Exploration of body mass index and circulating metabolic factors as predictors of metformin benefit in the Canadian Cancer Trials Group MA.32.
BACKGROUND: In the MA.32 randomized adjuvant breast cancer trial, metformin (vs placebo) did not impact invasive disease-free survival or overall survival in estrogen and/or progesterone receptor-positive or -negative breast cancer; exploratory analyses suggested a benefit in HER2-positive breast cancer. We investigated whether body mass index (BMI) and obesity-associated blood variables predicted metformin benefit in immunohistochemically defined breast cancer subtypes (luminal [estrogen/progesterone receptor positive, HER2 negative], triple-negative breast cancer [estrogen receptor, progesterone receptor, HER2 negative], HER2 positive). METHODS: A total of 3649 nondiabetic patients with high risk T1-3, N0-3, M0 breast cancer were randomly assigned. Baseline fasting plasma was assayed for insulin, glucose, leptin, and C-reactive protein; Homeostasis Model Assessment was calculated. For each breast cancer subtype and each outcome (distant recurrence free survival, overall survival, invasive disease-free survival), Cox models examined interactions of BMI and blood variables with metformin vs placebo outcomes. RESULTS: Mean age was 51.1-53.0 years; mean BMI was 27.3-27.5 kg/m2. Most cancers were T2, N0, or N1 and grade 2-3; 2104 (57.7%) were luminal, 925 (25.3%) TN, and 620 (17.0%) HER2 positive. Median follow-up was 95.9 months. In luminal breast cancer, statistically significant interactions were identified for leptin, insulin, and Homeostasis Model Assessment on distant recurrence-free survival, and in triple-negative breast cancer, a statistically significant interaction was identified for glucose on distant recurrence-free survival, with potential adverse effects of metformin at lower levels of each variable. In those with HER2-positive breast cancer, there was no variable that predicted metformin benefit. CONCLUSIONS: Body mass index and blood variables did not identify subgroups with luminal or triple-negative breast cancer who benefited from metformin or those with HER2-positive breast cancer who did not benefit. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01101438: 2010-04-09.