Onco type DX Breast Cancer PowerPoint Presentation

Slide 1 -

Oncotype DX®Breast Cancer Assay

Slide 2 -

Agenda Introduction Development of Oncotype DX® Clinical Studies Validation studies Hormonal therapy benefit study (NSABP B-14) Chemotherapy benefit study (NSABP B-20) Node + study (SWOG 8814) Decision Impact Studies TAILORx Genomic Health Clinical Laboratory Experience Clinical Summary

Slide 3 -

Breast Cancer Treatment Planning: History Treatment planning for N–, ER+ disease is based on: Traditional prognostic factors with limited predictive power (tumor size, patient age) or poor reproducibility (tumor grade) IHC markers (eg, Ki-67) lacking standardization and validation Limited insight into relative benefits of chemotherapy for different individuals Bundred. Cancer Treat Rev. 2001;27:137-142.

Slide 4 -

Breast Cancer Treatment Planning: Not Optimized Chemotherapy treatment for N–, ER+ disease Many women are offered chemotherapy, knowing that few benefit Prior to 2007, guidelines assumed all patients benefit equally Some patients are under-treated, many others are over-treated

Slide 5 -

Age: 61 ER: 95% PR: 95% Tumor Type: IDC Tumor Size: 0.6 cm* Tumor Grade: 2 HER-2 neu Neg (FISH) *Additional 6 mm on re-excision What Would Your Treatment Strategy Be For This Patient? www.adjuvantonline.com. Standard version 8.0. Accessed 8/07

Slide 6 -

Recurrence Score: 36Average Rate of Distant Recurrence at 10 Yrs: 25%

Slide 7 -

Oncotype DX®: Unmet Clinical Need for Better Markers Biopsy or Resection Optimize chemotherapy + local therapy + hormonal therapy Optimize local therapy and hormonal therapy Robust markers High risk/Large chemo benefit Low risk/Little chemo benefit

Slide 8 -

Development and Validation of a 21-Gene Assay for N–, ER+, Tam+ Patients Develop real-time RT-PCR method for paraffin block Select candidate genes (250 genes) Model building studies (N = 447, including 233 from NSABP B-20) Commit to a single 21-gene assay Validation studies in NSABP B-14 and Kaiser Permanente YEAR 2001 2002 2002 2003 2003 Paik et al. N Engl J Med. 2004;351:2817-2826.

Slide 9 -

Oncotype DX® Technology: Final Gene Set Selection 21 genes and Recurrence Score (RS) algorithm Paik et al. SABCS 2003. Abstract #16. Cobleigh et al. Clin Cancer Res. 2005;11(24 Pt 1):8623-8631. Esteban et al. Proc ASCO 2003. Abstract #3416. Objective Gene expression and relapse-free interval correlations across three independent studies – testing 250 genes in 447 patients

Slide 10 -

Oncotype DX® 21-Gene Recurrence Score (RS) Assay PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 ESTROGEN ER PR Bcl2 SCUBE2 INVASION Stromelysin 3 Cathepsin L2 HER2 GRB7 HER2 BAG1 GSTM1 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC CD68 16 Cancer and 5 Reference Genes From 3 Studies Paik et al. N Engl J Med. 2004;351:2817-2826.

Slide 11 -

Oncotype DX® Clinical Validation: RS as Continuous Predictor 95% CI My RS is 30. What is the chance of recurrence within 10 years?

Slide 12 -

Oncotype DX® Clinical Validation: The NSABP B-14 Study* *Paik et al. N Engl J Med. 2004;351:2817-2826.

Slide 13 -

Objective: Prospectively validate RS as predictor of distant recurrence in N–, ER+ patients Design Multicenter study with prespecified 21-gene assay, algorithm, endpoints, analysis plan Oncotype DX® Clinical Validation: Genomic Health – NSABP B-14 Paik et al. N Engl J Med. 2004;351:2817-2826.

Slide 14 -

Oncotype DX® Clinical Validation:B-14 Results – Distant Recurrence Distant Recurrence Over Time – All 668 Patients Proportion Without Distant Recurrence at 10 years = 85% 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% 0 2 4 6 8 10 12 14 16 Years Paik et al. N Engl J Med. 2004;351:2817-2826. Proportion without Distant Recurrence

Slide 15 -

Oncotype DX® Clinical Validation: B-14 Results – Distant Recurrence Distant Recurrence for the three distinct cohorts identified P <0.001 RS <18 n = 338 RS 18-30 n = 149 RS 31 n = 181 Paik et al. N Engl J Med. 2004;351:2817-2826. Proportion without Distant Recurrence

Slide 16 -

Oncotype DX® Clinical Validation:B-14 Results – Distant Recurrence Risk Group % of 10-yr Rate of Patients Recurrence 95% CI Low (RS <18) 51% 6.8% 4.0%, 9.6% Intermediate (RS 18-30) 22% 14.3% 8.3%, 20.3% High (RS ≥31) 27% 30.5% 23.6%, 37.4% Test for the 10-year Distant Recurrence comparison between the low-and high-risk groups: P <0.001 Paik et al. N Engl J Med. 2004;351:2817-2826.

Slide 17 -

Oncotype DX® Clinical Validation: B-14 Results Multivariate Analysis Confirms Power of RS Multivariate Cox Models: Age, Size + RS P value 95% CI Hazard Ratio Variable <0.001 (2.23, 4.61) 3.21 Recurrence Score 0.231 (0.86, 1.85) 1.26 Size >2.0 cm 0.084 (0.48, 1.05) 0.71 Age ≥50 Age at surgery used as a binary factor: 0 = <50 yr, 1 = ≥50 yr. Clinical tumor size (CTS) used as a binary factor: 0 = ≤2 cm, 1 = >2 cm. Recurrence Score used as a continuous variable, with HR relative to an increment of 50 RS units. Paik et al. N Engl J Med. 2004;351:2817-2826.

Slide 18 -

Oncotype DX® Clinical Validation: The Kaiser Permanente Study Habel et al. Breast Cancer Res. 2006;May 31;8(3):R25.

Slide 19 -

The Kaiser Permanente Study: Methods Study Design Study Population Data Sources Matched Case-Control Kaiser Permanente patients <75 yr in 14 Northern California hospitals diagnosed with node-negative BC 1985-94, no chemotherapy (N = 4964) Cases: Deaths from BC (n = 220) Controls: Randomly selected, matched on age, race, diagnosis year, KP facility, tamoxifen (n = 570) Cancer registry, medical records, archived diagnostic slides, and tumor blocks Habel et al. Breast Cancer Res. May 2006.

Slide 20 -

The Kaiser Permanente Study: Risk of BC Death at 10 Years: ER+, Tam+ Patients 10-yr 10-yr Absolute Absolute Risk Classifier Risk1 Risk Kaiser NSABP B14 Recurrence Score Low (<18) 2.8% 3.1% Intermediate (18-30) 10.7% 12.2% High (>31) 15.5% 27.0% 1Based on methods by Langholz and Borgan, Biometrics 1997;53:767-774. Habel et al. Breast Cancer Res. May 2006.

Slide 21 -

The Kaiser Permanente Study: Conclusions “The RS has now been shown to be strongly associated with risk of breast cancer-specific mortality among LN–, ER+, tam-treated patients participating in a clinical trial and among similar patients from the community setting.” “Combining Recurrence Score, tumor grade, and tumor size provides better risk classification than any one of these factors alone.” Habel et al. Breast Cancer Res. May 2006.

Slide 22 -

Oncotype DX® Prediction of Tam Benefit: NSABP B-14 Placebo and Tamoxifen Arms* *Paik et al. ASCO 2004. Abstract #510.

Slide 23 -

Design Objective: Determine whether the 21-gene RS assay provides predictive information for patients who were treated with tamoxifen (likelihood of recurrence) Tamoxifen Benefit and Oncotype DX™ NSABP B-14 Tam Benefit Study in N–, ER+ Patients Randomized Placebo-Eligible Tam-Eligible Paik et al. ASCO 2004. Abstract #510.

Slide 24 -

All Patients (N = 645) 0 2 4 6 8 14 16 Years 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Placebo Tamoxifen 12 10 B-14 Overall Benefit of Tamoxifen Paik et al. ASCO 2004. Abstract #510. Proportion without Distant Recurrence

Slide 25 -

B-14 Benefit of TamoxifenBy Recurrence Score Risk Category Low Risk (RS<18) N 171 142 Int Risk (RS 18-30) N 85 69 High Risk (RS≥31)1 N 99 79 Interaction P = 0.06 Paik et al. ASCO 2004. Abstract #510. 1 The results should not be used to conclude that tamoxifen should not be given to the high-risk group Proportion without Distant Recurrence Proportion without Distant Recurrence Proportion without Distant Recurrence

Slide 26 -

Analysis of Placebo and Tam-Treated Patients in NSABP B-14 Results Subset of Oncotype DX® genes is prognostic 5 proliferation genes Cyclin B1, Ki-67, MYBL2, Survivin, STK15 PR Quantitative measurement of the ER gene expression by the Oncotype DX® assay predicts the benefit of tamoxifen Quantitative ER and Recurrence Score are only modestly correlated Paik et al. ASCO 2004. Abstract #510.

Slide 27 -

Analysis of Placebo and Tam-Treated Patients in NSABP B-14 Conclusions RS combines prognostic and predictive factors into one assay report RS performance is derived from measurement of expression of each of the 21 genes on a continuous scale with high precision and reproducibility Paik et al. ASCO 2004. Abstract #510.

Slide 28 -

Oncotype DX® Prediction of Chemo Benefit: NSABP B-20 Study* *Paik et al. J Clin Oncol. 2006;24:3726-3734

Slide 29 -

Chemotherapy Benefit and Oncotype DX® Design Objective: Determine the magnitude of the chemo benefit as a function of the 21-gene RS assay Randomized Tam + MF Tam + CMF Tam NSABP B-20 Chemo Benefit Study in N–, ER+ Pts Paik et al. J Clin Oncol. 2006;24:3726-3734.

Slide 30 -

B-20 Results 0 2 4 6 8 10 12 Years 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 All Patients Tam + Chemo Tam P = 0.02 N Events 424 33 227 31 Proportion without Distant Recurrence Tam vs Tam + Chemo – All 651 Patients Paik et al. J Clin Oncol. 2006. 4.4% absolute benefit from tam + chemo at 10 years

Slide 31 -

B-20 Results: Tam vs Tam + Chemo 28% absolute benefit from tam + chemo Paik et al. J Clin Oncol. 2006. p = 0.61 p = 0.39 Low RS p < 0.001 Int RS High RS Proportion without Distant Recurrence

Slide 32 -

Low RS <18 Int RS 18-30 High RS ≥31 0 10% 20% 30% 40% B-20 Results: Absolute % Increase in Proportion Distant Recurrence-Free at 10 Years n = 353 n = 134 n = 164 % Increase in Proportion Distant Recurrence-Free at 10 Yrs (mean ± SE) Paik et al. J Clin Oncol. 2006.

Slide 33 -

Summary of Treatment Benefit Related to RS and Breast Cancer Death in NSABP B-14 and B-20

Slide 34 -

Largest Tamoxifen Benefit Observed in Low- and Intermediate-Risk Recurrence Score Groups

Slide 35 -

Largest Chemotherapy Benefit Observed in High-Risk Recurrence Score Group

Slide 36 -

Recurrence Score in N-, ER+ patients Standardized Quantitative Oncotype DX Assay 1) Paik et al NEJM 2004, 2) Habel et al Breast Cancer Research 2006 3) Paik et al JCO 2006, 4) Gianni et al JCO 2005 Lower RS’s Lower likelihood of recurrence Greater magnitude of TAM benefit Minimal, if any, chemotherapy benefit Higher RS’s Greater likelihood of recurrence Lower magnitude of TAM benefit Clear chemotherapy benefit

Slide 37 -

Correlation of RS with traditional prognostic factors including age, tumor size, and tumor grade Results from NSABP B20 Results

Slide 38 -

NSABP B20 Results: Many Younger Patients Have Low Recurrence Scores Paik et al. J Clin Oncol. 2006.

Slide 39 -

NSABP B20 Results: Many Small Tumors Have Intermediate to High RS Paik et al. J Clin Oncol. 2006.

Slide 40 -

NSABP B20 Results: Significant Proportion of High-Grade Tumors Have Low RS Grading by pathologist at local clinical trial site Grading by pathologist at central lab Paik et al. J Clin Oncol. 2006.

Slide 41 -

Prospective multi-center study of the impact of the 21-gene Recurrence Score (RS) assay on medical oncologist (MO) and patient (pt) adjuvant breast cancer (BC) treatment selection Shelly S. Lo1, John Norton1, Patricia B. Mumby1, Jeffrey Smerage2, Joseph Kash3, Helen K. Chew4, Daniel Hayes2, Andrew Epstein5, Kathy S. Albain1 1Loyola University, Maywood IL, 2University of Michigan, Ann Arbor MI, 3Edward Hospital, Naperville IL, 4UC Davis, Sacramento CA, 5Mount Sinai Medical Center, New York NY ASCO 2007, Abstract #577

Slide 42 -

Background There is little data regarding the impact of the RS on medical oncologist (MO) and patient (pt) decision making. A multi-center study was designed to prospectively examine whether the RS can affect MO and pt adjuvant treatment selection. ASCO 2007, Abstract #577

Slide 43 -

Methods 17 MOs at 1 community and 3 academic practices participated. Each participating MO consecutively offered enrollment to eligible women with N-, ER+ BC. Each participating MO and consenting patient completed pre- and post-RS assay questionnaires. MOs stated their adjuvant treatment recommendation and confidence in it pre and post RS assay. Pts indicated treatment choice pre and post RS assay. In addition, patients completed measures for quality of life, anxiety, and decisional conflict pre and post assay. RS assay results were returned to MO and shared with pt for routine clinical care. ASCO 2007, Abstract #577

Slide 44 -

Change in MO Treatment Recommendation by RS ASCO 2007, Abstract #577

Slide 45 -

MO Treatment Recommendations Changed 31.5% of the Time Treatment recommendation changed for 28 (31.5%) cases after results of RS Assay known. The most common change was from a recommendation of CHT to HT in 22.5% of cases ASCO 2007, Abstract #577

Slide 46 -

Other Findings Confidence was increased in 76% of the MO recommendations. RS Assay impacted patient adjuvant treatment decisions 95% of patients were glad they had the test performed 12 (13.5%) patient treatment decisions did not match their MO treatment recommendation. This may be due to: Patients choosing different treatment option than that recommended Inadequate communication between MOs and pts Patient misunderstanding of survey question ASCO 2007, Abstract #577

Slide 47 -

Conclusions RS Assay changed physician adjuvant treatment recommendation 31.5% of the time Results from the RS assay were associated with less adjuvant chemotherapy administration The most common treatment recommendation change for MO was changing recommendation from CHT to HT in 22.5% of cases Of the 6 pts whose physicians thought their RS represented equipoise, 1 pt chose chemotherapy, 3 chose HT, 1 chose observation, and 1 understood the concept of equipoise. Results of the RS Assay increased physician confidence in treatment recommendation ASCO 2007, Abstract #577

Slide 48 -

TAILORx(PACCT-1 Trial)Sponsored by NCI Administered by ECOG Participating cooperative groups include ECOG, SWOG, NCCTG, CALGB, NCIC, ACOSOG, and NSABP

Slide 49 -

Trial Assigning IndividuaLized Options for Treatment (Rx) (TAILORx) Premise Integration of a molecular profiling test (Oncotype DX®) into the clinical decision-making process Potential Implications Reduce chemotherapy overtreatment in those likely to be appropriately treated with hormonal therapy alone Reduce inadequate treatment by identifying individuals who derive great benefit from chemotherapy Evaluate benefit of chemotherapy where uncertainty still exists about its utility

Slide 50 -

TAILORx: Scientific Rationale for NCI and Breast Intergroup Selecting Oncotype DX® Assay for First PACCT trial Validated prognostic test for tamoxifen-treated patients Predictive of distant recurrence May be used as categorical or continuous variable Paik et al. NEJM, 2004 Also validated in population-based Kaiser study Habel et al. Breast Cancer Research, May 2006 Lower RS predictive of tamoxifen benefit Paik et al. ASCO 2005, abstr 510 Higher RS predictive of chemotherapy benefit Paik et al. JCO, August 2006 Correlates more strongly with outcome than Adjuvant! Bryant et al. St. Gallen, 2005 Predictive of local recurrence in tam-treated patients Mamounas, SABCS 2005, abstr 29 Sparano, Clinical Breast Cancer, 2006Sparano, ASCO Educational Book 2007

Slide 51 -

TAILORx PrimaryStudy Group

Slide 52 -

Schema: TAILORx Node-Neg, ER-Pos Breast Cancer RS <10 Hormone Therapy Registry RS 11-25 Randomize Hormone Rx vs Chemotherapy + Hormone Rx RS >25 Chemotherapy + Hormone Rx Oncotype DX® Assay Register Specimen banking Primary study group

Slide 53 -

Study Design: Primary Objectives To determine whether adjuvant hormonal therapy (ie, experimental arm) is not inferior to adjuvant chemohormonal (standard arm) for patients in the “primary study group” (Oncotype DX® RS 11-25) To create a tissue and specimen bank for patients enrolled in this trial to learn more about breast cancer

Slide 54 -

TAILORx: Key Points Participating groups ECOG, SWOG, NCCTG, CALGB, NCIC, ACOSOG, and NSABP Adjuvant therapy Choice of hormonal and/or chemotherapy regimen is at discretion of treating physician Other trials May enroll on other CTSU or other cooperative group studies if treatment assignment on other trial is consistent Payment for the Oncotype DX Assay Genomic Health will assist in securing reimbursement for patients who have health insurance By agreement with NCI to avoid bias in enrollment in the trial, patients who are uninsured or who have copayments or deductibles will not be responsible for the cost of the Oncotype DX®

Slide 55 -

Oncotype DX® Extensively Studied:Study Experience in >3300 Patients *Published studies

Slide 56 -

Recurrence Score in N-, ER+ patients Conclusions 1) Paik et al NEJM 2004, 2) Habel et al Breast Cancer Research 2006 3) Paik et al JCO 2006, 4) Gianni et al JCO 2005 Lower RS’s Lower likelihood of recurrence Greater magnitude of TAM benefit Minimal, if any, chemotherapy benefit Higher RS’s Greater likelihood of recurrence Lower magnitude of TAM benefit Clear chemotherapy benefit

Slide 57 -

Genomic Health Today Physician Usage and Adoption 65,000+ Oncotype DX® test results delivered* >7,500 physicians have ordered the test* Reimbursement for Oncotype DX Coverage for Medicare patients Coverage >90% of privately insured lives *As of August 5, 2008

Slide 58 -

Conclusions The Oncotype DX® Recurrence Score assay predicts the likelihood of adjuvant chemotherapy benefit It also is a prognostic assay for the risk of distant recurrence at ten years assuming five years of adjuvant tamoxifen treatment Oncotype DX® Recurrence Score assay shows consistent results across multiple independent studies