ACRIN Breast Committee
ACRIN Breast CommitteeFall Meeting 2010
6657 CONTRAST-ENHANCED BREAST MRI FOR EVALUATION OF PATIENTS UNDERGOING NEOADJUVANT TREATMENT FOR LOCALLY
ADVANCED BREAST CANCER
Nola Hylton, PhDJeffrey Blume, PhD6657 Trial Team
ACRIN Breast Committee
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 150007/150012, ACRIN 6657, CBIIT,
InterSPORE)
ACRIN Breast Committee
I-SPY-1 SCHEMANeoadjuvant Chemotherapy for Breast Cancer
• Patients recruited and enrolled through CALGB 150007 (single consent)Patients recruited and enrolled through CALGB 150007 (single consent)
• Eligibility: women with locally-advanced breast cancer (≥3 cm tumors) Eligibility: women with locally-advanced breast cancer (≥3 cm tumors)
receiving neoadjuvant chemotherapyreceiving neoadjuvant chemotherapy
• MRI’s and core biopsies at multiple time-points during treatmenMRI’s and core biopsies at multiple time-points during treatmentt
• Original target accrual: 244 patientsOriginal target accrual: 244 patients
Surgery
Anthracycline TaxaneClinicalStudy
MRI MRI MRI MRI
Core biopsy
Core biopsy
ACRIN Breast Committee
Multi-parametric MR imaging markers (ADC, SER, tCho) for measuring response to targeted agents
ACRIN ACRIN 66936693
(I-SPY 2)(I-SPY 2)
ACRIN ACRIN 66936693
(I-SPY 2)(I-SPY 2)I-SPY 2
T + novel agent
Choline (tCho) measured by MRS for early prediction of response
ACRIN ACRIN 6657 6657
ExtensionExtension
ACRIN ACRIN 6657 6657
ExtensionExtension
Contrast enhanced breast MRI for measuring response and predicting 3-yr RFS
ACRIN ACRIN 6657 6657
OriginalOriginal
ACRIN ACRIN 6657 6657
OriginalOriginal
I-SPY 1Standard AC-
T
Progression of imaging studies
2002
2007
2010
ACRIN Breast Committee
SURGERY
Anthracycline TaxaneClinicalStudy
MRI MRI MRI MRI
Core biopsy
Core biopsy
Can MRI predict disease-free survival following treatment?
3-YR DFS
Primary Imaging Question:
ACRIN 6657 Imaging Questions
ACRIN Breast Committee
SURGERY
Anthracycline TaxaneClinicalStudy
MRI MRI MRI MRI
Core biopsy
Core biopsy
Can MRI provide early prediction of response to treatment?
INTERMEDIATE ENDPOINTS Clinical Response, pCR, RCBSecondary
Imaging Question:
ACRIN 6657 Imaging Questions
ACRIN Breast Committee
ACRIN 6657 Imaging Protocol
• Eligibility: I-SPY enrollment; women with ≥ 3 cm invasive Eligibility: I-SPY enrollment; women with ≥ 3 cm invasive
breast cancer receiving anthracycline-cyclophosphamide breast cancer receiving anthracycline-cyclophosphamide
(AC) chemotherapy followed by a taxane (T)(AC) chemotherapy followed by a taxane (T)
• Four MRI exams: baseline, after 1 cycle AC, between AC Four MRI exams: baseline, after 1 cycle AC, between AC
and T, following T before surgeryand T, following T before surgery
• MRI protocol: MRI protocol:
unilateral, sagittal, scan of symptomatic breastunilateral, sagittal, scan of symptomatic breast
2D, fat-suppressed,T2-weighted fast spin echo sequence2D, fat-suppressed,T2-weighted fast spin echo sequence
3-time point contrast-enhanced 3D, fat-suppressed, T1-weighted series3-time point contrast-enhanced 3D, fat-suppressed, T1-weighted series
ACRIN Breast Committee
Status – 6657 Original
• 237 patients enrolled May 2002 - March 2006 at 9 237 patients enrolled May 2002 - March 2006 at 9
institutionsinstitutions
• 3-year recurrence-free survival (RFS) follow-up 3-year recurrence-free survival (RFS) follow-up
completed in August 2009completed in August 2009
• Analysis Set = 216 Analysis Set = 216 (7 ineligible; 14 with incomplete (7 ineligible; 14 with incomplete
imaging)imaging)
• Preliminary analysis of secondary question:Preliminary analysis of secondary question:– Correlation of imaging and residual disease size after Correlation of imaging and residual disease size after
surgerysurgery
– Early prediction of response (after 1 cycle of AC)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 Variable pCR = 0/1
OR p-value
Clin Size2/Clin Size1 1.07 0.924
Log(LD2/LD1) 8.67 0.054
Log(Vol2/Vol1) 19.81 <0.0001
Peak SER2/Peak SER1 0.72 0.650
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 LNsDiameter of largest metastasis (mm)
Area (cm x cm)
RCB = 1.4 x [fcell x (d1 d2)] 0.17 + [dmet x (1 - (1 - ) LN ) / ] 0.17
Symmans et al. J Clin Oncol. 2007 Oct 1;25(28):4414-22.
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 0 pCR, no invasive tumor
– RCB I scattered residual disease
– RCB II moderate tumor burden
– RCB III significant tumor burden
Symmans et al JCO 2007Symmans 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:
− 1st paper submission (early prediction of response) November 2010
− 2nd 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 TeamACRIN 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 NetworkI-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
