ACRIN Breast Committee
Fall Meeting 2010
6657 Extension-CONTRAST-ENHANCED BREAST MRI and MRS FOR EVALUATION OF
PATIENTS UNDERGOING NEOADJUVANT TREATMENT FOR LOCALLY ADVANCED BREAST
CANCER
Nola Hylton ,PhD
Constantine Gatsonis, PhD
Pat Bolan, PhD
6657 Trial Team
ACRIN Breast Committee
ACRIN 6657 Trial Extension
Clinical
Study
Anthracycline
MRI/MRS
Taxane
Surgery
MRI/MRS
MRI/MRS
Core
biopsy
• Both CALGB 150007 and ACRIN 6657 were amended and re-opened in
September 2007; additional target accrual of 140 patients
• Same treatment paradigm as in original trials
• ACRIN 6657 amended to add single voxel 1H MR spectroscopy to the imaging
protocol; testing MRS [choline] as a marker of early response
• Short term endpoint used (pCR)
ACRIN Breast Committee
6657 Extension Aims
• New aims are testing total choline concentration [tCho]
measured by single voxel 1H MR spectroscopy following
1 cycle of chemotherapy for distinguishing responsive
and non-responsive tumors. Includes:

Reproducibility testing

1.5 T versus 3.0 T comparison

Acute (20-28 hour) versus persistent (48-96 hours) post treatment time
point comparison
ACRIN Breast Committee
6657 Extension Aims
• Accrual to-date:
 114 patients accrued
 96 enrolled at 1.5 T
 16 enrolled at 3.0 T
 44 enrolled at 20-28 hr
 26 enrolled at 48-96 hr
 28 enrolled outside of protocol time points
 14 – time point data missing
• Analysis to-date
ACRIN Breast Committee
Quality Control Phantom Scans
Design (ISMRM 2008 poster)
• Standard phantoms
• Entry and Weekly scanning
Motivation
• Set entry threshold
• Monitor site consistency
• Acquire data for retrospective analysis
- measurement precision (SE)
- compare fitting methods
- detection thresholds
- identify technical problems
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2 liter bottle
Vegetable oil
40 mm ø sphere w/
1 mM PCho
20 mm
voxel
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Subject MRS Data Status
withdrew /
ineligible (9)
acquisition
error (7)
Pending
Data (13)
• 112 subjects as of 9/15
• Status is per-subject
no cho (20)
• both MR1 and MR2 must be
good
• No cho:
Pending
Analysis
(9)
• low snr (1.5T), difficult
voxel placements, too fatty
no data acquired
/ submitted (22)
Good (32)
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• No data
• Some lost
• Some not acq’d: why?
Example: Good quality
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Example: No choline
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Example: Acquisition error
ACRIN Breast Committee
Example: Analysis Pending
Choline
peak is
over-fit
ACRIN Breast Committee
MRS Data Quality, per-subject by Quartile
100%
90%
80%
70%
60%
no choline
50%
acq. error
40%
Good
30%
20%
10%
0%
Q1
ACRIN Breast Committee
Q2
Q3
Q4
MRS Data by Field Strength
1.5T
3T
96 (86%)
16 (14%)
Good data rate
48%
89%
Acq. error rate
14%
0%
No choline rate
38%
11%
# subjects
ACRIN Breast Committee
6657 MRS Summary
Accrual ongoing
Early termination?
• Competing with ISPY2
• Stopping pt analysis:
• need 43 subjects with a drop in [tCho] and final path
• have 14 responders, 9 non-responders by [tCho] with path
MRS Analysis work
• Better fitting (SVD, magnitude fitting, detection
thresholds)
• Voxel placement grading
ACRIN Breast Committee
ACRIN Breast Committee
Fall Meeting 2010
6693 MR Imaging Biomarkers for Assessment of Breast Cancer Response to
Neoadjuvant Treatment
Nola Hylton ,PhD
Mark Rosen, MD, PhD
Eunhee Kim, PhD
Pat Bolan, PhD
Savannah Partridge, PhD
6657 Trial Team
ACRIN Breast Committee
ISPY-2 Adaptive Trial Design
AC
(4 cycles)
Paclitaxel *
(12 weekly cycles)
Screening
R
A
N
D
O
M
I
Z
E
O
N
S
T
U
D
Y
MRI
Biopsy
Blood Draw
MUGA/ECHO
CT/PET
Paclitaxel* +
Investigational Agent A
(12 weekly cycles)
AC
(4 cycles)
Paclitaxel* +
Investigational Agent B
(12 weekly cycles)
AC
(4 cycles)
MRI
Biopsy
Blood Draw
Consent #2
Treatment Consent
MRI
Blood Draw
S
U
R
G
E
R
Y
MRI
Blood Draw
* HER2 positive participants will also receive Trastuzumab. An
investigational agent may be used instead of Trastuzumab.
• Target accrual: 800 patients over 4 years, 20 sites
• ISPY-2 opened in March 2010; 4 sites open (~15 patients enrolled)
ACRIN Breast Committee
Tissue
Overall Objective for ACRIN 6693
• Evaluate tumor apparent diffusion coefficient (ADC),
alone and in combination with SER as a marker of
early response
• Multi-parametric MRI biomarkers will be evaluated in
the setting of the ISPY-2 adaptive neoadjuvant breast
cancer trial testing targeted agents in combination with
paclitaxel
ACRIN Breast Committee
Diffusion-Weighted MRI (DWI)
• Measures the mobility of
water diffusing in tissue
• Sensitive to restriction of
water motion
– cell density/cellularity
– membrane integrity,
microstructure
• Reduced diffusion in tumors
• Sensitive to cell death and
necrosis associated with
response to treatment
ACRIN Breast Committee
Cancer Imaging. 2006; 6(1): 135–143.
DWI Studies in ACRIN 6657
• DWI optional in 6657
• DWI data collected:
– Original 6657: 16 cases with visit 1 and 2
– Extension: 26 cases with visit 1 and 2
• Sample sizes too small for meaningful
analysis
– original and extension treated separately
because of differing visit 2 timepoints
ACRIN Breast Committee
Prior Breast DWI Studies
• ADC increases over the course of neoadjuvant
chemotherapy in breast tumors [1, 2]
• ADC change occurs earlier than changes in size
(volume or LD) [1,2]
• Predictive value of ADC
– Baseline ADC lower in clinical responders [3]
– Change in ADC significantly greater in responders [2,3]
1.
2.
3.
Pickles et al. Magn Reson Img 2006; 24:843–847.
Sharma et al. NMR Biomed 2008; 22(1):104-13.
Iacconi et al. Eur Radiol 2010; 20(2):303-8.
ACRIN Breast Committee
Recent Findings UW/SCCA
• 17 patients with invasive breast cancer
• Neoadjuvant treatment
– Metronomic - weekly doxorubicin/daily
cyclophosphamide followed by paclitaxel
• Imaged with DWI
– Prior to treatment, mid-, post-treatment
DCE
ACRIN Breast Committee
DWI
ADC
Recent Findings UW/SCCA
• Significant increases in ADC observed over the
course of chemotherapy (p<0.05, pre-post)
Pre-treatment
• Serial tumor
ADC histograms
in a responding
patient
Mid-treatment
Post-treatment
ADC (x10-3mm2/s)
ACRIN Breast Committee
Recent Findings UW/SCCA
• Baseline ADCmin lower in • Change in ADCmin midpCR patients (p=0.038)
treatment greater in pCR
patients (p=0.044)
Change in ADCmin
Baseline ADCmin by Path
Response
0.6
1
0.4
0.4
*
0.2
*
0.2
mm2/s)
0.6
ADC (x10-3
1.2
0.8
ADC
0.8
0
0
1
-0.4
0
ADCminResidual
pre
pCR
Disease
-0.6
Treatment Timepoint
Presented at the ISMRM Workshop on Improving Cancer Treatment with
Advanced MR, Santa Cruz, CA, Sept. 20, 2010.
ACRIN Breast Committee
2
pCR
Residual
-0.2
Status of ACRIN 6693
• approved by ACRIN Steering Committee – Sept 2009
• Protocol submitted to CTEP – June 2010
• Protocol concept disapproved by CTEP – August 2010
• Revisions and re-submission planned – November 2010
– More clearly defined objectives for evaluating ADC, integration with
ISPY-2, results from ISPY-1
ACRIN Breast Committee