1. Joan Albanell Medical Oncology Hospital del Mar, Barcelona The Spanish Experience

3. T1N0 ER+ Breast Cancer Risk of relapse and death 12% 8-9 Relapse despite chemo In 88 women chemo was unncessary since they would not relapse anyway Chemo avoids 3-4 relapses What the oncologist should recommend ?

4. Duric et al. Lancet Oncology 2001 Participatory medicine and why is so difficult to develop clinically useful biomarkers

6. * Note: Question in 2009 stated generally as follows: “Can need for chemo-hormonal therapy in endocrine responsive uncertain disease be predicted using gene expression profile X?” 2009 Saint Gallen Breast Cancer Conference Panel Vote ODX 09* Yes 32% No 54% Abstention 14%

8. 16 CANCER RELATED GENES 5 REFERENCE GENES Estrogen Proliferation HER2 Invasion Others RT-PCR Oncotype Recurrence Score for ER+ Early Breast Cancer (paraffin) Paik et al. NEJM 2005 ER PR Bcl2 SCUBE2 GRB7 HER2 Ki-67 STK15 Survivin Cyclin B1 MYBL2 Stromelysin 3 Cathepsin L2 GSTM1 CD68 BAG1 Beta-actin GAPDH RPLPO GUS TFRC

10. 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 Recurrence Score Group Predicts Chemo Benefit High Risk Patients (RS≥31) N Events TAM + Chemo 117 13 TAM 47 18 Low Risk Patients (RS<18) N Events TAM + Chemo 218 8 TAM 135 4 Int Risk Patients (RS 18-30) N Events TAM + Chemo 89 9 TAM 45 4

12. 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 Onco type DX ® Assay Register Specimen banking Primary study group

13. B= Archived samples from prospective trials I= Actionable (Clinical Utility)

15. High Recurrence Score ® result predictive of chemotherapy benefit in node-positive patients Albain KS, et al. Lancet Oncol . 2009; [Epub ahead of print]. DFS BY TREATMENT & RS GROUP 1.00 0.75 0.50 0.25 0.00 0 2 4 6 8 10 Years since registration Stratified log-rank P = 0.97 at 10 years 0 2 4 6 8 10 Years since registration Stratified log-rank P = 0.48 at 10 years 0 2 4 6 8 10 Years since registration Stratified log-rank P = 0.033 at 10 years CAF  T (n = 91, 26 events) Tam (n = 55, 15 events) CAF  T (n = 46, 22 events) Tam (n = 57, 20 events) CAF  T (n = 47, 26 events) Tam (n = 71, 28 events) RS < 18 RS 18-30 RS ≥ 31 No benefit to CAF over time if low or intermediate RS Strong benefit if high RS

17. Annals of Oncology (in press)

19. Study Objectives Primary Objective 1) To characterize the impact of Onco type DX in adjuvant therapy decision-making in a cohort of consecutive patients with node-negative, ER+, HER2 negative breast cancer Secondary Objectives 1) To explore the relationship between routine clinico-pathological characteristics and the probability of a change in adjuvant therapy recommendation after Onco type DX testing. 2) To assess the confidence of medical oncologists in their recommendation before and after Onco type DX testing. 3) To correlate local ER and PR IHC results with quantitative mRNA measurements of ER and PR by Onco type DX.

21. Characteristics of the patients and distribution of Recurrence Scores No of patients % Mean RS No of patients % No of patients % No of patients % 107 16.0 62 57.9 35 32.8 10 9.3 <50 years 40 37.4 17.5 23 57.5 15 37.5 2 5.0 ≥ 50 years 67 62.6 17.5 39 58.2 20 29.9 8 11.9 pT1 91 85.0 16.9 55 60.4 28 30.8 8 8.8 pT2 16 15.0 20.3 7 43.8 7 43.8 2 12.5 Low 37 34.6 14.5 25 67.6 11 29.7 1 2.7 Intermediate 46 43.0 18.2 25 54.3 17 37.0 4 8.7 High 20 18.7 22.2 9 45.0 6 30.0 5 25.0 Unknown 4 3.7 Negative 16 15.0 27.6 3 18.8 7 43.8 6 37.5 Positive 90 84.1 15.6 59 65.6 27 30.0 4 4.4 Unknown 1 0.9 <20% 61 57.0 14.5 43 70.5 16 26.2 2 3.3 ≥ 20% 29 27.1 22.1 14 48.3 9 31.0 6 20.7 Unknown 17 15.9 Low RS Intermediate RS High RS Characteristic (RS<18) (RS 18-30) (RS ≥31 ) Progesterone receptor Ki-67 Total Median age, years (range) 53.0 (29-78) Tumor size Tumor grade

23. Treatment recommendation shifted 32% of the times after Onco type DX testing 11.2% HT alone to CHT 20.6% CHT to HT alone

25. Treatment shift in women with Pre-RS recommendation of CHT No of patients % p value 22 56.4 0.358 <50 years (N=17) 11 64.7 ≥ 50 years (N=22) 11 50.0 0.114 pT1 (N=28) 18 64.3 pT2 (N=11) 4 36.4 0.424 Low (N=9) 4 44.4 Intermediate (N=16) 11 68.8 High (N=12) 6 50.0 0.002 Negative (N=9) 1 11.1 Positive (N=30) 21 70.0 0.774 <20% (N=18) 11 61.1 ≥ 20% (N=16) 9 56.3 Change from CHT to HT alone Characteristic Total (N=39) Median age, years (range) (N=39) Tumor size (N=39) Tumor grade (N=37) Progesterone receptor (N=39) Ki67 (N=34)

26. Treatment shift in women with Pre-RS recommendation of HT alone No of patients % p value 12 17.6 0.192 <50 years (N=23) 6 26.1 ≥ 50 years (N=45) 6 13.3 0.173 pT1 (N=63) 10 15.9 pT2 (N=5) 2 40.0 0.007 Low (N=28) 1 3.6 Intermediate (N=30) 7 23.3 High (N=8) 4 50.0 0.792 Negative (N=7) 1 14.3 Positive (N=60) 11 18.3 0.023 <20% (N=43) 3 7.0 ≥ 20% (N=13) 4 30.8 Progesterone receptor (N=67) Ki67 (N=56) Change from HT to CHT Characteristic Total (N=68) Median age, years (range) Tumor size (N=68) Tumor grade (N=66)

27. Onco type DX ® assay also provides quantitative data for ER, PR, HER2 ER score PR score HER2 score

28. Spain: Correlation between percentage of expression (IHC) and quantitative single gene report for ER and PR by Onco type DX Quantitative Single ER Gene Report Quantitative Single PR Gene Report Percentage of ER stained cells Percentage of PR stained cells Negative (<6.5) Positive (≥6.5) Negative (<5.5) Positive (≥5.5) Estrogen receptor Progesterone receptor Pearson r=0.343 p=0.001 Pearson r=0.779 p<0.001

30. 3) In women with CHT recommendation before Onco type testing, treatment shifted to HT alone in 54.6% of the times. Positive progesterone receptor status was associated with a greater chance of changing to HT alone. 4) In women with HT alone recommendation before Onco type testing, treatment shifted to CHT in 17.6% of the times. Intermediate/high tumor grade and high proliferative index (Ki-67) were significantly associated with a greater chance of changing to CHT. 5) Medical oncologists confidence improved after the RS in 60.2% of the cases. 6) Good correlation between ER and PR IHC testing vs. single gene Onco type DX assays. Spanish Experience Summary (II/II)

35. Saint Gallen 2011

36. How Has the Voting Changed? 2009 v 2011 * Note: Question in 2009 stated generally as follows: “Can need for chemo-hormonal therapy in endocrine responsive uncertain disease be predicted using gene expression profile X?” ** Note: Question in 2011 stated as follows: “May gene expression profile X be used to predict chemo-hormonal therapy response in an endocrine-responsive cohort? Yes or No?” 12 th International St. Gallen Breast Cancer Conference Expert Consensus Panel Discussion March 19, 2011 ODX 09* ODX 11** Yes 32% 84.4% No 54% 11.1% Abstention 14% 4.4%