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

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

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

Evaluating Biomarkers for Clinical Use Key Principles Does the test deliver what patients, physicians, regulators, and payers need? Most importantly, tests must be Fit for Purpose with evidence relevant to that specific purpose Consistent results across multiple well-designed studies are required to provide evidence for analytic performance, clinical validity, and clinical utility (see Roadmap to Establish Clinical Utility) Test must be shown to have value beyond traditional measures Has the test been brought to a standardized implementation? And has the evidence which supports its use been obtained in that standardized implementation? Hayes DF. Am Soc Clin Oncol Ed Book. 2008:30-34. Simon R. J Clin Oncol. 2005;23:7332-7341. 3

Key Questions When Evaluating Genomic Classifiers Strongly prognostic? Accurate and reliable? Fit for purpose Predictive of chemotherapy benefit? Incorporated in treatment guidelines? What is the level of evidence? Hayes DF. Am Soc Clin Oncol Ed Book. 2008:30-34. Simon R. J Clin Oncol. 2005;23:7332-7341. 4

The Oncotype DX Gene Panel Was Developed from Clinical Trial Evidence 250 cancer-related genes were selected based on extensive literature review (candidate-gene approach) Genes were analyzed for expression and relapse-free interval correlations across 3 independent studies of 447 breast cancer patients Study site N Node status ER status Treatment NSABP B-20, Pittsburgh, PA 233 N ER+ Tamoxifen (100%) Rush University, Chicago, IL 78 10 positive nodes ER+/ Tamoxifen (54%) Chemotherapy (80%) Providence St. Joseph s Hospital, Burbank, CA 136 N+/ ER+/ Tamoxifen (41%) Chemotherapy (39%) From these studies, 21 genes were selected Paik S, et al. SABCS 2003. Abstract 16. Cobleigh MA, et al. Clin Cancer Res. 2005;11:8623-8631. Esteban J, et al. Proc Am Soc Clin Oncol. 2003;22: abstract 3416. 5

The Recurrence Score Result Uses Key Genes Linked to Critical Molecular Pathways 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 Paik S, et al. N Engl J Med. 2004;351:2817-2826. 6

Distant recurrence at 10 years The Recurrence Score Result Assesses Individual Tumor Biology for ER+ Breast Cancer 40 % 35 % 30 % 25 % 20 % 15 % 10 % 5 % 0 % CONTINUOUS BIOLOGY 0 5 10 15 20 25 30 35 40 45 50 Recurrence Score value LOW RECURRENCE SCORE DISEASE Indolent Hormone therapy-sensitive Minimal, if any, chemotherapy benefit HIGH RECURRENCE SCORE DISEASE Aggressive Less sensitive to hormone therapy Large chemotherapy benefit Paik S, et al. N Engl J Med. 2004;351:2817; Paik S, et al. J Clin Oncol. 2006;24:3726; Habel LA, et al. Breast Cancer Res. 2006;8:R25-R39. 7

HER2 Expression (relative to ref genes; log 2 ) Continuous Biology: ER and HER2 Expression as Measured by RT-PCR N = 10,618 15 14 HER2+ 13 12 11 10 Triple-negative* 9 8 7 6 ER+ HER2 2 3 4 5 6 7 8 9 10 11 12 13 14 ER Expression (relative to ref genes; log 2 ) Shak S, et al. Breast Cancer Res Treat. 2006;100(suppl 1): abstract 6118. *> 94% of these cases are PR ; rarely strongly PR+ 8

Clinical Validation of the Oncotype DX Breast Cancer Assay in Node-Negative Disease

Oncotype DX Clinical Validation: NSABP B-14 Objective: Prospectively validate the Recurrence Score result as a predictor of distant recurrence in nodenegative, ER+ patients Randomized Registered Placebo not eligible Tamoxifen eligible Tamoxifen eligible Multicenter study with prespecified 21-gene assay, algorithm, endpoints, analysis plan Paik S, et al. N Engl J Med. 2004;351:2817-2826. 10

Proportion without distant recurrence Oncotype DX Clinical Validation: NSABP B-14, Distant Recurrence 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% RS, Recurrence Score result Paik S, et al. N Engl J Med. 2004;351:2817-2826. Distant recurrence over time All Patients, n = 668 RS < 18, n = 338 RS 18-30, n = 149 RS 31, n = 181 0 2 4 6 8 10 12 14 16 Years *10-Year distant recurrence comparison between low- and high-risk groups: P < 0.001 10-Year rate of recurrence = 6.8%* 95% CI: 4.0%, 9.6% 10-Year rate of recurrence = 14.3% 95% CI: 8.3%, 20.3% 10-Year rate of recurrence = 30.5%* 95% CI: 23.6%, 37.4% P < 0.001 11

Oncotype DX Clinical Validation: NSABP B-14, Subgroup Analysis by Tumor Grade All patients N=668 Well Moderate 224 166 41 17 296 139 80 77 All Patients Low Risk (RS <18) Int Risk (RS 18-30) High Risk (RS 31) Poor 148 33 28 87 20 40 60 80 100 RS, Recurrence Score % Distant Recurrence-free at 10 Years 12 Paik S, et al. N Engl J Med. 2004;351:2817-2826.

Oncotype DX Clinical Validation: NSABP B-14, Subgroup Analysis by Tumor Size All patients (N=668) Size 1 cm 109 65 27 17 All Patients Low Risk (RS <18) Int Risk (RS 18-30) High Risk (RS 31) Size 1-2 cm Size 2-4 cm Size >4 cm 305 149 72 84 220 110 44 66 34 14 6 14 RS, Recurrence Score Paik S, et al. N Engl J Med. 2004;351:2817-2826. 20 40 60 80 100 % Distant Recurrence-free at 10 Years 13

Oncotype DX Clinical Validation: NSABP B-14, Subgroup Analysis by Age All patients (N=668) Age <40 Age 40-50 Age 50-60 Age >60 59 16 10 33 135 66 29 40 173 81 48 44 301 175 62 64 All Patients Low Risk (RS <18) Int Risk (RS 18-30) High Risk (RS 31) RS, Recurrence Score Paik S, et al. N Engl J Med. 2004;351:2817-2826. 40 60 80 100 % Distant Recurrence-free at 10 Years 14

Oncotype DX Clinical Validation: NSABP B-20 Objective: Prospectively determine the relationship between Recurrence Score result and chemotherapy benefit in node-negative, ER+ patients Tam + MF Randomized Tam + CMF Tam Multicenter study with prespecified 21-gene assay, algorithm, endpoints, analysis plan Paik S, et al. J Clin Oncol. 2006;24:3726-3734. 15

Proportion without distant recurrence High Recurrence Score Result Correlates with Greater Benefit from Chemotherapy (NSABP B-20) 1.0 0.9 0.8 0.7 0.6 PATIENTS WITH HIGH RS 28% absolute benefit from tamoxifen + chemotherapy 0.5 N Events 0.4 0.3 All patients RS < 18 Tamoxifen + chemotherapy Tamoxifen Tamoxifen + chemotherapy Tamoxifen 424 227 218 135 33 31 8 4 P = 0.02 P = 0.61 4.4% absolute benefit from tamoxifen + chemotherapy 0.2 RS 18-30 Tamoxifen + chemotherapy Tamoxifen 89 45 9 4 P = 0.39 0.1 RS 31 Tamoxifen + chemotherapy Tamoxifen 117 47 13 18 P < 0.001 0 2 4 6 8 10 12 Years RS, Recurrence Score result Paik S, et al. J Clin Oncol. 2006;24:3726-3734. 16

Average Rate of Distant Recurrence at 10 Years High Recurrence Score Disease Is Chemo-sensitive Whereas Low Recurrence Score Disease is Not (NSABP B-20) % Decrease in Distant Recurrence at 10 Years (mean ± SE) Node Negative, ER-Positive Breast Cancer Chemotherapy Benefit Recurrence Score vs Distant Recurrence at 10 Years Tam vs Tam + CMF/MF Absolute Benefit of Chemotherapy (CMF/MF) at 10 Years by Recurrence Score Group 50% 45% 40% 35% 30% Rate: Tam 95% Cl: Tam Rate: Tam + CMF/MF 95% Cl: Tam + CMF/MF Tam 50% 40% 30% 25% 20% 20% 15% 10% Tam + CMF/MF 10% 5% 0% 0% 0 5 10 15 20 25 30 35 40 45 50 Breast Cancer Recurrence Score -10% Recurrence Score < 18 (n = 353) Recurrence Score 18-30 (n = 134) Recurrence Score 31 (n = 164) 17

Recurrence Score NSABP B-20: Many Small Tumors Have Intermediate to High Recurrence Score Disease 100 P=0.001 80 60 40 16% 25% 30% 33% 20 20% 19% 23% 21% 0 64% 56% 46% 46% N = 110 N = 318 N = 196 N = 24 1 cm 1.1-2 cm 2.1-4 cm >4 cm Clinical tumor size 18 Paik S, et al. J Clin Oncol. 2006;24:3726-3734.

Recurrence Score NSABP B-20: Many Younger Patients Have Low Recurrence Score Disease P=0.018 41% 24% 28% 19% 14% 21% 22% 21% 44% 55% 50% 60% N = 63 N = 226 N = 166 N = 196 19 Paik S, et al. J Clin Oncol. 2006;24:3726-3734.

Recurrence Score NSABP B-20: Significant Proportion of High-Grade Tumors Have Low Recurrence Score Disease Recurrence Score P < 0.001 P<0.001 12% 22% 42% 5% 12% 61% 16% 22% 22% 73% 56% 36% N = 77 N = 339 N = 163 12% 24% 19% 83% 64% 19% N = 119 N = 340 N = 190 20 Paik S, et al. J Clin Oncol. 2006;24:3726-3734.

NSABP B-20: The Recurrence Score Result Is the Strongest Predictor of Chemotherapy Benefit Assessable B20 Patients (n = 651) Variable HR Lower 95% Upper 95% P Recurrence Score 0.32 0.11 0.94.038 Age 50 yrs 2.02 0.75 5.47.162 Tumor size >2 cm 1.34 0.49 3.68.569 Quantitative ER 50 1.96 0.73 5.30.183 Quantitative PR 50 1.87 0.70 4.97.214 Grade site Poor Moderate 0.27 0.60 0.02 0.06 3.01 6.42.284.672 Grade, pathologist A Poor Moderate 0.73 1.04 0.19 0.23 2.89 4.58.657.963 Grade, pathologist B Poor Moderate 0.32 0.36 0.06 0.06 1.77 2.03.192.244 21 Paik S, et al. J Clin Oncol. 2006;24:3726-3734.

Oncotype DX Node-Negative Clinical Experience

Clinical Experience Supports Findings from NSABP B-14 and NSABP B-20 RS Groups by Patient Age <50 yrs (n=367) RS Groups by Tumor Grade 50 yrs (n=1497) Grade 1 (n=277) RS Groups by Tumor Size Grade 2 (n=964) 2 cm (n=1447) Grade 3 (n=289) >2 cm (n=402) Not all grade 1 tumors have low RS values. Only 31% of grade 3 tumors have high RS values. Small tumors have proportionately fewer high RS values. However, there is a range of RS values across both categories of tumor size. Liebermann N, et al. ASCO 2011. Abstract 632 (poster presentation). 23

Does the Recurrence Score Impact Treatment Decisions? Is the Oncotype DX Assay Cost-Savings and Cost- Effective?

Meta-Analysis: The Recurrence Score Result Changes Decisions Across 7 Independent Decision Impact Studies Before RS CT + HT HT After RS CT + HT HT CT + HT HT Total Asad et al. 24 36 8 13 81 Henry et al. 6 7 2 14 29 Klang et al. 69 105 20 119 313 Liang et al. 125 85 3 47 260 Lo et al. 20 20 3 40 83 Oratz et al. 19 14 3 32 68 Thanasoulis et al. 8 30 2 38 78 RS, Recurrence Score result; CT, chemotherapy; HT, hormone therapy N = 912 patients Consistent, large impact of RS on treatment decisions in both directions: Half of patients initially recommended CT+HT are changed to HT only Some patients initially recommended HT alone have CT added upon being informed of High RS Disease Asad J, et al. Am J Surg. 2008;196:527-529; Henry LR, et al. J Surg Oncol. 2009;99:319-323; Klang SH, et al. Value Health. 2010;13:381-387; Liang H, et al. SABCS 2007: Abstract 2061; Lo SS, et al. J Clin Oncol. 2010;28:1671-1676; Oratz R, et al. J Oncol Pract. 2007;3:182-186; Thanasoulis T, et al. Am Soc Br Surg Annual Meeting 2008. Hornberger J, et al. SABCS 2010. Poster P2-09-06. 25

Meta-Analysis: Overall Impact of Recurrence Score on Treatment Decisions Treatment plan after RS Treatment plan prior to Oncotype DX Treatment plan after RS 88% 12% 52% 48% 4% change 33% change CT + HT HT Overall, the RS led to a 37% change in treatment decisions 33% from CT + HT HT 4% from HT CT + HT RS, Recurrence Score result Hornberger J, et al. SABCS 2010. Poster P2-09-06. 26

Most Patients Were Positively Influenced by the Recurrence Score 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 * 0 20 40 60 80 100 * 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 Recurrence Score result helped reduce patients anxiety and decisional conflict Lo SS, et al. SABCS 2008. Abstract 3113. [poster presentation] 27

The Oncotype DX Assay Reduces Unnecessary Treatment and is Cost Saving Studies show net savings up to $2,000 per patient tested with Oncotype DX 1,2 Saves patients the negative health and QOL impact of unnecessary chemotherapy 3 A reduction in chemotherapy use of approximately 30%, as observed in the Hornberger meta-analysis 4, results in $195,000 savings per 100 patients tested annually 5 1. Hornberger J, et al. Am J Manag Care. 2005;11:313-324.2. Horberger J, et al. J Oncol Pract 2011; 7: e38s-e45s. 3. Lo SS, et al. J Clin Oncol. 2010;28:1671-1676. 4. Hornberger J, et al. SABCS 2010. Poster P2-09-06. 5. Data on file. 28

Oncotype DX Testing in Node-Positive Disease

Validity of the Oncotype DX Assay Consistently Demonstrated in Node-Positive Patients Study Type Nodal status No. of patients TransATAC 1 SWOG 8814 2 Prospective Tam vs anastrozole Prospective Tam vs CAF Tam Node positive Node negative 1231 Node positive 367 ECOG 2197 3 Prospective AC vs AT Node positive Node negative 465 Total N+ patients in all three studies =905 1. Dowsett M, et al. J Clin Oncol. 2010;28(11):1829-1834. 2. Albain KS, et al. Lancet Oncol. 2010;11(1):55-65. 3. Goldstein LJ, et al. J Clin Oncol. 2008;26:4063-4071. 30

Trans ATAC Study Overview ATAC study population (N = 9366) Tamoxifen Anastrozole Tamoxifen + Anastrozole (combination arm not examined) Primary Analysis: To determine whether Oncotype DX assay significantly adds to a proportional hazards model for time to distant recurrence (age, tumor size, grade, treatment) in node-negative, HR+, patients with no adjuvant chemotherapy Secondary analyses: Determine whether the relationship between continuous Recurrence Score result and time to distant recurrence differs by nodal status or treatment arm Determine the relationship of predefined Recurrence Score groups with time to distant recurrence by nodal status and treatment arm Evaluate whether Recurrence Score result adds to the Adjuvant! Online estimate of risk Dowsett M, et al. J Clin Oncol. 2010;28(11):1829-1834. 31

Trans ATAC: The Recurrence Score Value Is a Significant Predictors of Distant Recurrence (node-negative patients, both treatment arms) Variable HR (95% CI)* P value Recurrence Score / 50* 5.25 (2.84, 9.73) < 0.001 Tumor Size: > 2 vs 2 cm 2.78 (1.70, 4.57) < 0.001 Central grade Moderate vs Well Poor vs Well 1.70 (0.75, 3.86) 2.06 (0.82, 5.17) 0.270 Multivariate analysis adjusted for treatment arm and patient age *Hazard Ratio for a 50-point increment in Recurrence Score value Multivariate analysis confirms that the Oncotype DX Recurrence Score result as a continuous variable is a highly significant predictor of time to distant recurrence Dowsett M, et al. J Clin Oncol. 2010;28(11):1829-1834. 32

Proportion distant recurrence-free Trans ATAC: Recurrence Score Value Is Prognostic in Node-Positive Patients Node+ (n = 306; both treatment arms) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 Log-rank P < 0.001 N (%) Events Low 160 (52%) 25 Int 94 (31%) 25 High 52 (17%) 24 0 1 2 3 4 5 6 7 8 9 Years 83% 72% 51% Dowsett M, et al. J Clin Oncol. 2010;28(11):1829-1834. Recurrence Score group Hazard ratio* (95% CI) High vs Low 2.7 (1.5-5.1) Int vs Low 1.8 (1.0-3.2) 33

9-Year risk of distant recurrence (%) 100 Trans ATAC: Rate of Distant Recurrence Increases with Number of Positive Nodes for All Recurrence Score Values 0 10 20 30 40 50 60 70 80 90 Mean 95% CI 0 5 10 15 20 25 30 35 40 45 50 Recurrence Score 4 Positive nodes n = 63 1-3 Positive nodes n = 243 Node negative n = 872 Low Recurrence Score suggests a low risk of recurrence for patients with 1-3 positive nodes. Dowsett M, et al. J Clin Oncol. 2010;28(11):1829-1834. 34

SWOG 8814:Oncotype DX Clinical Validation in Node-Positive Patients Tamoxifen 5 yrs n = 361 SWOG 8814 Postmenopausal, node-positive, ER-positive breast cancer N = 1477 CAF 6 + tamoxifen n = 550 CAF 6 tamoxifen n = 566 SUB ANALYSIS Patients with samples (n = 666) RT-PCR obtained (n = 601) Tamoxifen alone (n = 148) CAF + T (n = 243) CAF T (n = 219) Sample for primary analysis 148 + 219 = 367 (40% of parent trial) Superior disease-free survival and overall survival over 10 years Albain KS, et al. Lancet Oncol. 2010;11(1):55-65. 35

SWOG 8814: Recurrence Score Result Is Prognostic for Node-Positive Patients (Tamoxifen Arm) DFS by risk group (tamoxifen-alone arm) OS by risk group (tamoxifen-alone arm) 1.00 1.00 0.75 0.75 0.50 0.50 Stratified log-rank P = 0.017 at 10 years Stratified log-rank P = 0.003 at 10 years 0.25 0.00 RS < 18 (n = 55) RS 18-30 (n = 46) RS 31 (n = 47) 0.25 0.00 RS < 18 (n = 55) RS 18-30 (n = 46) RS 31 (n = 47) 0 2 4 6 8 10 0 2 4 6 8 10 Years since registration Years since registration 10-Year DFS: 60%, 49%, 43% 10-Year OS: 77%, 68%, 51% RS, Recurrence Score result Albain KS, et al. Lancet Oncol. 2010;11(1):55-65. 36

SWOG 8814: Breast Cancer-Specific Survival of Node-Positive Patients by Treatment and Recurrence Score Group BREAST CANCER-SPECIFIC SURVIVAL BY TREATMENT RS < 18 RS 18-30 RS 31 100 100 100 75 75 75 50 25 Stratified log-rank P = 0.56 at 10 years CAF T (n = 91, 10 events) Tamoxifen (n = 55, 4 events) 0 0 2 4 6 8 10 Years since registration 10-yr BCSS T: 92% vs CAF T: 87% No benefit to CAF over time for low Recurrence Score 50 25 Stratified log-rank P = 0.89 at 10 years CAF T (n = 46, 10 events) Tamoxifen (n = 57, 11 events) 0 0 2 4 6 8 10 Years since registration 10-yr BCSS T: 70% vs CAF T: 81% Interaction P = 0.021 50 25 Stratified log-rank P = 0.033 at 10 years CAF T (n = 47, 18 events) Tamoxifen (n = 71, 20 events) 0 0 2 4 6 8 10 Years since registration 10-yr BCSS T: 54% vs CAF T: 73% Strong benefit to CAF over time for high Recurrence Score RS, Recurrence Score result 37 Albain KS, et al. Lancet Oncol. 2010;11(1):55-65.

Is the Oncotype DX Assay Included in Treatment Guidelines?

Oncotype DX Is the Only Multigene Expression Assay Incorporated into NCCN, ASCO, and St. Gallen s Guidelines NCCN Guidelines TM Consider use in > 0.5 cm, HR+, HER2 disease pt1, pt2, or pt3; pn0 and pn1mi ( 2 mm axillary node metastasis) ASCO Guidelines Newly diagnosed patients with node-negative, ER+ breast cancer who will receive tamoxifen St. Gallen Consensus Oncotype DX has been shown to predict chemotherapy benefit among patients with HR+ disease Harris L, et al. J Clin Oncol. 2007;33(25):5287-5312. Adapted from NCCN Practice Guidelines in Oncology v.2.2011. Goldhirsch A, et al. Ann Oncol. 2011;22:1736-1747. ASCO is a trademark of the American Society of Clinical Oncology. NCCN and NCCN Guidelines are trademarks of the National Comprehensive Cancer Network. ASCO and NCCN do not endorse any therapy or product. 39

The Oncotype DX Assay Provides Consistent Results in Over 4,000 Breast Cancer Patients Studied Study Design N Nodal status Prognostic Predictive NSABP B-14 1 Kaiser Permanente 2 Prospective; tam only Prospective; case-control 668 Neg YES - 790 cases/controls Neg YES - NSABP B-14 3 Prospective; placebo vs tam 645 Neg YES YES Quantitative ER predicts tamoxifen benefit NSABP B-20 4 Prospective; tam ± chemo 651 Neg - YES RS predicts chemotherapy benefit ECOG 2197 5 Prospective; AC vs AT 465 Neg/Pos YES - SWOG 8814 6 Prospective; tam ± chemo 367 Pos YES YES RS predicts chemotherapy benefit TransATAC 7 Prospective; tam vs AI 1231 Neg/Pos YES - 1. Paik S, et al. N Engl J Med. 2004;351:2817-2826. 2. Habel LA, et al. Breast Cancer Res. 2006;6:R25-R39. 5. Goldstein LJ, et al. J Clin Oncol. 2008;26:4063-4071. 3. Paik S, et al. J Clin Oncol. 2005;23(16S): abstract 510. 6. Albain KS, et al. Lancet Oncol. 2010;11:55-65. 4. Paik S, et al. J Clin Oncol. 2006;24:3726-3734. 7. Dowsett M, et al. J Clin Oncol. 2010;28:1829-1834. 40

The Oncotype DX Assay Fulfills Criteria for Level I Evidence Level of evidence I II Category Study design Validation studies available A B B Prospective Prospective using archived samples Prospective using archived samples None required One or more with consistent results None, or inconsistent results C Prospective / observational III C Prospective / observational IV-V D Retrospective / observational Two or more with consistent results None, or one with consistent results, or inconsistent results Not applicable* *Level of evidence IV and V studies will never be satisfactory for determination of medical utility Proper study design determines strength of results and level of evidence 41 Simon RM, et al. J Natl Cancer Inst. 2009;101:1446-1452.

Patient Cases

Can You Guess the Recurrence Score? 68 & 69 year-old patients, small node-negative tumors, grade 2 & 3 PATIENT A 68-year-old patient with 1.1-cm tumor Menopausal Status: Postmenopausal Tumor Type: Infiltrating Ductal Carcinoma (IDC) Tumor Size: 1.1 cm ER Status (IHC): Positive PR Status (IHC): Positive HER2/neu Status: Negative Histologic Grade: 2 Lymph Node Status: Negative General Health: Fair PATIENT B 69-year-old patient with 1.3-cm tumor Menopausal Status: Postmenopausal Tumor Type: Infiltrating Ductal Carcinoma (IDC) Tumor Size: 1.3 cm ER Status (IHC): Positive (2) PR Status (IHC): Positive (2) HER2/neu Status: Negative (IHC) Histologic Grade: 3 Lymph Node Status: Negative General Health: PS 0 CASE SUBMITTED BY: Victor G. Vogel, MD CASE SUBMITTED BY: Ella Tepper, MD 43

Can You Guess the Recurrence Score? 68 & 69 year-old patients, small node-negative tumors, grade 2 & 3 PATIENT A RESULTS Clinical Experience Patients with a Recurrence Score of 34 in the clinical validation study had an Average Rate of Distant Recurrence at 10 years of 23% (95% CI: 18%-28%). PATIENT B RESULTS Clinical Experience Patients with a Recurrence Score of 11 in the clinical validation study had an Average Rate of Distant Recurrence at 10 years of 7% (95% CI: 5%-10%). 44

Can You Guess the Recurrence Score? 45 & 46 year-old patients, small node-negative tumors, grade 2 & 3 PATIENT A 45-year-old patient with 0.9-cm tumor Menopausal Status: Premenopausal Tumor Type: Infiltrating Ductal Carcinoma (IDC) 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 Lymph Node Status: Negative (0/2 SLNs) CASE SUBMITTED BY: Barbara Schwartzberg, MD PATIENT B 46-year-old patient with 0.7-cm tumor Menopausal Status: Premenopausal Tumor Type: Infiltrating Ductal Carcinoma (IDC) 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 Lymph Node Status: Negative CASE SUBMITTED BY: Barbara Schwartzberg, MD 45

Can You Guess the Recurrence Score? 45 & 46 year-old patients, small node-negative tumors, grade 2 & 3 PATIENT A RESULTS Clinical Experience Patients with a Recurrence Score of 15 in the clinical validation study had an Average Rate of Distant Recurrence at 10 years of 10% (95% CI: 7%-12%). PATIENT B RESULTS Clinical Experience Patients with a Recurrence Score of 35 in the clinical validation study had an Average Rate of Distant Recurrence at 10 years of 24% (95% CI: 18%-30%). 46

Conclusions

The Oncotype DX Report Provides Valuable Information Along a Continuum of ER+ Breast Cancer 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 48

The Oncotype DX Breast Cancer Assay Quantitatively predicts the likelihood of breast cancer recurrence and assesses the benefit from both hormonal therapy and chemotherapy (Level I Evidence) High and low Recurrence Score 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 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. 49