1. 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

2. ACRIN 6657 Trial Extension Surgery Anthracycline Taxane Clinical Study 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 1 H MR spectroscopy to the imaging protocol; testing MRS [choline] as a marker of early response Short term endpoint used (pCR)

3. ACRIN Breast Committee 6657 Extension Aims New aims are testing total choline concentration [tCho] measured by single voxel 1 H 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

4. 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

5. ACRIN Breast Committee 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

6. ACRIN Breast Committee Vegetable oil 40 mm ø sphere w/ 1 mM PCho 20 mm voxel 2 liter bottle

7. ACRIN Breast Committee 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)

8. ACRIN Breast Committee Example: Good quality

9. ACRIN Breast Committee Example: No choline

10. ACRIN Breast Committee Example: Acquisition error

11. ACRIN Breast Committee Example: Analysis Pending Choline peak is over-fit

12. ACRIN Breast Committee MRS Data Quality, per-subject by Quartile 0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100% Q1Q2Q3Q4 no choline acq. error Good

13. ACRIN Breast Committee MRS Data by Field Strength 1.5T3T # subjects96 (86%)16 (14%) Good data rate48%89% Acq. error rate14%0% No choline rate38%11%

14. 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

15. 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

16. 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) SURGERYSURGERY Tissue ONSTUDYONSTUDY MRI Biopsy Blood Draw MUGA/ECHO CT/PET Screening RANDOMIZERANDOMIZE Consent #2 Treatment 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) MRI Biopsy Blood Draw MRI Blood Draw MRI Blood Draw *HER2 positive participants will also receive Trastuzumab. An investigational agent may be used instead of Trastuzumab.

17. ACRIN Breast Committee E valuate 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

18. 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.

19. 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

20. 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.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.

21. 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 DCEDWI ADC

22. 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 -3 mm 2 /s) Pre-treatment Mid-treatment Post-treatment

23. ACRIN Breast Committee Recent Findings UW/SCCA Baseline ADC min lower in pCR patients (p=0.038) Change in ADC min mid- treatment greater in pCR patients (p=0.044) Baseline ADC min by Path Response 0 0.2 0.4 0.6 0.8 1 1.2 ADCmin pre ADC pCR Residual Disease * Change in ADC min -0.6 -0.4 -0.2 0 0.2 0.4 0.6 0.8 012 Treatment Timepoint pCR Residual *  ADC (x10 -3 mm 2 /s) Presented at the ISMRM Workshop on Improving Cancer Treatment with Advanced MR, Santa Cruz, CA, Sept. 20, 2010.

24. 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