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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).

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ACRIN Breast Committee

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Acrin breast committee

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 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

Anthracycline

Taxane

ClinicalStudy

Surgery

MRI

MRI

MRI

MRI

Core biopsy

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

2002

ACRIN 6657 Original

Contrast enhanced breast MRI for measuring response and predicting 3-yr RFS

I-SPY 1

Standard AC-T

2007

ACRIN 6657 Extension

Choline (tCho) measured by MRS for early prediction of response

ACRIN 6693

(I-SPY 2)

Multi-parametric MR imaging markers (ADC, SER, tCho) for measuring response to targeted agents

I-SPY 2

T + novel agent

2010


Acrin breast committee

ACRIN 6657 Imaging Questions

SURGERY

Taxane

Anthracycline

ClinicalStudy

3-YR

DFS

MRI

MRI

MRI

MRI

Core biopsy

Core biopsy

Can MRI predict disease-free survival following treatment?

Primary ImagingQuestion:


Acrin breast committee

ACRIN 6657 Imaging Questions

SURGERY

Taxane

Anthracycline

ClinicalStudy

MRI

MRI

MRI

MRI

Core biopsy

Core biopsy

INTERMEDIATE ENDPOINTS

Clinical Response, pCR, RCB

SecondaryImagingQuestion:

Can MRI provide early prediction of response to treatment?


Acrin breast committee

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

  • 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)


    Acrin breast committee

    Results from I-SPY 1

    Response to Therapy is Associated with Better Relapse Free Survival


    Acrin breast committee

    AXILLARY NODAL BURDEN

    +

    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):4414-22.

    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 0pCR, no invasive tumor

      • RCB Iscattered residual disease

      • RCB IImoderate tumor burden

      • RCB IIIsignificant tumor burden

    Symmans et al JCO 2007


    Acrin breast committee

    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


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