ACRIN Breast Committee
Fall Meeting 2010
6657 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
150007/150012, ACRIN 6657, CBIIT, InterSPORE)
ACRIN Breast Committee
I-SPY-1 SCHEMA
Neoadjuvant Chemotherapy for Breast Cancer
Anthracycline
Clinical
Study
MRI
Core
biopsy
Taxane
Surgery
MRI
MRI
MRI
Core
biopsy
• Patients recruited and enrolled through CALGB 150007 (single consent)
• Eligibility: women with locally-advanced breast cancer (≥3 cm tumors)
receiving neoadjuvant chemotherapy
• MRI’s and core biopsies at multiple time-points during treatment
• Original target accrual: 244 patients
ACRIN Breast Committee
Progression of imaging studies
ACRIN
6657
Original
2002
ACRIN
6657
Extension
2007
ACRIN
6693
(I-SPY 2)
2010
Contrast enhanced breast MRI for
measuring response and predicting
3-yr RFS
I-SPY 1
Standard AC-T
I-SPY 2
T + novel agent
ACRIN Breast Committee
Choline (tCho) measured by MRS
for early prediction of response
Multi-parametric MR imaging markers
(ADC, SER, tCho) for measuring
response to targeted agents
ACRIN 6657 Imaging Questions
MRI
Core
biopsy
Taxane
Anthracycline
Clinical
Study
MRI
MRI
MRI
S
U
R
G
E
R
Y
Core
biopsy
Primary Imaging
Question:
ACRIN Breast Committee
Can MRI predict
disease-free
survival following
treatment?
3-YR
DFS
ACRIN 6657 Imaging Questions
MRI
Core
biopsy
Taxane
Anthracycline
Clinical
Study
MRI
MRI
MRI
S
U
R
G
E
R
Y
Core
biopsy
Secondary
Imaging
Question:
Can MRI provide
early prediction of
response to
treatment?
ACRIN Breast Committee
INTERMEDIATE ENDPOINTS
Clinical Response, pCR, RCB
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)
• Four MRI exams: baseline, after 1 cycle AC, between AC and T,
following T before surgery
• 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 2002 - March 2006 at 9
institutions
• 3-year recurrence-free survival (RFS) follow-up completed
in August 2009
• Analysis Set = 216 (7 ineligible; 14 with incomplete imaging)
• 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
Radiologist
assessment
• Morphologic Pattern
• Tumor Volume
• Peak Signal Enhancement Ratio (SER)
ACRIN Breast Committee
By computer
analysis
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
0.72
0.650
Peak SER2/Peak SER1
ACRIN Breast Committee
Results from I-SPY 1
Response to Therapy is Associated with
Better Relapse Free Survival
ACRIN Breast Committee
Residual Cancer Burden
PRIMARY
TUMOR
BURDEN
RCB = 1.4
x [fcell
x (d1
d2)] 0.17 + [dmet x (1 - (1 -  ) LN ) / ] 0.17
PRIMARY TUMOR BURDEN
Area (cm x cm)
Area (cm x cm)
% CANCER
CELLULARITY
%
CANCER
CELLULARITY
Symmans et al. J
Clin Oncol. 2007
Oct 1;25(28):441422.
+ AXILLARY NODAL BURDEN
Number of positive LNs
Diameter of largest metastasis (mm)
ACRIN Breast Committee
Residual Cancer Burden
• 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
ACRIN Breast Committee
Symmans et al JCO 2007
Results from I-SPY 1
Survival by Residual Cancer Burden
(RCB) Index
ACRIN Breast Committee
Results from I-SPY 1
pCR is a Better Predictor by Subtype
ACRIN Breast Committee
Summary of Results – 2010
Prediction of Pathologic Response
ACRIN Breast Committee
Summary of Results – 2010
Prediction of RCB and ‘in-breast’ component
ACRIN Breast Committee
Summary of Results – 2010
• 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
ACRIN Breast Committee
Publications
• 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
ACRIN Breast Committee
Additional studies planned
• 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
ACRIN Breast Committee
6657/I-SPY 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
•
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
ACRIN Breast Committee