III Congreso Internacional de Oncologia del Interior XII Jornadas de Oncologia del Interior Cordoba Argentina. Farmacogenomica y Cancer de Mama

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1 III Congreso Internacional de Oncologia del Interior XII Jornadas de Oncologia del Interior Cordoba Argentina Farmacogenomica y Cancer de Mama Vicente Valero, M.D., F.A.C.P. Professor of Medicine Deputy Chairman Department of Breast Medical Oncology U. T. MD Anderson Cancer Center Professor of Internal Medicine The University of Texas Health Science Center School of Medicine Houston, Texas

2 Adjuvant Chemotherapy Adjuvant chemotherapy significantly improves DFS and OS in women with early stage breast cancer Benefits must be balanced with potential short term and long term risks such as: Premature ovarian failure Cognitive dysfunction Late cardiac effects Neuropathy Chemotherapy-associated leukemia/mds

3 Issues or Questions in Adjuvant Therapy in Breast Cancer

4 1) Does adjuvant chemotherapy have a superior therapeutic index than hormonal therapy alone in HER-2 neu normal ER+ EBC? 2) Does adjuvant anthracycline-based therapy has a superior therapeutic index than non-anthracycline therapy in HER-2 neu normal ER+ EBC? 3) Does adjuvant taxane and anthracycline-based therapy has a superior therapeutic index than non-anthracycline or anthracycline therapy in HER-2 neu normal ER+ EBC? 4) Does our current knowledge of tumor biology and genomic data would allow us to made a clinical decision?

5 Stage I Breast Cancer A 39-year-old woman presents to see her medical oncology after she underwent a left segmental mastectomy and later skin-sparing mastectomy and SLND. There is a 8 mm breast primary. There is extensive DCIS. One SLN was negative for metastatic disease. She does not have any serious co-morbidities. Pathologic Findings: Histology: Invasive ductal carcinoma, grade 2-3 ER: 70% cells positive PR: 20% cells positive HER-2: 0 IHC LVI: No

6 Stage II Breast Cancer A 45-year-old woman presents to see her medical oncology after she underwent a right mastectomy and SLND. There is a 2.2 cm breast primary. Two SLN were negative for metastatic disease. She does not have any serious co- morbidities. Pathologic Findings: Histology: Invasive ductal carcinoma, grade 2 ER: 100% cells positive PR: 100% cells positive HER-2: 0 IHC LVI: No

7 Stage II Breast Cancer A 50-year-old woman presents to see her medical oncology after she underwent a bilateral mastectomy and right SLND and left ALND. There is a right 8 mm and left 4 cm breast primaries. None of seven right SLN were positive. Three of 24 left axillary nodes were positive for metastatic disease. She does not have any serious co-morbidities. Pathologic Findings: Histology: Invasive lobular carcinoma, classic, grade 2 ER: 100% cells positive PR: 90% cells positive HER-2: Normal 0 IHC

8 Prognostic & predictive markers utilized in breast cancer management Prognostic (recurrence risk) Axillary node status Histologic type/grade Tumor size Patient age Lymphatic/Vascular invasion ER/PR status HER2 neu status Oncotype DX test Predictive (treatment benefit) ER/PR status HER2 neu status Oncotype DX test These markers can be used to estimate the risk of disease recurrence These markers can be used to predict treatment benefit Cianfrocca and Goldstein. Oncologist. 2004;9(6): ; Lonning PE. Ann Oncol. 2007;18(suppl 8):viii3-viii7. 8

9 Decision Support Tools Prediction of prognosis Adjuvant! Online * Nottingham Prognostic Index (NPI) Tumor size, stage of disease, histologic grade Genomic tools DNA microarrays Real-time polymerase chain reaction (PCR) *Paik S, et al. N Engl J Med. 2004;351(27): ; Galea MH et al. Breast Cancer Res Treat. 1992;22(3): ; Paik S. Curr Opin Obstet Gynecol 2006;18:59-63.

10 Adjuvant! Online Estimates: Risk of cancer-related mortality or relapse without therapy Risk reduction with therapy Risk of side effects from therapy Limitations Prognostic factors not all inclusive HER2 status and LVI not included Small tumors not well characterized Available at:

11 1) Does adjuvant chemotherapy have a superior therapeutic index than hormonal therapy alone in HER-2 neu normal ER+ EBC? 2) Does adjuvant anthracycline-based therapy has a superior therapeutic index than non-anthracycline therapy in HER-2 neu normal ER+ EBC? 3) Does adjuvant taxane and anthracycline-based therapy has a superior therapeutic index than non-anthracycline or anthracycline therapy in HER-2 neu normal ER+ EBC? 4) Does our current knowledge of tumor biology and genomic data would allow us to made a clinical decision?

12 Node-Negative, ER-Positive NSABP B-20:Tamoxifen vs. Chemo + Tamoxifen Disease-Free Survival Overall Survival 89% 87% 79% 83% HR: 0.52 HR: 0.78 Fisher B, et al: Lancet 2004

13 Oral CEF vs Oral CMF for Node-Positive Breast Cancer: NCIC MA5 Outcomes 100 Recurrence-Free Survival year Survival Rate Percentag ge HR=1.31 ( ) stratified log-rank, P= CEF 52% 45% CMF Percentag ge HR=1.18 (0.94 to 1.49) stratified log-rank, P=0.085 CEF 62% 58% CMF Time (years) Time (years) Levine et al. J Clin Oncol :5166.

14 Node Positive Breast Cancer CALGB 9344: AC versus AC-Paclitaxel % + 1 Proportion Disease-Free % % % + 1 P= (adjusted, Wald chisquare) P= (Unadjusted, Wilcoxon) 74% % + 1 No paclitaxel Paclitaxel Number of Events Paclitaxel 491 No paclitaxel % % Year Number at Risk Paclitaxel No paclitaxel Henderson et al. JCO 2003.

15 1.0 Node Positive Breast Cancer BCIRG 001: FAC vs TAC: DFS probability TAC FAC 75% 68% Cumulative N Events HR P-value TAC Stratified Log Rank 0.0 FAC DFS Time(months)

16 Stage I-II Node Negative Breast Cancer: Adjuvant Therapy You recommend which of the following primary therapy: 1. FAC/FEC x 6 then HT 2. AC/EC x 4 then HT 3. TC x 4 then HT 4. Dose-dense AC-T then HT 5. AC/FAC x4 then w-paclitaxel then HT 6. TAC x 6 then HT 7. CMF x 6 then HT 8. No chemotherapy, proceed with HT alone

17 Stage II-III Node Positive Breast Cancer: Adjuvant Therapy You recommend which of the following primary therapy: 1. FAC/FEC x 6 then HT 2. TC x 4 then HT 3. Dose-dense AC-T then HT 4. AC/FAC x4 then w-paclitaxel then HT 5. TAC x 6 then HT 6. No chemotherapy, proceed with HT alone

18 Adjuvant Breast Cancer Treatment Chemotherapy treatment for early breast cancer: Many women are offered chemotherapy, knowing that few benefit Guidelines assume all patients benefit equally Some patients are under-treated, many others are over-treated

19 1) Does adjuvant chemotherapy have a superior therapeutic index than hormonal therapy alone in HER-2 neu normal ER+ EBC? 2) Does adjuvant anthracycline-based therapy has a superior therapeutic index than non-anthracycline therapy in HER-2 neu normal ER+ EBC? 3) Does adjuvant taxane and anthracycline-based therapy has a superior therapeutic index than non-anthracycline or anthracycline therapy in HER-2 neu normal ER+ EBC? 4) Does our current knowledge of tumor biology and genomic data would allow us to made a clinical decision?

20 CAF ± Tamoxifen vs CMF ± Tamoxifen in High-Risk, Node Negative Breast Cancer: INT 0102 Trial Design Pre- and postmenopausal women with T1 to T3a nodenegative invasive breast adenocarcinoma High risk disease* N=2690 R A N D O M I Z E n=676 n=674 Primary end point: Disease-free survival Secondary endpoint: Overall survival CMF Cyclophosphamide (100 mg/m 2 Days 1-14) Methotrexate (40 mg/m 2 Days 1 + 8) Fluorouracil (600 mg/m 2 Days 1 + 8) q28 days x 6 cycles CMF Tamoxifen (20 mg/d on day 29 of cycle 6 and continued for 5 years) CAF Cyclophosphamide (100 mg/m 2 Days 1-14) Doxorubicin (30 mg/m 2 Days 1 + 8) Fluorouracil (500 mg/m 2 Days 1 + 8) q28 days x 6 cycles CAF Tamoxifen (20 mg/d on day 29 of cycle 6 and continued for 5 years) *Patients were classified as high risk based on either a) initial characteristics [tumor 2 cm or hormone receptor positive] or b) subsequent S-phase fraction DNA analysis showing 4.4 for diploid tumors or 7 for aneuploid tumors. Hutchins et al. J Clin Onc. 2005;23:8313. n=669 n=671

21 High-Risk, Node Negative Breast Cancer CAF ± Tamoxifen vs CMF ± Tamoxifen: INT 0102 Outcomes Percent tages Disease-Free Survival Overall Survival 100 HR = 1.09 ( ); HR = 1.19 ( ); P=0.13* 40 P=0.03* Years from Registration Percent tages Years from Registration At Risk Failures Hutchins et al. J Clin Onc. 2005;23: Year Estimates CAF arms % CMF arms % At Risk Failures 10-Year Estimates CAF arms % CMF arms %

22 Oral CEF vs Oral CMF for Node-Positive Breast Cancer: NCIC MA5 Trial Design Pre- or perimenopausal Axillary node-positive Non-metastatic Previous modified radical mastectomy or lumpectomy Axillary dissection R A N D O M I Z E D n=351 n=359 CEF: Cyclophosphamide (75 mg/m 2 Days 1-14) + Epirubicin (60 mg/m 2 Days 1 + 8) + Fluorouracil (500 mg/m 2 Days 1 + 8) CMF: Cyclophosphamide (100 mg/m 2 Days 1-14) + Methotrexate (40 mg/m 2 Days 1 + 8) + Fluorouracil (600 mg/m 2 Days 1 + 8) Primary end point: Recurrence-free survival Secondary end points: Overall survival, toxicity Patients administered CEF received antibiotic prophylaxis that consisted of cotrimoxazole two tablets po bid for the duration of chemotherapy. If this could not be tolerated, then norfloxacin 400 mg po bid or ciprofloxacin 500 mg po bid was used. NCIC = National Cancer Institute of Canada Clinical Trials Group; RT = radiotherapy. Levine et al. J Clin Oncol :5166. Breast RT for patients who underwent lumpectomy (50 Gy total in 25 fractions)

23 Oral CEF vs Oral CMF for Node-Positive Breast Cancer: NCIC MA5 Outcomes 100 Recurrence-Free Survival year Survival Rate Percentag ge HR=1.31 ( ) stratified log-rank, P= CEF 52% 45% CMF Percentag ge HR=1.18 (0.94 to 1.49) stratified log-rank, P=0.085 CEF 62% 58% CMF Time (years) Time (years) Levine et al. J Clin Oncol :5166.

24 Adverse Events Congestive heart failure CEF: 4 patients CMF: 1 patient Acute leukemia CEF: 5 patients CMF: 1 patient Levine MN, et al. J Clin Oncol. 2005;23:

25 The Meta-Analysis

26 Meta-Analysis: Relapse-Free Survival % 41.6% CMF Anthracycline Recur rrence yr gain: 3.4% (SE: 1.2) Log rank 2P = Yrs Recurrence Rates (%/Yr) and Log Rank Analyses Yrs 0-4 Yrs 5-9 Yr 10+ Anthracycline 7.80 (2136/27371) 3.41 (396/11607) 2.71 (48/1770) CMF 8.38 (1945/23211) 3.68 (325/8822) 2.80 (25/892) Rate Ratio, From 0.89 SE SE SE 0.26 (O-E)/V / / /15.4

27 Does our current knowledge of tumor biology and genomic data would allow us to made a clinical decision? Does every molecular subgroup of breast cancer benefit it?

28 HER2 Status Predicts Response to Adjuvant Anthracycline-Based Chemotherapy: NCIC CTG MA.5 Relap pse-free Survival (%) Overall Survival (%) HER2+ CEF 20 CMF HR=0.52 ( ) 0 P= Years CEF 40 CMF 20 0 P=0.06 HR=0.65 ( ) Years Relap pse-free Survival (%) Overall Survival (%) HER2- neg CEF CMF 20 P=0.49 HR=0.91 ( ) Years P=0.68 CMF CEF HR=1.06 ( ) 0 5 Years Pritchard K et al. N Eng J Medicine. 2006; 354:

29 The Meta-Analysis

30 Meta-Analysis: DFS Study HR 95% CI Anthracycline Better NSABP-B NSABP-B15 Brussels Milan Overall DBCCG-89-D NCIC MA Total P = Nonanthracycline Better P <.0001 P = 1.0 Heterogeneity c25 = 5.3; P =.38 Heterogeneity c25 = 7.6; P = Test for interaction chi 2 = 13.7; P <.001 HER2 positive HER2 negative Reprinted by permission of Oxford University Press. Gennari A, et al. J Natl Cancer Inst. 2008;100:14-20.

31 1) Does adjuvant chemotherapy have a superior therapeutic index than hormonal therapy alone in HER-2 neu normal ER+ EBC? 2) Does adjuvant anthracycline-based therapy has a superior therapeutic index than non-anthracycline therapy in HER-2 neu normal ER+ EBC? 3) Does adjuvant taxane and anthracycline-based therapy has a superior therapeutic index than nonanthracycline or anthracycline therapy in HER-2 neu normal ER+ EBC? 4) Does our current knowledge of tumor biology and genomic data would allow us to made a clinical decision?

32 Node Positive Breast Cancer CALGB 9344: AC versus AC-Paclitaxel % + 1 Proportion Disease-Free % % % + 1 P= (adjusted, Wald chisquare) P= (Unadjusted, Wilcoxon) 74% % + 1 No paclitaxel Paclitaxel Number of Events Paclitaxel 491 No paclitaxel % % Year Number at Risk Paclitaxel No paclitaxel Henderson et al. JCO 2003.

33 CALGB 9344: AC ± Paclitaxel Outcomes for 4 Subgroups of Patients A. HER2 Negative, ER Negative B. HER2 Negative, ER Positive No paclitaxel Paclitaxel Paclitaxel No paclitaxel P = P =.071 DFS (%) Yrs C. HER2 Positive, ER Negative D. HER2 Positive, ER Positive DFS (%) Paclitaxel No paclitaxel P = Yrs Hayes DF, et al. N Engl J Med. 2007;357: Copyright 2007 Massachusetts Medical Society. All rights reserved. DFS (%) DFS (%) Yrs Paclitaxel No paclitaxel P = Yrs

34

35 DFS Outcomes pakt- pakt+ Patients with pakt-negative breast tumors do not appear to benefit from the addition of paclitaxel. Yang et al. J Clin Oncol 2010;28:

36 1) Does adjuvant chemotherapy have a superior therapeutic index than hormonal therapy alone in HER-2 neu normal ER+ EBC? 2) Does adjuvant anthracycline-based therapy has a superior therapeutic index than non-anthracycline therapy in HER-2 neu normal ER+ EBC? 3) Does adjuvant taxane and anthracycline-based therapy has a superior therapeutic index than nonanthracycline or anthracycline therapy in HER-2 neu normal ER+ EBC? 4) Does our current knowledge of tumor biology and genomic data would allow us to made a clinical decision?

37 Goals of the Breast Cancer Pharmacogenomic Program Evaluate gene expression profiling as a potential diagnostic tool Combination of multiple genes may yield more robust predictors of outcome than any single gene alone. Identify individual genes that are associated with outcome. Combine these into a multivariate prediction model = predictive signature Use gene expression data to: define new therapeutic targets gain new insights into the biology of breast cancer

38 Several criteria has to be met before clinical use of a test could be considered Assay measurements have to be reproducible and robust. The predictor must be fully defined (including cut off values). The predictive performance of the test has to be validated on independent cases that are clinically relevant. Technically sound test with known accuracy Is the new predictor better than the current alternative methods? Does the use of the test improve clinical outcome?

39 In February 2007 the FDA cleared MammaPrint as a prognostic aid It requires a punch biopsy of the fresh surgically resected cancer. The specimen is placed in RNA later and mailed to Amsterdam for analysis. Report indicates either low risk (10-year MFS 90% [CI: 85-96%) or high risk (10-year MFS 71% [CI: 65-78%) status for recurrence. FDA indication: estimate prognosis of node negative, < 5cm cancers in woman < 55 years old. FDA seal EU CE mark CLIA Certification CAP Accreditation

40 70-Gene prognostic gene signatures (MammaPrint TM Agendia Inc) N=98 70-gene prognostic signature Partial validation results n=296 (61 pt same as above) Patients included: < 5 cm cancer <51 years 151 Node-negative 144 Node-positive 90 adjuvant chemo (C) 20 adjuvant endocrine (T) 20 both C + T 226 ER+ / 69 ER- MJ van de Vijver et al, New Engl J Med 347:1999, 2002

41 2 nd Validation of the 70-gene signature Probability Patients Events Risk group Genetic low risk Genetic high risk 10-year MFS 90% (85%-96%) 10-year MFS 71% (65%-78%) Patients Included N=302 <61 years < 5cm tumor node-negative patients no adjuvant therapy 90 ER- / 212 ER Year GLR GHR Number at risk Discordance rates clinical vs MammaPrint High risk by Adjuvant N=246 Low risk by Adjuvant N=45 67% High gene signature risk 33% Low gene sign. risk 64% Low gene signature. risk 36% High gene sign. risk There was an about 30% discordant risk prediction between Adjuvant Online and the gene signature! SABS 2004, Dr Martine Piccart-Gephart JBI, Brussels M Buyse et al, J Natl Cancer Inst 98:1183, 2006

42 Discordant risk assessment by Adjuvant Online and the 70-gene signature according to ER status The 70-gene signature is most efficient for ER+ breast cancers to define low and high prognostic risk groups. Almost all ER- patients are classified high risk. M Buyse et al, J Natl Cancer Inst 98:1183, 2006

43 Survival by gene signature and Adjuvant Online status AO low risk (<10% risk of relapse) AO high risk Gene signature high risk N=307 The 70-gene signature can re-stratify clinically high or low risk patients into risk categories. M Buyse et al, J Natl Cancer Inst 98:1183, 2006

44 Prospectively conducted RASTER trial JM Bueno-de-Mesquita et al, Lancet Oncol, 8: ,2007

45 Revised MINDACT Trial Design Node Neg Breast Cancer: Gene Expression Profile and Adjuvant! Risk Determined Good Prognosis Gene Profile Good Prognosis Adjuvant! n-=3300 (55%) Poor Prognosis Gene Profile Poor Prognosis Adjuvant! n-=730 (780) DISCORDANT Gene Profile and Adjuvant! Prognostic Markers N=1920 (32%) RANDOMIZE Hormonal Therapy Alone Chemo or not per Adjuvant! Chemo or not per Gene Expression ChemoRx + Hormonal Therapy

46 MammaPrint Prognosis in Patients 241 women with 1 3 Positive Nodes ER positive or ER negative 53% received adjuvant chemotherapy 64% received adjuvant hormone therapy Median follow-up of 7.8 years Response Good Risk n = 99 Poor Risk n = % CI P Value ~ 8 Year OS 95% 73% % <0.001 ~ 8 Year Likelihood of Distant Metastases as First Event 95% 77% % % Mook, S. 30 th Annual San Antonio Breast Cancer Symposium. December San Antonio, TX. Abstract 50.

47 Conclusions It requires a punch biopsy of the fresh surgically resected cancer. The specimen is placed in RNA later and mailed to Amsterdam for analysis. Report indicates either low risk (10-year OS ~90%) or high risk status for recurrence. Mammaprint calls almost all ER- cancers high risk MammaPrint was developed as a prognostic factor FDA indication: estimate prognosis of node negative, < 5cm cancers in woman < 55 years old. ASCO/NCCN guidelines have not endorsed it yet.

48 Conclusion The 70-gene prognostic signature is technically robust and reproducible. It has shown prognostic value in two published independent validation sets. Gene signature based prognostic categories are partly independent of clinical variable based risk prediction methods. It can define a group of patients with good prognosis among the ER+ patients. It is perfectly reasonable to use the 70-gene signature to define ER+ patients who are at low risk for recurrence and therefore can be safely treated with endocrine therapy alone

49 The Oncotype DX assay uses a genomic approach to predict recurrence risk and response to adjuvant therapy 16 INFORMATIVE CANCER GENES AND 5 REFERENCE GENES Estrogen Proliferation HER2 Invasion Others Reference ER PR Bcl2 SCUBE2 Ki-67 STK15 Survivin Cyclin B1 MYBL2 GRB7 HER2 Stromelysin 3 Cathepsin L2 CD68 GSTM1 BAG1 Beta-actin GAPDH RPLPO GUS TFRC Paik S, et al. N Engl J Med. 2004;351:2817. Risk category Recurrence Score value (0-100) Low < 18 Intermediate High 31 49

50 Tamoxifen benefit and the Oncotype DX assay NSABP B-14 tamoxifen benefit study in node-negative, ER+ patients Randomized Placebo-eligible Tamoxifen-eligible Objective: determine whether the Oncotype DX assay provides information on 1) Prognosis (likelihood of recurrence) 2) Response to tamoxifen (change in likelihood of recurrence with tamoxifen) 3) Both Paik S, et al. N Engl J Med. 2004;351:

51 Oncotype DX clinical validation: NSABP B-14, Distant Recurrence Proportion without dis stant 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: Distant recurrence over time All Patients, n = 668 RS < 18, n = 338 RS 18-30, n = 149 RS 31, n = Years *10-Year distant recurrence comparison between low- and high-risk groups: P < 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%* P < % CI: 23.6%, 37.4% 51 51

52 Many Small Tumors Have Intermediate to High Recurrence Scores 100 p= Recurrence.Score Score % 25% 30% 33% 20% 19% 23% 21% 0 64% 56% 46% 46% N=110 N=318 N=196 N=24 A:<= 1cm B: cm C: cm D:>= 4.1cm 1 cm cm cm > 4 cm Clinical.Tumor.Size Clinical Tumor Size Paik et al. J Clin Oncol

53 B-14 Overall Benefit of Tamoxifen All Patients (N = 645) 85% DRFS % Placebo Tamoxifen Years Paik et al. J Clin Oncol. 2006;24:

54 B-14 benefit of tamoxifen by Recurrence Score risk category DISTANT RECURRENCE-FREE INTERVAL RS < 18 RS RS 31* P = P = P = N Placebo 171 Tamoxifen N Placebo 85 Tamoxifen N Placebo 99 Tamoxifen Years Years Years Interaction P = 0.06 *Results should not be used to indicate that tamoxifen should not be given to the high-risk group RS, Recurrence Score result Paik et al. ASCO 2004; Abstract

55 Oncotype DX clinical validation: NSABP B-20 Objective: To determine the relationship between Recurrence Score value 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:

56 High Recurrence Score result correlates with greater benefit from chemotherapy (NSABP B-20) 1.0 Proportion without dista ant recurrence All patients RS < 18 RS RS 31 Tamoxifen + chemotherapy Tamoxifen Tamoxifen + chemotherapy Tamoxifen Tamoxifen + chemotherapy Tamoxifen Tamoxifen + chemotherapy Tamoxifen N Events PATIENTS WITH HIGH RS 28% absolute benefit from tamoxifen + chemotherapy P = 0.02 P = 0.61 P = 0.39 P < % absolute benefit from tamoxifen + chemotherapy 0.0 RS, Recurrence Score result Years Paik S, et al. J Clin Oncol. 2006;24:

57 Derivation of Samples from ATAC Patients in ATAC 9366 Eligible for TransATAC 5880 Blocks received with sufficient tumour 1856 ER+/PgR+ samples with reportable RS 1308 Combination arm or ER-/PgR Blocks not received or insufficient tumour µm sections unavailable or ER-PgR- 464 or ineligible pathology or insufficient/inadequate quality RNA 84

58 Results: TTDR by Recurrence Score Group Node Negative, Both Treatment Arms n=872 9 yr Proportion Distant Rec currence-free Logrank p<0.001 Low Int High N (%) Events 513 (59%) (26%) (15%) 28 RS Group HR* 95%CI High vs Low 5.2 ( ) Int vs Low 2.5 ( ) 96% 88% 75% Years *Hazard ratio for RS group adjusted for tumour size, grade, age and treatment

59 TransATAC Study: Percent of Distant Recurrence at 9 Yrs, Node Negative All Patients, Low RS (n = 513) All Patients, Int RS (n = 229) All Patients, High RS (n = 130) All Patients (n = 872) Tamoxifen, Low RS (n = 245) Tamoxifen, Int RS (n = 117) Tamoxifen, High RS (n = 70) All Tamoxifen (n = 432) Anastrozole, Low RS (n=268) Anastrozole, Int RS (n=112) Anastrozole, High RS (n = 60) All Anastrozole (n = 440) Events, n Distant Recurrence at 9 Yrs, % Dowsett M, et al. SABCS Abstract 53.

60 TAILORx Study Design 21- G en ER+ and/or PgR+ Node negative HER2 negative Meet standard clinical criteria for chemotherapy in addition to hormonal therapy (N = 10,046) PRE R E G I S T E R e R ec u r r e n ce S co r e A ss R E G I S T E R S P E C I M E N B A N K Secondary Group 1 Recurrence score <11 Primary Study Group Recurrence score Secondary Group 2 Recurrence score > 25 R A N D * Arm A ET Arm B ET Arm C CT + ET Arm D CT + ET a y *Randomization is stratified by tumor size, menopausal status, planned CT, and planned radiation.

61 Data for Oncotype DX in Node-Positive Patients ATAC SWOG 88 61

62 Results: TTDR by Recurrence Score Group Node Positive, Both Treatment Arms n=306 9 yr Proportion Distant Rec currence-free Logrank p<0.001 Low Int High N (%) 160 (52%) 94 (31%) 52 (17%) Events RS Group HR* 95%CI High vs Low 2.7 ( ) Int vs Low 1.8 ( ) 83% 72% 51% Years *Hazard ratio for RS group adjusted for tumour size, grade, age and treatment Dowsett et al., SABCS 2008, Abstract # 53

63 TransATAC Study: Percent of Distant Recurrence at 9 Yrs, Node Positive All Patients, Low RS (n = 160) All Patients, Int RS (n = 94) All Patients, High RS (n = 52) All Patients (n = 306) Tamoxifen, Low RS (n = 79) Tamoxifen, Int RS (n = 47) Tamoxifen, High RS (n = 26) All Tamoxifen (n = 152) Anastrozole, Low RS (n = 81) Anastrozole, Int RS (n = 47) Anastrozole, High RS (n = 26) All Anastrozole (n = 154) Events, n Distant Recurrence at 9 Yrs, % Dowsett M, et al. SABCS Abstract 53.

64 Oncotype DX clinical validation in node-positive patients (SWOG 8814 sub-analysis) SWOG 8814 Postmenopausal, node-positive, ER-positive breast cancer N = 1477 Tamoxifen CAF 6 CAF 6 5 yrs + tamoxifen tamoxifen n = 361 n = 550 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 = 367 (40% of parent trial) Superior disease-free survival and overall survival over 10 years Albain KS, et al. Lancet Oncol. 2010;11(1):

65 SWOG 88-14: High Recurrence Score result predictive of chemotherapy benefit in node-positive patients DFS BY TREATMENT & RS GROUP RS < 18 RS RS Stratified log-rank P = 0.97 at 10 years Stratified log-rank P = 0.48 at 10 years Stratified log-rank P = at 10 years 0.00 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) Years since registration RS, Recurrence Score result Albain KS, et al. Lancet Oncol. 2010;11(1): Years since registration No benefit to CAF over time if low or intermediate RS Years since registration Strong benefit if high RS 65 65

66 Potential Intergroup Trial #2 Node Positive ER+ and/or PgR+ HER2 negative (IHC 0-1+ or FISH [-]) Oncotype DX Assay RS? Randomize Hormonal Rx* vs. Chemotherapy* + Hormonal Rx* RS >? Chemotherapy* + Hormonal Rx* *Choice of therapy at investigator discretion including option of adjuvant chemotherapy trials

67 Prospective Multi-center Study of the Impact of Oncotype DX Assay on Medical Oncologist and Patient Adjuvant Breast Cancer Treatment Selection Lo SS, Mumby PB, Norton J, et al. J Clin Oncol. 2010;28. doi: /jco

68 Change in medical oncologist treatment recommendation by Recurrence Score result Treatment recommendation Pre- Recurrence Score Post- Recurrence Score Number Mean Number Mean (%) RS (%) RS CHT 42 (47.2) (25.8) 29 HT alone 46 (51.7) (67.4) 16 Equipoise 1 (1.1) 19 6 (6.7) 19 CHT, chemo and hormonal therapy; HT, hormonal therapy; equipoise defined as either chemo and hormonal therapy, hormonal therapy alone, or enrollment onto the TAILORx clinical trial; RS, Recurrence Score result Lo SS, Mumby PB, Norton J, et al. J Clin Oncol. 2010;28. doi: /jco

69 Medical oncologist treatment recommendation pre- to post-oncotype DX assay Number of cases (%) CHT HT 20 (22.5) HT CHT 3 (3.4) CHT or HT Equipoise 5 (5.6) Treatment plan did not change 61 (68.5) Total 89 (100) Treatment recommendation changed for 28 (31.5%) cases after results of the Oncotype DX assay were known The most common change was recommendation from CHT to HT (22.5% of cases) Lo SS, Mumby PB, Norton J, et al. J Clin Oncol. 2010;28. doi: /jco

70 Stage I Breast Cancer A 39-year-old woman presents to see her medical oncology after she underwent a left segmental mastectomy and later skin-sparing mastectomy and SLNB. There is a 8 mm breast primary. There is extensive DCIS. One SLN was negative for metastatic disease. She does not have any serious co-morbidities. Pathologic Findings: Histology: Invasive ductal carcinoma, grade 2-3 ER: 70% cells positive PR: 20% cells positive HER-2: 0 IHC LVI: No ONCOTYPE-DX Recurrence score 59!! (35%)

71 Stage II Breast Cancer A 45-year-old woman presents to see her medical oncology after she underwent a right mastectomy and SLNB. There is a 2.2 mm breast primary. One SLN was negative for metastatic disease. She does not have any serious co- morbidities. Pathologic Findings: Histology: Invasive ductal carcinoma, grade 2 ER: 100% cells positive PR: 100% cells positive HER-2: 0 IHC LVI: No ONCOTYPE DX: Recurrence score is 9 (7%).

72 Stage II Breast Cancer A 50-year-old woman presents to see her medical oncology after she underwent a bilateral mastectomy and right SLND and left ALND. There is a right 8 mm and left 4 cm breast primaries. None of seven right SLN were positive. Three of 24 left axillary nodes were positive for metastatic disease. She does not have any serious co-morbidities. Pathologic Findings: Histology: Invasive lobular carcinoma, classic, grade 2 ER: 100% cells positive PR: 90% cells positive HER-2: Normal 0 IHC Oncotype-DX Recurrence Score 12

73 Conclusions The Recurrence Score has been validated as a prognostic marker for ER+, node -, early stage breast cancer The Recurrence Score is also predictive of hormonal therapy benefit in this population The Recurrence Score is also predictive of chemotherapy benefit in this population

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76 Concordance of prediction results of 5 different predictors applied to the same 295 cases 500+ genes Despite < 5% overlap in genes, there was 70-80% concordance in assignment of prognosis 21 genes 70 genes 200+ genes C Fan et al., N Engl J Med 355:560, 2006

77 Summary Growing evidence that single genes and multigene tools may help to identify patients who may benefit from an anthracycline and or taxane-regimens; but using HER2 to select patients who should not receive an anthracycline is not endorsed by guidelines yet Explaining the rational and the advantages and the disadvantages for chemotherapy regimens that include anthracyclines and taxanes are an important part of the management of ER+ and HER-2 normal EBC Information from work over the last two decade has begun to challenge the rationale for the use of anthracyclines and taxane in some scenarios and to suggest alternatives, but this evidence is still not definitive

78 Anthracyclines and taxanes current backbone of adjuvant chemotherapy for patients with most patients with early breast cancer Recent studies suggest that different breast cancer subtypes respond differentially to cytotoxic treatment More research needed on alternative methods to select patients for chemotherapy More research needed on alternative nonchemotherapy therapies for patients with ER+, HER- 2 normal EBC Are there any markers that will identify who will benefit from therapy?

79