ACOSOG Z1101/ACRIN 6694: Preoperative MRI to select patients for breast conserving therapy Isabelle Bedrosian, MD Associate Professor Department of Surgical Oncology University of Texas M.D. Anderson Cancer Center

Is MRI detected cancer clinically significant? Clinical experience Using mammography alone, <10% of patients experience local recurrence after BCT Preoperative MRI 15-20% of pts have additional cancer not seen on mammogram that necessitates mastectomy In many patients MRI detected disease must not be clinically significant/or appropriately treated with adjuvant RT/endocrine therapy/chemotherapy

Tumor subtype and local recurrence rate following BCT ER or PR+, her-2 – (luminal A) ER or PR +, her-2 + (luminal B) ER/PR -, her-2 + (her-2) ER/PR/ Her-2 – (basal) LR rate at 5 years 0.8% 1.5% 8.4% 7.1% Nguyen et al, JCO 2008

Hypothesis Preoperative breast MRI improves staging and selection of patients with ER/PR/Her-2 negative and Her-2 amplified tumors for BCT, thus lowering rates of local recurrence.

ACOSOG Z1101 Phase III trial Stage I-II patients eligible for BCT based on clinical exam/ mammogram/US Breast MRI No Breast MRI Based on MRI findings, not eligible for BCS Based on MRI findings, BCS can be attempted Breast Conserving Surgery Mastectomy Endpoints of interest: . local recurrence rates . re-excision rates

Trial endpoints Primary Secondary LR rates at 5 years between the MRI and no MRI arm Secondary Rates of re-excision, including conversion to mastectomy Rates of re-excision in women undergoing MRI guided localization False positive MRI rates Time to local recurrence Overall survival Contralateral breast cancer rates

Eligibility criteria Women with her-2 positive breast cancer OR Triple negative breast cancer Stage I-II, unilateral cancer No previous breast cancer history No preoperative chemotherapy No plans for partial breast irradiation following lumpectomy No BRCA carriers

Correlatives Medical care costs associated with preoperative breast MRI PI: Tina Yen and Tina Shih Molecular predictors of loco-regional recurrence PI: Funda Meric-Bernstam Relationship between host response, extent of disease and recurrence in ER negative breast cancer PI: Brian Czerniecki QOL PI: Kathy Yao

Status Concept has been accepted by ACOSOG and ACRIN ACOSOG-ACRIN collaboration in place Concept submitted to CTEP Informally reviewed: no survival endpoint, therefore, formal review deferred Concept submitted to DCP Review pending ACOSOG-ACRIN trial development group being put together

MRI Controversy Persists….. Does improved preoperative staging achieved by using MRI translate into lower local recurrences rates in patients treated with breast conserving therapy?

Is the MRI detected disease clinically significant? >95% of patients can be appropriately selected for BCT by diagnostic mammogram and clinical evaluation LR at 10 yrs after BCT and adjuvant systemic therapy: 7-10% There has never been a randomized prospective trial to answer this question

Proposed Multi-Center Trial Stage I-IIIA breast cancer patients eligible for BCT based on mammogram/US Mastectomy BCT Successful BCT Unsuccessful BCT LR Rates @ 5 years MRI No MRI Randomize

MRI working group Brian Czerniecki MD, PhD Judy Boughey, MD University of Pennsylvania Judy Boughey, MD Mayo Clinic, MN Kari Rosenkranz, MD Dartmouth Christina Finlayson, MD UCHSC

Proposed Multi-Center Trial Patients to be stratified by ER (?) Age T size institution Anticipate that 15% of patients in the MRI arm will be converted to mastectomy and never have an attempt at BCT LR rates in no MRI arm is projected at 5% at 5 years and in MRI arm would like to see reduced to 2% at 5 years Collaborative effort with ACRIN

Inclusion/Exclusion Criteria Stage I-IIIA breast cancer Include Stage 0? Eligible for BCT based on mammogram And US if routinely used by the institution MRI performed within 60 days of breast cancer diagnosis Exclusion: Patients receiving neoadjuvant chemotherapy Patients who will receive PBI Contraindications to MRI

Tumor subtype and local recurrence rate following BCT Hypothesize that occult MF/MC disease is a function of underlying tumor biology which if left intact (ie no surgery) would increase likelihood of LR event Define groups of women likely to really benefit from preoperative MRI How do we define tumor subtype? Microarray/gene analysis based Constructed from ER/PR/her-2

Statistical considerations Superiority study Total accrual: 1020 patients 561 patients in MRI arm 459 patients in no MRI arm 90% power to detect difference in primary endpoint Accrual estimated at 200 patients/year Total accrual period 4.5 years Total study duration: 8.1 years

ACRIN Collaboration May 2009 Major point of debate ACRIN breast committee approved the general scheme and collaboration with ACOSOG ACRIN working group in development Major point of debate PBI pts

Correlatives Cost analysis HRQOL Compare the costs incurred in the 2 study arms (direct/indirect) HRQOL Fear of recurrence questionnaire Hospital anxiety and depression scale Tissue based correlatives linked to local recurrence Immune based Cellular stress

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MRI in the preoperative staging of breast cancer Size of index tumor-MRI more sensitive than mammogram Identification of multifocal/multicentric disease-MRI more sensitive than mammogram Detection of contralateral breast cancer-MRI more sensitive than mammogram

Impact of MR on LR Retrospective study 121 patients with preoperative MR (group A) vs 225 patients without preoperative MR (group B) Mean follow-up of 40 months LR 1.2% group A vs 6.5% group B Groups not balanced More advanced tumors in group B Discrepancies in patients receiving systemic therapy between the 2 groups Fischer, Eur Radiol, 2004

Impact of MR on LR-2 Retrospective study 756 women with early stage cancer All underwent mammogram 215 also had MRI All underwent BCT No differences in LR or survival rates between the women who had breast MRI and those that did not Limitation- retrospective analysis that does not account for potential biases Patient numbers too small to detect small differences in LR rates between groups Solin, JCO, 2008

Impact of MR on Re-operation COMICE trial (UK) Prospective randomized trial MRI: 816, no MRI: 807 Primary endpoint Reduction in re-operation rates in MRI arm No difference in re-operation rates (18.75% vs. 19.33%) SABCS, 2008

Does MRI lead to too many mastectomies? Mayo series, JCO 2009 Fox Chase Cancer Center, JACS 2009 1.6% 4.6% Bilateral mastectomy as first procedure 19.5% 27.7% Mastectomy as first procedure 38.1 days 56.9 days Time from dx to surgery No MRI MRI

Background Preoperative Staging Goal Extent of disease appropriate selection of patients for BCT perform a single definitive operation appropriate staging of patients and appropriate selection of surgical therapy: minimize LR Extent of disease Size of index tumor Identification of multifocal/multicentric disease Detection of contralateral breast cancer