ACOSOG Z1101/ACRIN 6694: Preoperative MRI to select patients for breast conserving therapy

1. 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

2. 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

3. Tumor subtype and local recurrence rate following BCT Nguyen et al, JCO 2008

4. 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.

5. 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 Breast Conserving Surgery • Endpoints of interest: • . local recurrence rates • . re-excision rates ACOSOG Z1101 Phase III trial

6. Trial endpoints • Primary • 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

7. 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

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

9. 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

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

12. 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

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

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

15. 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

16. Inclusion/Exclusion Criteria • Inclusion: • Stage I-IIIA breast cancer • IncludeStage 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

17. 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

18. 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

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

20. Correlatives • Cost analysis • 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

21. thank you

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

23. 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

24. 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

25. 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

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

27. Background • Preoperative Staging • Goal • 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