Metformin does not improve breast cancer outcomes in moderate- to high-risk breast cancer

Results of the phase III MA.32 trial show that the addition of metformin to standard therapy in moderate- to high-risk hormone receptor (HR) positive or negative breast cancer does not improve breast cancer related outcomes. As such, metformin should not be used as breast cancer treatment in this setting. However, an exploratory analysis did suggest a benefit of metformin in HER2-positive patients, but this finding requires further investigation.

Obesity is known to be associated with poor breast cancer outcomes, with higher insulin levels believed to be responsible for this association. Metformin promotes modest weight loss and lowers insulin by approximately 15-20% in non-diabetic breast cancer survivors. Furthermore, neoadjuvant studies using this agent have shown that metformin reduces Ki67 levels in cancer cells. Finally, preclinical research with metformin has shown that it slows breast cancer growth in vitro and in vivo. Based on these findings, the MA.32 study evaluated the potential anticancer activity of metformin in breast cancer patients.

Study design

The primary objective of the phase III study was to compare the invasive disease-free survival (iDFS) between breast cancer patients treated with metformin or placebo in addition to standard breast cancer therapy. In this study, an iDFS event was defined as breast cancer recurrence (locoregional or distant), the emergence of a new primary cancer (breast or non-breast) or death of any cause.

The study enrolled patients (18-74 years) with invasive breast cancer (T1c-T3, N0-3, M0) diagnosed within 1 year and excised with negative margins. All patients received standard therapy and were required to be non-diabetic. Patients were randomized (1:1) to oral metformin (850 mg twice a day for 5 years, with a one-month ramp-up of 850 mg daily) or placebo. The enrollment of 3,649 patients was completed in March 2013. In March 2016 (second interim analysis) futility was declared in ER-negative patients after which the follow-up continued in ER-positive patients only.

Results

The median age of the 2,553 ER-positive patients was 52 years, about 60% was post-menopausal and four out of five had an ECOG PS of 0. About half of the patients had T2 disease, two thirds had N0-N1 disease and roughly 45% and 41% of patients had grade 2 or 3 disease, respectively. In ER-positive patients, metformin was associated with a modest increase in the incidence of grade ≥3 adverse events (21.7% vs. 18.7%). No difference was seen in terms of iDFS between metformin and placebo (18.5% vs. 18.3%; HR[95%CI]: 1.01[0.84-1.21]; p=0.93). Similarly, no difference was observed in terms of overall survival (OS) between both treatment arms (HR[95%CI]: 1.10[0.86-1.41]; p= 0.47). Similar results were found for distant DFS, breast cancer free interval and invasive breast cancer free survival.

A longer follow-up of the results in ER-negative patients confirmed the previously concluded futility with a HR of 1.01 (95%CI: 0.79-1.30) and 0.89 (95%CI: 0.64-1.23) for iDFS and OS respectively. Finally, researchers also performed an exploratory analysis focusing on HER2-positive breast cancer patients. This analysis included 620 patients of whom 69.2% were node positive. In total, 99 iDFS events were reported in this subgroup of patients (78.8% breast-cancer related). In the full HER2-positive population, metformin was associated with a better iDFS (HR[95%CI]: 0.64[0.43-0.95], p= 0.003) and OS (HR[95%CI]: 0.53[0.30-0.98]; p= 0.04) than placebo. Previous studies have revealed that the presence of at least one C allele of a prespecified ATM associated snp (rs11212617) is associated with a higher metformin benefit on glucose control in diabetes. Interestingly, a significant interaction was found between the presence of at least one C allele of this snp and a more pronounced iDFS and OS benefit with metformin in HER2-positive patients (HER2-positive with C-allele: HR[95%CI]: 0.51[0.31-0.83] and 0.35[0.17-0.73] for iDFS and OS respectively. HER2-positive without C-allele: HR[95%CI]: 1.32[0.58-2.96] and 2.15[0.56-8.36] for iDFS and OS, respectively).

Conclusions

Adding metformin to standard therapy in moderate- to high-risk ER⁺ breast cancer does not improve iDFS, OS or other breast cancer outcomes. Therefore, metformin should not be used as breast cancer treatment in this population. Metformin also did not yield any clinical benefit in ER-negative patients. In contrast, exploratory analyses in HER2⁺ patients do suggest a clinical benefit of metformin, especially in patients with at least one C allele of the es11212617 snp. These findings deserve further research.

Reference

Goodwin P, et al. CCTGMA.32, a phase III randomized double-blind placebo-controlled adjuvant trial of metformin (MET) vs placebo (PLAC) in early breast cancer (BC): Results of the primary efficacy analysis (clinical trials.gov NCT01101438). Presented at SABCS 2021; abstract GS1-08.