1. The Use of Genomics in Early Stage Breast Cancer Hope S. Rugo, MD Professor of Medicine Director, Breast Oncology and Clinical Trials Education UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, CA

6. 70 Gene-Expression Signature (Mammaprint ® ) Prognostic for Survival in Early Breast Cancer* Good signature Poor signature Probability of Remaining Metastasis-free St. Gallen, High Risk St. Gallen, Low Risk Probability of Remaining Metastasis-free NEJM 347 (25), 2002 Validated Prognostic Tool in Several Additional Independent Data Sets

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

11. NSABP B-20: Many Younger Patients Have Low Recurrence Score ® Results NSABP B-20: Many Small Tumors Have Intermediate to High Recurrence Score ® Values NSABP B-20: Significant Proportion of High-Grade Tumors Have Low Recurrence Score ® Values Paik S, et al. J Clin Oncol . 2006;24:3726-3734.

12. Onco type DX ® and Patient Age: Distribution of RS Risk Groups by Age Group Shak S, et al. SABCS 2010. Poster P3-10-01 . n 145,240 5,794 117,744 21,702 RS (mean) 18.6 21.3 18.6 18.2

13. S8814 N+ ER+ Single Gene Analyses might “Misclassify”Dominant Biology of Tumor Example: Some High ER (by either Allred Score or RT-PCR) have High RS Albain, et al, 2009

14. Summary of Key Differences Between Genomic Assays 1. Paik S, et al. N Engl J Med. 2004;351:2817; 2. Paik S, et al. J Clin Oncol. 2006;24:3726. 3. Bueno-de-Mesquita JM, et al. Lancet Oncol . 2007; 8:1079-1087; 4. Mook S, et al. Breast Cancer Res Treat . 2009;116:295-302. ASCO is a trademark of the American Society of Clinical Oncology. ASCO does not endorse any therapy or product. NCCN is a trademark of the National Comprehensive Cancer Network . Onco type DX ® (Genomic Health) MammaPrint ® (Agendia) Mammostrat ® (Clarient) Insight ® Dx (Clarient) Does the test strongly predict recurrence risk? YES YES NO YES Is the test clinically validated in uniform patient populations? YES NO YES NO Can the test be performed in a clinically practical manner? FFPE (failure < 3% 1,2 ) Fresh tissue (failure 27% 3,4 ) FFPE (failure rate unpublished) FFPE (failure rate unpublished) What types of samples does the test accept? Surgical excisions, core biopsies Surgical excisions, core biopsies Surgical excisions Surgical excisions Does the test supply a result on a continuous scale or a risk category? Continuous; individualized risk assessment Group risk assessment (low, high) Group risk assessment (low, intermediate, high) Continuous Does the test predict chemotherapy benefit? YES NO NO NO What platform does the test use? RT-PCR Microarray IHC IHC/FISH What type of regulatory clearance does the test have? CLIA CLIA/FDA CLIA CLIA Is the test recommended in published treatment guidelines of ASCO ® and NCCN ® ? YES NO NO NO Is the test widely reimbursed? Medicare & > 95% of US privately insured lives Medicare & private insurance with signed Assignment of Benefits form No public information available Test uses CPT codes No public information available Test uses CPT codes

15. Summary of Practical Differences Between MammaPrint ® and the Onco type DX ® Assay 1. Paik S, et al. N Engl J Med. 2004;351:2817; 2. Paik S, et al. J Clin Oncol. 2006;24:3726. 3. Bueno-de-Mesquita JM, et al. Lancet Oncol . 2007; 8:1079-1087; 4. Mook S, et al. Breast Cancer Res Treat . 2009;116:295-302. ASCO is a trademark of the American Society of Clinical Oncology. ASCO does not endorse any therapy or product. NCCN is a trademark of the National Comprehensive Cancer Network . Onco type DX ® (Genomic Health) MammaPrint ® (Agendia) Does the test strongly predict recurrence risk? YES YES Is the test clinically validated in uniform patient populations? YES NO Can the test be performed in a clinically practical manner? FFPE (failure < 3% 1,2 ) Fresh tissue (failure 27% 3,4 ) What types of samples does the test accept? Surgical excisions, core biopsies Surgical excisions, core biopsies Does the test supply a result on a continuous scale or a risk category? Continuous; individualized risk assessment Group risk assessment (low, high) Does the test predict chemotherapy benefit? YES NO What platform does the test use? RT-PCR Microarray What type of regulatory clearance does the test have? CLIA CLIA/FDA Is the test recommended in published treatment guidelines of ASCO ® and NCCN ® ? YES NO Is the test widely reimbursed? Medicare & > 95% of US privately insured lives Medicare & private insurance with signed Assignment of Benefits form

16. What about Node-Positive Disease?

18. Recurrence Score ® Result Is Prognostic for Node-Positive Patients (Tamoxifen Arm) 0 2 4 6 8 10 0 2 4 6 8 10 1.00 0.75 0.50 0.25 0.00 1.00 0.75 0.50 0.25 0.00 RS < 18 (n = 55) RS 18-30 (n = 46) RS ≥ 31 (n = 47) Stratified log-rank P = 0.017 at 10 years RS < 18 (n = 55) RS 18-30 (n = 46) RS ≥ 31 (n = 47) Stratified log-rank P = 0.003 at 10 years DFS by risk group (tamoxifen-alone arm) OS by risk group (tamoxifen-alone arm) Years since registration Years since registration Albain KS, et al. Lancet Oncol . 2009; [Epub ahead of print]. RS, Recurrence Score result 10-Year DFS : 60%, 49%, 43% 10-Year OS : 77%, 68%, 51%

19. S8814 CAFT vs T Breast Cancer Specific Survival by RS S8814 S8814 S8814 Albain, et al. Lancet Oncology 12/10/09 epub Interaction p = 0.021 10 yr BCSS T: 92% vs CAF-T: 87% 10 yr BCSS T: 70% vs CAF-T: 81% 10 yr BCSS T: 54% vs CAF-T: 73%

21. Relevance of Multigene Assays in the Clinical Practice Setting *Most frequent decision change in all studies was from CHT -> HT Study N Setting Type Change in Treatment Decision* Oratz, et al. 74 Community, USA Retrospective, 21 gene 25% Asad, et al. 85 Community, USA Retrospective, 21 gene 44% Kamal, et al. 80 Academic, USA Retrospective, 21 gene 18% Lo, et al. 89 Academic + Community, USA Prospective, 21 gene 32% Bueno-de Mequita, et al. 427 Community, Dutch Prospective, 70 gene 26%

24. Proportion of Node-Negative Patients Classified as Low, Intermediate and High Risk by RS and RSPC: RSPC has Prognostic Value BUT Does Not Add Predictive Value to RS – B14 and B20 n=1444 RSPC RS RSPC Classifies Fewer Patients as Having Intermediate Risk Tang et al, ASCO and SA 2010 54.2% 26.7% 19.1% 63.8% 17.8% 18.4% Low Risk Intermediate Risk High Risk 2010

25. Prediction of Chemotherapy Benefit in NSABP B-20: RS Is Most Significant P-value for interaction with chemotherapy treatment Trended to benefit with higher expression Trended to benefit with lower expression Greater benefit with higher RS Not predictive of benefit Paik S, et al. J Clin Oncol . 2006;24:3726-3734. Recurrence Score 0.037 Proliferation Gene Group Score by RT-PCR 0.133 PR Gene by RT-PCR 0.190 ER Gene by RT-PCR 0.393 HER2 Gene by RT-PCR 0.925

26. TAILORx SCHEMA PI: Sparano 21-Gene RS Assay N= 6906 Closed 8/20/10, N=11233 Closed 10/6/10, N=10259 N=1624 N=1729

27. S1007: A Phase III, Randomized Clinical Trial of Standard Adjuvant Endocrine Therapy +/- Chemotherapy in Patients with 1-3 Positive Nodes, Hormone Receptor-Positive and HER2-Negative Breast Cancer with Recurrence Score of 25 or Less Ana M. Gonzalez-Angulo, M.D.

28. Schema and Patient Flow Node-positive (1-3 nodes) HR-positive and HER2-negative breast cancer (N= 600) RS already Available Physician and patients discuss randomization knowing the RS (N= 8,800) Patients consent to study-sponsored RS testing, discussion of potential trials, tumor tissue submission and linkage to cancer registry data RECURRENCE SCORE (N= 3,800) Discuss alternative trials for high risk patients N= 5,600 Physician and patients discuss randomization knowing the RS N= 1,600 Record chosen therapy and followed for vital status through cancer registry N= 2,000 Chemotherapy; appropriate endocrine therapy N= 2,000 No Chemotherapy; appropriate endocrine therapy STEP 2 REGISTRATION/ RANDOMIZATION N= 4,000 Randomization stratified by 1. RS 0-13 vs. 14-25 2. Menopausal status 3. Axillary node dissection vs. Sentinel node biopsy RS > 25 RS < 25 Accept Refuse STEP 1 REGISTRATION Tumor tissue submission for RS STEP 2 RANDOMIZATION

29. Plan B Study schema West German Study Group Prospective study of >2,500 patients As of11/2010, 2094 pts registered , 1586 randomized Unable to predict RS with tumor grade or Ki67

30. Evaluate Clinical-Pathological risk and 70-gene signature risk EORTC-BIG MINDACT TRIAL DESIGN 6,000 Node negative women Clinical-pathological and 70-gene both HIGH risk Clinical-pathological and 70-gene both LOW risk Use Clin-Path risk to decide Chemo or not Use 70-gene risk to decide Chemo or not R1 55% 32% 13% N=1920 30% 288 Clin-Path Low 70-gene High: Ctx Clin-Path High 70-gene Low: CTx 70% 672 Clin-Path Low 70-gene High: no CTx 30% 288 Clin-Path High 70-gene Low: no Ctx 70% 672 Supported by the EU framework VI programme BIG-TRANSBIG Secretariat – Used with permission H 0 : 5y DMFS >92% (80% power) Discordant Clin-Path HIGH 70-gene LOW 70% N=1344 Clin-Path LOW 70-gene HIGH 30% N=576

33. Adjuvantonline 10 yr mortality 10 yr recurrence

38. 64 yo woman: mammographically detected, 1.3 cm grade 2 IDCA, no LVI, SNL neg, ER+++PR+, HER2 neg by FISH. RX: TC x 4 and AI

39. 47 yo woman, self exam detected 0.8 cm grade I IDC, 1 SNL + 0.9 cm CA with focal extranodal extension, 12 additional nodes negative. RX: tamoxifen

40. Copyright © American Society of Clinical Oncology Walgren, R. A. et al. J Clin Oncol; 23:7342-7349 2005 Personalized Medicine

41. Patient is on Study Randomize Randomize Surgery Surgery Learn, Adapt from each patient as we go along * Or equivalent Closed 8/20/10 Paclitaxel + Trastuzumab* + New Agent A Paclitaxel + New Agent C Paclitaxel + Trastuzumab Paclitaxel + Trastuzumab* + New Agent B Paclitaxel Paclitaxel + New Agent E AC AC HER 2 (+) HER 2 (–) Paclitaxel + New Agent F Paclitaxel + Trastuzumab* + New Agent C Paclitaxel + New Agent D Paclitaxel + New Agent GH Paclitaxel + Trastuzumab* + New Agent F MRI Residual Disease (Pathology) Key