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

conserving therapyIsabelle Bedrosian, MD

Associate ProfessorDepartment of Surgical OncologyUniversity of Texas M.D. Anderson

Cancer Center

Is MRI detected cancer clinically significant?

Preoperative MRI

15-20% of pts have additional cancer not seen on mammogram that necessitates mastectomy

Clinical experience

Using mammography alone, <10% of patients experience local recurrence after BCT

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.

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: 1 . local recurrence rates

2 . re-excision rates

ACOSOG Z1101 Phase III trial

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

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 TrialStage I-IIIA breast cancer patients eligible for BCT based on mammogram/US

Mastectomy

BCT

Successful BCT

Unsuccessful BCT

LR Rates@ 5 years

Mastectomy

BCT

Successful BCT

Unsuccessful BCT

LR Rates@ 5 years

Mastectomy

MRI No MRI

Randomize

MRI working group

• Brian Czerniecki MD, PhD– 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

• Inclusion:– 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– 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– 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

thank you

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 groupsFischer, 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 days56.9 daysTime from dx to surgery

No MRIMRI

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