clear postoperative margins it may be possible to use adjuvant tamoxifen instead of radiation therapy [II, B].

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PRIMARY SYSTEMIC THERAPY: Before primary systemic therapy, a biopsy for histology and analysis of predictive factors should be carried out. In addition, for these higher risk patients, a full clinical staging to rule out metastatic disease is necessary.

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Primary systemic therapy: is indicated for locally advanced breast cancer (stage IIIA, IIIB, IIIC) [III, B].

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It can employ chemotherapy or endocrine therapy on the basis of predictive factors similar to adjuvant treatment.

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Trastuzumab should be considered in the treatment protocol in HER2-positive tumors. It should be followed by both surgery and radiotherapy and postoperative systemic adjuvant treatment

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If possible it should be followed by both surgery and radiotherapy and postoperative systemic treatment .

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Primary systemic therapy is an alternative for large operable breast cancer, to allow breast-conserving surgery [I, A].

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Adjuvant Systemic Therapy

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Treatment is initiated providing that there is a relevant reduction of (calculated) risk of recurrence which can be reached with an acceptable level of treatment-related adverse effects.

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Hormone receptors and HER2 status are the most relevant predictive factors for the choice of treatment modality.

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Tumors with an incomplete (some expression) or high degree of expression of ER and/or PgR are considered endocrine responsive..

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Patients with no detectable expression of ER and PgR in their tumors are considered endocrine non-responsive

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Features indicative of uncertainty of endocrine responsiveness include : -low levels of steroid hormone receptor immunoreactivity, - lack of PgR, G3, high proliferation markers (Ki-67), HER2 overexpression and possibly uPA and PAI1

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Patients with tumors considered endocrine responsive may receive endocrine treatment alone , or a combination of endocrine therapy and chemotherapy

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Choice of treatment modalities according to St Gallen Consensus 2007 (Goldhirsch A et al., 2007)

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Endocrine therapy Patients with tumors considered uncertainly or highly endocrine responsive should be treated with endocrine therapy

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Patients with tumors of uncertain endocrine responsiveness are usually treated with a combination of endocrine therapy and chemotherapy

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Patients with endocrine non-responsive tumors derive greater benefit from chemotherapy and should not receive endocrine therapy.

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In addition to endocrine and chemotherapy, patients with HER2 overexpression or amplification should be considered for adjuvant treatment with trastuzumab .

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CHOICE OF TREATMENT MODALITIES

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For each individual, the choice of adjuvant therapy must take into account the potential benefits, possible side-effects and patient preference. Several decision-making tools have been developed to help doctor–patient communication for adjuvant treatment decisions.

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TREATMENT RECOMMENDATIONS FOR HORMONE-RESPONSIVE TUMOURS

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Endocrine therapy

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Treatment decisions are made on the basis of two main factors: (i) estimated endocrine responsiveness of tumor tissue (ii) risk of relapse

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In premenopausal patients tamoxifen alone (20 mg daily for 5 years) or the combination of ovarian function ablation with tamoxifen are standard therapies. Ovarian function ablation may be achieved by bilateral oophorectomy which leads to irreversible ablation of ovarian function. Gonadotropin-releasing hormone analogues (GnRHAs) generally lead to reversible ovarian suppression sufficient for therapeutic activity. GnRHAs should be given for at least 2 years, although optimal duration for this treatment has not been established

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Combining GnRHAs and aromatase inhibitors (AIs) in premenopausal patients is not indicated, as is the use of AIs alone. In premenopausal patients GnRHAs may be started concurrently with chemotherapy, leading to rapid amenorrhea

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Bilateral ovarectomy or irradiation of the ovaries leads to irreversible ablation of ovarian function. Gonadotropin-releasing hormone analogue (GnRHA) (e.g. goserelin 3.6 mg subcutaneously monthly) generally lead to reversible ovarian suppression. They should be given for at least 2 years, but optimal duration for this treatment has not yet been established.

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In postmenopausal patients :5 years of tamoxifen alone is still a viable option for certain patient categories. For the use of AIs a switch from tamoxifen to an AI after 2–3 years of tamoxifen or initial use of an AI for 5 years are most commonly accepted strategies .

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Initial use of an AI is the preferred option in patients at higher risk of relapse (large tumor size, node positivity, HER2-positive disease).

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For patients who have completed 5 years of tamoxifen the addition of an AI for a further period of 2–3 years may be recommended in cases with node-positive disease .

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The total duration of optimal adjuvant endocrine treatment is between 5 and 10 years, 5 years for tamoxifen alone being standard. Sequential rather than concurrent administration of cytotoxic and endocrine therapies should be used . It is unclear whether AIs should be started concurrently with chemotherapy (CT + ET) or sequentially after chemotherapy (CT/ET

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The long-term skeletal adverse effects associated with AIs are an issue of concern. Women treated with AIs should receive vitamin D and calcium supplements.

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There is no clear evidence for the concomitant use of bisphosphonates with AI in the adjuvant setting. However, several randomized controlled trials are ongoing with pending final results. Before commencing AI treatment, women should have BMD assessed by DEXA with a low threshold, and receive bisphosphonate if T-score is less than –2,5 SD, which equals to osteoporosis

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Patients with tumors of likely or uncertain endocrine responsiveness should be treated with endocrine therapy.

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It is unclear whether aromatase inhibitors should be started concurrently with chemotherapy (CT + ET) or sequentially after chemotherapy (CT/ET).

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In premenopausal patients gonadotropin-releasing hormone analogues can be started concurrently with chemotherapy, leading to rapid amenorrhea.

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Adjuvant aromatase inhibitors increase disease-free survival when compared with tamoxifen. This has been shown for anastrozole (1 mg daily for 5 years) and for letrozole (2.5 mg daily for 5 years) given upfront [I, A].

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Chemotherapy

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Adjuvant chemotherapy for intermediate or high-risk patients should use a combination regimen. *In 2006, the consensus is that such a combination should include an anthracycline and for a duration of at least four cycles of treatment.

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Adjuvant chemotherapy is generally recommended for intermediate- or high-risk patients. A multiplicity of chemotherapy regimens acceptable for adjuvant treatment exist . The use of anthracyclines for all patients and especially for patients with HER2-positive disease may be recommended.

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However, for some patients (elderly, cardiac contraindication, etc.) non-anthracycline-containing regimes (CMF) may still be appropriate [I, A].

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The optimal duration of the treatment is not known. However, at least four cycles (12–16 weeks) should be administered, generally aiming for six to eight cycles (18–24 weeks).

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Taxanes should be used in high-risk patients, especially with ER negative.

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The use of dose-dense schedules with prophylactic G-CSF is controversial, whilst high-dose therapy requiring peripheral blood stem cell support cannot be recommended at all.

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A shorter duration of chemotherapy (12–16 weeks) may be suitable for elderly patients, for whom the role of chemotherapy remains uncertain

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ADJUVANT CHEMOTHERAPY

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Premenopausal women may benefit from 3- to 6-monthly bisphosphonate infusions during the first year to prevent bone loss associated with temporary or permanent hormonal changes during adjuvant chemotherapy [II, B].

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Trastuzumab

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Patients with HER2 overexpression (3+) or HER2 gene amplification can benefit from adjuvant treatment with trastuzumab.

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There is no evidence for the use of trastuzumab in patients with node-negative, small (<1 cm) tumors, as in this group of patients side-effects may override possible benefits .

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On the basis of pharmacokinetic analyses, a three-weekly schedule (6 mg/kg) is considered equivalent to a weekly schedule (2 mg/ kg).

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The standard duration of adjuvant trastuzumab has not yet been established; for the time being 1 year is recommended. Trastuzumab may be started in parallel with a taxane, but it should not be given concurrently with an anthracycline .

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When given after an anthracycline-containing regimen, trastuzumab has cardiotoxic effects and heart function should be routinely monitored.

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Follow-up

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History taking, eliciting of symptoms and physical examination every 3–6 months for 3 years, every 6–12 months for 3 years, then annually [A].

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With attention paid to long-term side-effects, e.g. osteoporosis. Ipsilateral (after breast-conserving surgery) and contralateral mammography every 1–2 years.

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Not routinely recommended for asymptomatic patients: blood counts, chemistry, chest X-ray, bone scan, liver ultrasound, CT scans of chest and abdomen and any tumor markers such as CA 15-3 or carcinoembryonic antigen.

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Thank You