8/8/2011. PONDERing the Need to TAILOR Adjuvant Chemotherapy in ER+ Node Positive Breast Cancer. Overview

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1 Overview PONDERing the Need to TAILOR Adjuvant in ER+ Node Positive Breast Cancer Jennifer K. Litton, M.D. Assistant Professor The University of Texas M. D. Anderson Cancer Center Using multigene assay tests to help with treatment planning for women with estrogen receptor (ER) positive, node negative breast cancer Trials: TAILORx and MINDACT 21-Gene Recurrence Assay for women with ER-positive node positive disease The RESPONDER trial 21-Gene Recurrence Score (RS) Assay 16 Cancer and 5 Reference Genes From 3 Studies PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2 INVASION Stromelysin 3 Cathepsin L2 HER2 GRB7 HER2 ESTROGEN ER PR Bcl2 SCUBE2 GSTM1 CD68 BAG1 REFERENCE Beta-actin GAPDH RPLPO GUS TFRC RS = + 7 x HER2 Group Score - 4 x ER Group Score + 4 x Proliferation Group Score x Invasion Group Score + 5 x CD68-8 x GSTM1-7 x BAG1 Category RS (0-100) Low risk RS <18 Int risk RS 18 and <31 High risk RS 31 Paik et al. N Engl J Med. 2004;351: Clinical Validation: RS as Continuous Predictor Distant Recurrence at 10 40% 35% 30% 25% 20% 15% 10% 5% 0% Low-Risk Group Intermediate- Risk Group My RS is 30. What is the chance of recurrence within 10 years? 95% CI Recurrence Score High-Risk Group 21 Gene RS Clinical Validation: NSABP B-14 Objective: Prospectively validate RS as predictor of distant recurrence in N, ER+ patients Design Multicenter study with prespecified 21-gene assay, algorithm, endpoints, analysis plan Randomized Registered Placebo not eligible oxifen eligible oxifen eligible Paik et al. N Engl J Med. 2004;351: Gene RS Clinical Validation: B-14 Results for the three distinct cohorts identified 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Low Risk (RS <18) n = 338 P <0001 Intermediate Risk (RS 18-30) n = 149 High Risk (RS 31) n = Paik et al. N Engl J Med. 2004;351:

2 Benefit and the 21 Gene RS NSABP B-20 Chemo Benefit Study in N, ER+ Pts Design Objective: Determine the magnitude of the chemo benefit as a function of the 21-gene RS assay Randomized + MF + CMF Objective: Determine whether the 21-gene RS assay provides information on: 1) Prognosis (likelihood of recurrence) 2) Response to tamoxifen (change in likelihood of recurrence with tamoxifen) 3) Both Paik et al. J Clin Oncol. 2006;24: B-20 Results vs + Chemo All 651 Patients 4.4% absolute benefit from tam + chemo 0.2 All Patients Chemo P = 2 Paik et al. J Clin Oncol B-20 Results: vs + Chemo Low RS Low Risk Patients (RS<18) Low Risk Patients TAM + (RS Chemo < 18) TAM Chemo p = High RS High Risk TAM Patients + Chemo (RS 31) TAM + Chemo High Risk Patients (RS>31) Int Risk (RS TAM 18-30) + Chemo TAM Chemo 45 4 p < 01 Int RS Int Risk Patients (RS 18-31) 28% absolute benefit from tam + chemo p = 9 Paik et al. J Clin Oncol Standardized Quantitative 21 Gene RS Assay Recurrence Score in N-, ER+ patients Distant Recurrence at 10 40% 35% 30% 25% 20% 15% 10% 5% 0% Low Risk Group Lower RS s Lower likelihood of recurrence Greater magnitude of TAM benefit Minimal, if any, chemotherapy benefit Intermediate Risk Group Recurrence Score 1) Paik et al NEJM 2004, 2) Habel et al Breast Cancer Research ) Paik et al JCO 2006, 4) Gianni et al JCO 2005 High Risk Group Higher RS s Greater likelihood of recurrence Lower magnitude of TAM benefit Clear chemotherapy benefit TAILORx (PACCT-1 Trial) Sponsored by NCI Administered by ECOG Participating cooperative groups include ECOG, SWOG, NCCTG, CALGB, NCIC, ACOSOG, and NSABP Trial Assigning IndividuaLized Options for Treatment (Rx) (TAILORx) Premise Integration of a molecular profiling test (21 Gene RS) into the clinical decision-making process Potential Implications Further delineate who will receive more benefit than harm from the addition of chemotherapy to adjuvant endocrine therapy Evaluate benefit of chemotherapy where uncertainty still exists about its utility 2

3 Schema: TAILORx Node-Neg, ER-Pos Breast Cancer Gene-expression based profiles used were the 70-gene good-versus-poor outcome model developed by van de Vijver et al. and van't Veer et al. Register Specimen banking Oncotype DX Assay RS <10 Hormone Therapy Registry RS Randomize Hormone Rx vs + Hormone Rx Primary study group RS >25 + Hormone Rx van de Vijver MJ, He YD, van 't Veer LJ, et al. N Engl J Med 2002;347: MINDACT MINDACT = Microarray in Node Negative & 1 to 3 positive lymph node positive Disease may avoid The first project under the TRANSBIG network Aim: to prospectively validate the 70 gene signature and possibly reduce adjuvant chemotherapy administration Starting date: January 2007 (1st patient: February 2007) EORTC BIG 3-04 trial MINDACT Trial Design 6,000 Node - & 1-3 N+ women 55% N=3300 pathological and 70-gene both HIGH risk Evaluate Pathological risk and 70-gene signature risk Discordant cases Clin-Path HIGH 70-gene LOW Clin-Path LOW 70-gene HIGH N=1920 Use Clin-Path risk to decide 32% R-T pathological and 70-gene both LOW risk Use 70-gene risk to decide 13% N=780 Potential CT sparing in 10-15% 15% pts Endocrine therapy EORTC BIG 3-04 trial MINDACT Trial Design 6,000 Node - & 1-3 N+ women N=3300 pathological and 70- gene both HIGH risk ± 4000 patients R-C Evaluate Pathological risk and 70-gene signature risk 55% Use Clin-Path risk to decide If CT N= N+ women Potential impact of MINDACT in breast cancer management 32% 13% Discordant cases Clin-Path HIGH 70-gene LOW Clin-Path LOW 70-gene HIGH R-T pathological and 70- gene both LOW risk Use 70-gene risk to decide Endocrine therapy ± 3500 patients N=780 No CT, only HT Reduction of the proportion of women receiving unnecessary chemotherapy Conversion of microarray test into a cheaper, more user- friendly prognostic tool Discovery of gene signatures predicting for greater efficacy of endocrine therapy and/or chemotherapy Discovery of new drug targets Refinement in prognosis / prediction of treatment efficacy through proteomics Anthracycline- based Taxane-based R-E Sequence 2y 5y Letrozole 7yrs Letrozole 3

4 S1007: A Phase III, Randomized Clinical Trial of Standard Adjuvant Endocrine Therapy +/- in Patients with 1-3 Positive Nodes, Hormone Receptor-Positive and HER2-Negative Breast Cancer with Recurrence Score of 25 or Less Rationale for Approach and Trial Design SWOG 8814 Postmenopausal patients with Node+ and HR+ breast cancer N=1558 PI: Ana M. Gonzalez-Angulo, M.D. oxifen CAF + CAF Albain et al, Lancet Oncol2010 Rationale for Approach and Trial Design SWOG 8814 Rationale for Approach and Trial Design SWOG 8814 Patients with RS 25 Patients with by RS Albain et al, Lancet Oncol2010 Primary Objective To determine the effect of chemotherapy in patients with node positive breast cancer who do not have high RS by 21 Gene RS. Patients with 1-3 positive nodes, and HR+ and HER2-breast cancer with RS 25 DFS for patients treated with chemotherapy compared to no chemotherapy and dependence on the magnitude of RS. Inclusion Criteria Histologically confirmed diagnosis of node positive (1-3 positive nodes) Invasive breast carcinoma with positive ER or PR and HER2-negative RS of equal or less than 25 (after rounding to the nearest integer value) Determine the optimal cutpoint for recommending chemotherapy or not. 4

5 Node-positive (1-3 nodes) HR-positive and HER2-negative breast cancer (N= 8,800) Patients consent to study-sponsored sponsored RS testing, discussion of potential trials, tumor tissue submission and linkage to cancer registry data RS > 25 (N= 3,800) Discuss alternative trials for high risk patients STEP 1 REGISTRATION Tumor tissue submission for RS RECURRENCE SCORE RS < 25 N= 5,600 Physician and patients discuss randomization knowing the RS Refuse N= 1,600 Record chosen therapy and followed for vital status through cancer registry Accept (N= 600) RS already Available Physician and patients discuss randomization knowing the RS STEP 2 REGISTRATION RANDOMIZATION STEP 2 REGISTRATION/ RANDOMIZATION N= 4,000 Randomization stratified by 1. RS 0-13 vs Menopausal status 3. Axillary node dissection vs. Sentinel node biopsy N= 2,000 ; appropriate endocrine therapy N= 2,000 No ; appropriate endocrine therapy Secondary Objectives OS, DDFS, LDFI by receipt of chemotherapy or not and its interaction with RS. Toxicity Other molecular assays (PAM50 ROR) Impact of management with 21 Gene RS on patient-reported anxiety Impact of 21 Gene RS on the initial management cost Patient-reported utilities (QOL) for those randomized to chemotherapy vs. not Estimate the cost-effectiveness of management with 21 Gene RS vs. usual care Role of other assays as predictors of DFS, DDFS and LDFI for patients randomized to chemotherapy vs not Impact of treatment with chemotherapy versus not on patient-reported fatigue and cognitive concerns Impact of management with 21 Gene RS on patient-reported decision conflict, perceptions regarding 21 Gene RS testing, and survivor concerns prior to screening, after disclosure of test results, and during the randomized trial Endocrine Therapy Second Generation Regimens Third Generation Regimens Premenopausal Patients Postmenopausal Patients Correlative Studies Conclusions Tissue Collections Tumor Block Positive Node Negative Node Blood PAM50 Other planned prognostic/predictive scores and pharmacogenomic studies The 21-Gene Recurrence score can be an excellent tool for determining usefulness of chemotherapy in patients with ER+, Node negative tumors but intermediate scores remain clinically challenging TAILORx trial There is retrospective data that it also may be helpful with determining usefulness of chemotherapy for ER+, 1-3 positive nodes MINDACT RESPONDER trial 5

6 Thank you! 6