ACRIN Breast Committee Fall Meeting CONTRAST-ENHANCED BREAST MRI FOR EVALUATION OF PATIENTS UNDERGOING NEOADJUVANT TREATMENT FOR LOCALLY ADVANCED BREAST CANCER Nola Hylton, PhD Jeffrey Blume, PhD 6657 Trial Team ACRIN Breast Committee

ACRIN 6657 (Original Trial) ACRIN 6657 is evaluating contrast-enhanced MRI for assessing response to neoadjuvant treatment ACRIN 6657 is the imaging component of the larger I-SPY neoadjuvant breast cancer treatment trial (CALGB /150012, ACRIN 6657, CBIIT, InterSPORE)

ACRIN Breast Committee I-SPY-1 SCHEMA Neoadjuvant Chemotherapy for Breast Cancer Patients recruited and enrolled through CALGB (single consent)Patients recruited and enrolled through CALGB (single consent) Eligibility: women with locally-advanced breast cancer (≥3 cm tumors) receiving neoadjuvant chemotherapyEligibility: women with locally-advanced breast cancer (≥3 cm tumors) receiving neoadjuvant chemotherapy MRI’s and core biopsies at multiple time-points during treatmen tMRI’s and core biopsies at multiple time-points during treatmen t Original target accrual: 244 patientsOriginal target accrual: 244 patients Surgery Anthracycline Taxane Clinical Study MRI Core biopsy

ACRIN Breast Committee Multi-parametric MR imaging markers (ADC, SER, tCho) for measuring response to targeted agents ACRIN 6693 (I-SPY 2) ACRIN 6693 (I-SPY 2) I-SPY 2 T + novel agent Choline (tCho) measured by MRS for early prediction of response ACRIN 6657 Extension Contrast enhanced breast MRI for measuring response and predicting 3-yr RFS ACRIN 6657 Original I-SPY 1 Standard AC-T Progression of imaging studies

ACRIN Breast Committee SURGERYSURGERY Anthracycline Taxane Clinical Study MRI Core biopsy Can MRI predict disease-free survival following treatment? 3-YR DFS Primary Imaging Question: ACRIN 6657 Imaging Questions

ACRIN Breast Committee SURGERYSURGERY Anthracycline Taxane Clinical Study MRI Core biopsy Can MRI provide early prediction of response to treatment? INTERMEDIATE ENDPOINTS Clinical Response, pCR, RCB Secondary Imaging Question: ACRIN 6657 Imaging Questions

ACRIN Breast Committee ACRIN 6657 Imaging Protocol Eligibility: I-SPY enrollment; women with ≥ 3 cm invasive breast cancer receiving anthracycline-cyclophosphamide (AC) chemotherapy followed by a taxane (T) Eligibility: I-SPY enrollment; women with ≥ 3 cm invasive breast cancer receiving anthracycline-cyclophosphamide (AC) chemotherapy followed by a taxane (T) Four MRI exams: baseline, after 1 cycle AC, between AC and T, following T before surgery Four MRI exams: baseline, after 1 cycle AC, between AC and T, following T before surgery MRI protocol: MRI protocol:  unilateral, sagittal, scan of symptomatic breast  2D, fat-suppressed,T2-weighted fast spin echo sequence  3-time point contrast-enhanced 3D, fat-suppressed, T1-weighted series

ACRIN Breast Committee Status – 6657 Original 237 patients enrolled May March 2006 at 9 institutions 237 patients enrolled May March 2006 at 9 institutions 3-year recurrence-free survival (RFS) follow-up completed in August year recurrence-free survival (RFS) follow-up completed in August 2009 Analysis Set = 216 (7 ineligible; 14 with incomplete imaging) Analysis Set = 216 (7 ineligible; 14 with incomplete imaging) Preliminary analysis of secondary question: Preliminary analysis of secondary question: – Correlation of imaging and residual disease size after surgery – Early prediction of response (after 1 cycle of AC)

ACRIN Breast Committee MRI Measurements Tumor Longest Diameter Morphologic Pattern Tumor Volume Peak Signal Enhancement Ratio (SER) Radiologist assessment By computer analysis

ACRIN Breast Committee Volume and Peak SER Tumor volume computed based on enhancement thresholds –Sum of all pixels with percent enhancement PE > 70% * and SER > 0.9 Peak SER measured as highest mean value of 8 connected pixels measured over the entire tumor

ACRIN Breast Committee Summary of Results – RSNA 2008 MRI estimates residual disease size better than clinical exam or mammography Of MRI measurements, volume performs better than longest diameter or peak SER In univariate and multivariate models, MRI volume change after 1 cycle of chemotherapy was the only early measurement that predicted clinical response and pCR (2008 analysis) Predictor VariablepCR = 0/1 ORp-value Clin Size2/Clin Size Log(LD2/LD1) Log(Vol2/Vol1)19.81< Peak SER2/Peak SER

ACRIN Breast Committee Response to Therapy is Associated with Better Relapse Free Survival Results from I-SPY 1

ACRIN Breast Committee Residual Cancer Burden Area (cm x cm) % CANCER CELLULARITY PRIMARY TUMOR BURDEN AXILLARY NODAL BURDEN + % CANCER CELLULARITY PRIMARY TUMOR BURDEN Number of positive LNs Diameter of largest metastasis (mm ) Area (cm x cm) RCB = 1.4 x [fcell x  (d1 d2)] [dmet x (1 - (1 -  ) LN ) /  ] 0.17 Symmans et al. J Clin Oncol Oct 1;25(28):

ACRIN Breast Committee Integrates several pathologic features –Lymph node status –Extent of tumor bed –Tumor size –Tumor cellularity Output is continuous or 4 discrete categories –RCB 0pCR, no invasive tumor –RCB Iscattered residual disease –RCB IImoderate tumor burden –RCB IIIsignificant tumor burden Symmans et al JCO 2007 Residual Cancer Burden

ACRIN Breast Committee Survival by Residual Cancer Burden (RCB) Index Results from I-SPY 1

ACRIN Breast Committee pCR is a Better Predictor by Subtype Results from I-SPY 1

ACRIN Breast Committee Prediction of Pathologic Response Summary of Results – 2010

ACRIN Breast Committee Prediction of RCB and ‘in-breast’ component Summary of Results – 2010

ACRIN Breast Committee Analysis of primary question being finalized Prediction of 3-year recurrence-free survival (RFS) Primary question focused on ability of MRI to stratify survival among clinical partial/minimal responders Results from preliminary analysis are promising: −MRI predicts better than mammography or clinical exam −MRI can further stratify partial/minimal responders Summary of Results – 2010

ACRIN Breast Committee Primary and secondary aims: −1 st paper submission (early prediction of response) November 2010 −2 nd paper submission (survival prediction) February 2011 Additional publications planned: −Residual disease correlation with pathology (MMG, MRI) −Morphologic pattern association with response and surgical outcome −Conditional probability of MR response to taxane based on response to AC Publications

ACRIN Breast Committee Comparison of biopsy yield for MRI, US, physical exam Evaluation of MRI prediction among breast cancer subtypes by molecular and genomic signatures Testing of alternative quantitative metrics Additional studies planned

ACRIN Breast Committee 6657/I-SPY Trial Team ACRIN 6657 Trial Team ACRIN 6657 Trial Team N. Hylton, B. Joe, M. Watkins, S. Suzuki, D. Newitt, E. Proctor, UCSF; J. Blume, H. Marques, B. Herman, C. Gatsonis, B. Dunning, ACRIN DMC; M. Rosen, M. Schnall, U Penn; E. Pisano, UNC, E. Morris, MSKCC; W. Bernreuter, UAB; S. Polin, Georgetown; C. Lehman, S. Partridge, U Wash; P. Weatherall, UTSW; G. Newstead, U Chicago; P. Bolan, U Minnesota; B. LeStage, N. Sauers, ACRIN Advocates I-SPY Trial Network I-SPY Trial Network L. Esserman, J. Gray, L Vantveer, UCSF; A. DeMichelle, U Penn; L Carey, C. Perou, UNC, L. Montgomery, C. Hudis, MSKCC; H. Krontiras, UAB; M. Liu, Georgetown; J. Gralow, U Wash; D. Tripathy, UTSW; F Olopade, U Chicago; D. Yee, U Minnesota; S. Madhavan, K. Buetow, E. Petricoin NCICB