ACRIN Breast Committee

ACRIN Breast CommitteeFall Meeting 2010

6657 Extension-CONTRAST-ENHANCED BREAST MRI and MRS FOR EVALUATION OF PATIENTS UNDERGOING NEOADJUVANT TREATMENT FOR

LOCALLY ADVANCED BREAST CANCER

Nola Hylton ,PhDConstantine Gatsonis, PhD

Pat Bolan, PhD6657 Trial Team

ACRIN Breast Committee

ACRIN Breast Committee

ACRIN 6657 Trial Extension

Surgery

Anthracycline TaxaneClinicalStudy

MRI/MRS 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

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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

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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

Quality Control Phantom Scans

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Vegetable oil

40 mm ø sphere w/ 1 mM PCho

20 mm voxel

2 liter bottle

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Subject MRS Data Status

• 112 subjects as of 9/15

• Status is per-subject • both MR1 and MR2 must

be good

• No cho: • low snr (1.5T), difficult

voxel placements, too fatty

• No data• Some lost• Some not acq’d: why?

Good (32)

Pending Analysis

(9)

Pending Data (13)

withdrew / ineligible (9)

acquisition error (7)

no cho (20)

no data acquired /

submitted (22)

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Example: Good quality

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Example: No choline

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Example: Acquisition error

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Example: Analysis Pending

Choline peak is over-fit

ACRIN Breast Committee

MRS Data Quality, per-subject by Quartile

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Q1 Q2 Q3 Q4

no choline

acq. error

Good

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MRS Data by Field Strength

1.5T 3T

# subjects 96 (86%) 16 (14%)

Good data rate 48% 89%

Acq. error rate 14% 0%

No choline rate 38% 11%

ACRIN Breast Committee

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

6657 MRS Summary

ACRIN Breast Committee

ACRIN Breast CommitteeFall Meeting 2010

6693 MR Imaging Biomarkers for Assessment of Breast Cancer Response to Neoadjuvant Treatment

Nola Hylton ,PhDMark Rosen, MD, PhD

Eunhee Kim, PhDPat Bolan, PhD

Savannah Partridge, PhD6657 Trial Team

ACRIN Breast Committee

ACRIN Breast Committee

ISPY-2 Adaptive Trial Design

• Target accrual: 800 patients over 4 years, 20 sites• ISPY-2 opened in March 2010; 4 sites open (~15 patients enrolled)

S

U

R

G

E

R

Y

Tissue

ON

STUDY

MRIBiopsy

Blood DrawMUGA/ECHO

CT/PET

Screening

RANDOM

IZE

Consent #2Treatment Consent

Paclitaxel* + Investigational Agent A

(12 weekly cycles)AC

(4 cycles)

Paclitaxel *(12 weekly

cycles)

AC(4 cycles)

Paclitaxel* +Investigational Agent B

(12 weekly cycles)AC

(4 cycles)

MRIBiopsy

Blood Draw

MRIBlood Draw

MRIBlood Draw

* HER2 positive participants will also receive Trastuzumab. An investigational agent may be used instead of Trastuzumab.

ACRIN Breast Committee

• 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

Overall Objective for ACRIN 6693

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

Cancer Imaging. 2006; 6(1): 135–143.

ACRIN Breast Committee

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

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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. Pickles et al. Magn Reson Img 2006; 24:843–847. 2. Sharma et al. NMR Biomed 2008; 22(1):104-13. 3. Iacconi et al. Eur Radiol 2010; 20(2):303-8.

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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 DWI ADC

ACRIN Breast Committee

Recent Findings UW/SCCA

• Significant increases in ADC observed over the course of chemotherapy (p<0.05, pre-post)

• Serial tumor ADC histograms in a responding patient

ADC (x10-3mm2/s)

Pre-treatment

Mid-treatment

Post-treatment

ACRIN Breast Committee

Recent Findings UW/SCCA

• Baseline ADCmin lower in pCR patients (p=0.038)

• Change in ADCmin mid-treatment greater in pCR patients (p=0.044)

Baseline ADCmin by Path Response

0

0.2

0.4

0.6

0.8

1

1.2

ADCmin pre

AD

C

pCR ResidualDisease

*

Change in ADCmin

-0.6

-0.4

-0.2

0

0.2

0.4

0.6

0.8

0 1 2

Treatment Timepoint

pCRResidual

*

AD

C (x

10-3 m

m2/s

)

Presented at the ISMRM Workshop on Improving Cancer Treatment with Advanced MR, Santa Cruz, CA, Sept. 20, 2010.

ACRIN Breast Committee

•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

Status of ACRIN 6693