Tamoxifen versus tamoxifen plus octreotide LAR as adjuvant therapy for early-stage breast cancer in postmenopausal women: Update of NCIC CTG MA14 trial.

Abstract

542 Background: Early preclinical data involving insulin/IGF physiology suggested a potential role for the use of a somatostain analogue in the adjuvant treatment of breast cancer. In 1996, the NCIC CTG initiated a trial of tamoxifen (T) alone versus the combination of tamoxifen with LAR octreotide (oct) in postmenopausal women with early-stage breast cancer. The final analysis for event-free survival (EFS) was reported at ASCO in 2008; this is an update. Methods: This phase III trial randomized early- stage postmenopausal women to T 20 mg daily for 5 years with or without oct (90 mg depot injections monthly) initially prescribed for 5 years and then reduced to 2 years due to concerns over cholelithiasis. Patients were stratified by nodal status, adjuvant chemotherapy and ER. EFS, the primary endpoint, defined as time from randomization to recurrence, second malignancy, or death due to any cause, along with relapse free survival ( RFS) and overall survival (OS) were assessed with an adjusted log- rank statistic and step-wise forward adjusted Cox analyses. Results: 667 women were accrued (333 to T and 334 to T + oct). MA.14 now has a median follow-up of 9.8 years, and 252 EFS events (130 on T and 122 on T +oct). The EFS hazard ratio (HR) is 0.93 (95% CI 0.73, 1.20; p-value = 0.57). We saw significantly longer EFS for women under 60 (p = 0.003), who had less than T2 tumours (p = 0.03), with N0 disease (p = 0.01), median or lower BMI (p < 0.0001), and lower c-peptide levels (p < 0.0001). Relapse-free survival (RFS, 78 events on T and 70 on T + oct) likewise had a non-significant (p = 0.40) HR of 0.87 (0.63, 1.21) as did OS (86 deaths on T and 84 on T + oct) with a HR of 0.94 (0.69, 1.27; p = 0.69). The number of breast cancer specific deaths in this older population was 54 on T, 57 on T + oct. Conclusions: Attempted manipulation of the insulin/IGF pathway with somatostatin analogue did not result in the intended declines in IGF-I or insulin levels in this trial. Insulin secretion estimated by c-peptide level is confirmed as an important negative prognostic factor. Targeting the insulin/IGF axis with metformin and/or antireceptor antibodies and/or specific tyrosine kinase inhibitors in ongoing trials will be of interest. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis, Pfizer