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
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

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. 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

6. 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

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: Funda Meric-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. 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

14. 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

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
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

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 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

20. 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

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-MRI more sensitive than mammogram
Detection of contralateral breast cancer-MRI more 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 %)
SABCS, 2008

26. 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

27. 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