The Oncotype DX Assay in the Contemporary Management of Invasive Early-stage Breast Cancer

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1 The Result Uses Key Genes Linked to Critical Molecular Pathways The Oncotype DX Assay in the Contemporary Management of Invasive Early-stage Breast Cancer 16 BREAST CANCER RELATED GENES Estrogen Proliferation HER2 Invasion Others ER PR Bcl2 SCUBE2 Ki-67 STK15 Survivin Cyclin B1 MYBL2 GRB7 HER2 Stromelysin 3 Cathepsin L2 CD68 GSTM1 BAG1 5 REFERENCE GENES Beta-actin GAPDH RPLPO GUS TFRC 4 Cancer The Biology Century Understanding and treating the underlying tumor biology Cancer genetic studies demonstrate the transition of basic research to clinical application (i.e. BRCA testing) Targeted cancer therapies developed based on the unique tumor genetic characteristics (i.e. tamoxifen and trastuzumab) Sequencing of the human genome Gene expression profiling shown to predict clinical outcome Scientific breakthroughs making personalized medicine in cancer a reality 2 The Result Assesses Individual Tumor Biology for ER+ Breast Cancer Distant recurrence at 10 years 4 35% 3 25% 2 15% 1 5% value LOW RECURRENCE SCORE DISEASE Indolent Hormone therapy-sensitive Minimal, if any, chemotherapy benefit CONTINUOUS BIOLOGY HIGH RECURRENCE SCORE DISEASE Aggressive Less sensitive to hormone therapy Large chemotherapy benefit Paik S, et al. N Engl J Med. 2004;351:28; Paik S, et al. J Clin Oncol. 2006;24:3726; Habel LA, et al. Breast Cancer Res. 2006;8:R25-R39. 5 Key Questions When Evaluating Genomic Classifiers Accurate and reliable? Strongly prognostic? Fit for purpose Predictive of chemotherapy benefit? Clinical Validation of the Oncotype DX Breast Cancer Assay in Node-Negative Disease Incorporated in treatment guidelines? What is the level of evidence? Hayes DF. Am Soc Clin Oncol Ed Book. 2008: Simon R. J Clin Oncol. 2005;23:

2 NSABP B- Objective: Prospectively validate the result as a predictor of distant recurrence in nodenegative, ER+ patients Randomized Registered Placebo not eligible eligible eligible Multicenter study with prespecified 21-gene assay, algorithm, endpoints, analysis plan 7 NSABP B-, Subgroup Analysis by Tumor Size All patients (N=668) Size 1 cm Size 1-2 cm Size 2-4 cm RS, Size >4 cm NSABP B-, Distant Recurrence NSABP B-, Subgroup Analysis by Age Distant recurrence over time Year rate of recurrence = 6.8%* 95% CI: 4., 9.6% 8 10-Year rate of recurrence =.3% 7 95% CI: 8.3%, 20.3% 6 10-Year rate of recurrence = 30.5%* 95% CI: 23.6%, 37.4% 5 4, n = RS < 18, n = RS 18-30, n = 9 1 RS 31, n = RS, result Years Proportion without distant recurrence *10-Year distant recurrence comparison between low- and high-risk groups: 8 RS, All patients (N=668) Age <40 Age Age Age > NSABP B-, Subgroup Analysis by Tumor Grade All patients N=668 Well Moderate Poor RS, 9 NSABP B-20 Objective: Prospectively determine the relationship between result and chemotherapy benefit in node-negative, ER+ patients Randomized Tam Multicenter study with prespecified 21-gene assay, algorithm, endpoints, analysis plan Tam + MF Tam + CMF 12 2

3 High Result Correlates with Greater Benefit from Chemotherapy (NSABP B-20) NSABP B-20: Many Younger Patients Have Low Disease Proportion without distant recurrence PATIENTS WITH HIGH RS 28% absolute benefit from 0.7 tamoxifen + chemotherapy N Events All patients P = % absolute benefit from tamoxifen + chemotherapy RS < 18 P = RS P = RS Years RS, result 13 P= % 24% 28% 19% % 21% 22% 21% 44% 55% 5 6 N = 63 N = 226 N = 166 N = High Disease Is Chemo-sensitive Whereas Low Recurrence Score Disease is Not (NSABP B-20) NSABP B-20: Significant Proportion of High-Grade Tumors Have Low Disease Node Negative, ER-Positive Breast Cancer Chemotherapy Benefit Average Rate of Distant Recurrence at 10 Years vs Distant Recurrence at 10 Years Tam vs Tam + CMF/MF 5 45% Rate: Tam 95% Cl: Tam 4 Rate: Tam + CMF/MF 95% Cl: Tam + CMF/MF 35% Tam 3 25% 2 15% Tam + 1 CMF/MF 5% Breast Cancer % Decrease in Distant Recurrence at 10 Years (mean ± SE) Absolute Benefit of Chemotherapy (CMF/MF) at 10 Years by Group < (n = 353) (n = 134) (n = 164) 12% 22% 42% 16% 22% 22% 73% 56% 36% N = 77 N = 339 N = 163 P< % 12% 61% 12% 24% 19% 83% 64% 19% N = 119 N = 340 N = 190 NSABP B-20: Many Small Tumors Have Intermediate to High Disease 100 P= % 25% 3 33% Does the Impact Treatment Decisions? % 23% 21% 64% 56% 46% 46% 0 N = 110 N = 318 N = 196 N = 24 1 cm cm cm >4 cm Clinical tumor size 15 3

4 Meta-Analysis: Overall Impact of on Treatment Decisions The Oncotype DX Assay The Only Multi-gene Assay Incorporated into 4 Major Guidelines to Predict Adjuvant Chemotherapy Benefit in ER+, HER2- Early Stage Breast Cancer Treatment plan after RS Treatment plan prior to Oncotype DX Treatment plan after RS NCCN Guidelines > 0.5 cm, node negative, N1mi Quantifies risk of recurrence as a continuous variable and predicts responsiveness to both tamoxifen and chemotherapy 1 ASCO Guidelines Node negative Predicts the risk of recurrence and may be used to identify patients likely to benefit from tamoxifen or chemotherapy 2 88% 12% 52% 48% St Gallen Consensus Node negative, node positive Provides not only prognostic but also predictive information regarding the utility of cytotoxic therapy in addition to endocrine therapy 3 CT + HT HT 4% change 33% change RS, result Hornberger J, et al. SABCS Poster P Overall, the RS led to a 37% change in treatment decisions 33% from CT + HT HT 4% from HT CT + HT 19 NICE Node negative 1 NCCN Practice Guidelines in Oncology. V Harris L, et al. J Clin Oncol Goldhirsch A, et al. Ann Oncol NICE Diagnostics Guidance Recommended as an option for guidance of chemotherapy decisions in patients at intermediate risk * of distant recurrence 4 ASCO is a trademark of the American Society of Clinical Oncology. NCCN and NCCN Guidelines are trademarks of the National Comprehensive Cancer Network. The guidelines do not endorse products or therapies. *Intermediate risk of distant recurrence is defined as Nottingham Prognostic Index score above 3.4 or being at intermediate risk by other decision making tools or protocols 22 Most Patients Were Positively Influenced by the Result Immediately Post-RS 12 Months Later N= 89 patients I am glad I took the RS assay RS results were easy to understand I think the RS helped support treatment decision I would have made the same treatment decision without RS I feel the RS influenced my treatment decision * Patient Cases * Those not satisfied noted a negative impact on QOL, treatment side effects including aches, hot flashes, pain, mood alteration, and negative impact on self image. In addition, the result helped reduce patients anxiety and decisional conflict Lo SS, et al. SABCS Abstract [poster presentation] & 69 year-old patients, small node-negative tumors, grade 2 & 3 Is the Oncotype DX Assay Included in Treatment Guidelines? PATIENT A 68-year-old patient with 1.1-cm tumor Menopausal Status: Postmenopausal Tumor Size: 1.1 cm ER Status (IHC): Positive PR Status (IHC): Positive HER2/neu Status: Negative Histologic Grade: 2 General Health: Fair PATIENT B 69-year-old patient with 1.3-cm tumor Menopausal Status: Postmenopausal Tumor Size: 1.3 cm ER Status (IHC): Positive (2) PR Status (IHC): Positive (2) HER2/neu Status: Negative (IHC) Histologic Grade: 3 General Health: PS 0 Victor G. Vogel, MD Ella Tepper, MD 24 4

5 68 & 69 year-old patients, small node-negative tumors, grade 2 & 3 PATIENT A RESULTS Patients with a of 34 in the clinical at 10 years of 23% (95% CI: 18%-28%). PATIENT B RESULTS Patients with a of 11 in the clinical at 10 years of 7% (95% CI: 5%-1). Conclusions & 46 year-old patients, small node-negative tumors, grade 2 & 3 The Oncotype DX Report Provides Valuable Information Along a Continuum of ER+ Breast Cancer PATIENT A 45-year-old patient with 0.9-cm tumor Menopausal Status: Premenopausal Tumor Size: 0.9 cm ER Status (IHC): Positive (99%) PR Status (IHC): Positive (13%) HER2/neu Status: Negative (1.7 by FISH) Ki-67: 38% Histologic Grade: 2 (0/2 SLNs) Barbara Schwartzberg, MD PATIENT B 46-year-old patient with 0.7-cm tumor Menopausal Status: Premenopausal Tumor Size: 0.7 cm ER Status (IHC): Positive (91%) PR Status (IHC): Positive (99%) HER2/neu Status: Negative (0.7 by FISH) Ki-67: 35% Histologic Grade: 3 Barbara Schwartzberg, MD The Oncotype DX report provides valuable information on: Node-negative prognosis Node-negative predicted chemotherapy benefit Quantitative data on ER/PR/HER2 Node-positive report contains an additional page with prognosis and predicted chemo benefit information specific to node-positive patients & 46 year-old patients, small node-negative tumors, grade 2 & 3 The Oncotype DX Breast Cancer Assay PATIENT A RESULTS Patients with a of 15 in the clinical at 10 years of 1 (95% CI: 7%-12%). PATIENT B RESULTS Patients with a of 35 in the clinical at 10 years of 24% (95% CI: 18%-3). Quantitatively predicts the likelihood of breast cancer recurrence and assesses the benefit from both hormonal therapy and chemotherapy (Level I Evidence) High and low results reflect different intrinsic tumor biology You cannot predict the risk of distant recurrence or chemotherapy benefit by relying on clinical and pathological variables Changes treatment decisions based on traditional measures 37% of time, sparing patients the negative health and QOL impact of unnecessary chemotherapy and resulting in cost savings Only assay incorporated into ASCO, NCCN and St Gallen s clinical practice guidelines Longest history of commercial genomic assays with over 200,000 patients tested worldwide 27 ASCO is a trademark of the American Society of Clinical Oncology and NCCN is a trademark of the National Comprehensive Cancer Network. ASCO and NCCN do not endorse any therapy or product. 30 5