Phase 2 Trial Data on Metformin Do Not Support Further Investigation as a Breast Cancer Therapy

Metformin is a biguanide most commonly used for the treatment of patients with type 2 diabetes mellitus, although previous observational studies have suggested that its use is associated with decreased cancer risk. “These data suggest that the insulin pathway plays a major role in breast cancer prognosis and may represent a therapeutic target,” said Dr Ospedali Galliera of Genoa, Italy, who was an investigator on the MYME trial that investigated the potential antitumor effects of metformin. In this randomized phase 2 clinical trial, the efficacy of metformin plus first-line chemotherapy was compared with chemotherapy alone in metastatic breast cancer.

Included in the MYME study were 126 nondiabetic women with stage IV, human epidermal growth factor receptor 2–negative breast cancer. Patients were randomized to receive either 8 cycles of nonpegylated liposomal doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 every 21 days along with metformin 2000 mg daily until progression (Arm A) or chemotherapy alone (Arm B). The primary end point was progression- free survival (PFS), with 98 PFS events required for 80% power. Secondary end points were overall survival (OS), safety, and outcome by insulin resistance status (homeostasis model assessment [HOMA] index ≥2.5).

After a median follow-up of 39.6 months (range, 1-71 months), 111 PFS events and 70 deaths were observed in the 121 evaluable patients. Median PFS was 9.4 months (95% confidence interval [CI], 7.8-10.4) in Arm A and 10.1 months (95% CI, 7.7-11.5) in Arm B; P = 0.61. The 12-month PFS rate was 28.6% (95% CI, 17.4%-40.8%) in Arm A versus 37.1% (95% CI, 25.2%-49.0%) in Arm B. Median OS was 34.4 months (95% CI, 19.3-37.2) in Arm A and 27.2 months (95% CI, 19.4-38.8) in Arm B; P = 0.43. The 12-month OS rate was 80.5% (95% CI, 67.6%-88.7%) in Arm A versus 92.8% (95% CI, 82.0%-96.6%) in Arm B.

At evaluation, 57 (46.7%) patients had a HOMA index >2.5. Stratified by HOMA, median PFS was significantly longer (P = 0.03) in patients with a HOMA index <2.5 (10.7 months; 95% CI, 9.6-12.8) than in patients with HOMA index ≥2.5 (8.5 months; 95% CI, 6.4-9.9). Median OS was 30.8 months (95% CI, 19.4-41.4) in patients with HOMA index <2.5 and 33.6 months (95% CI, 19.3-38.8) in patients with HOMA index ≥2.5; P = 0.81.

Over the 771 chemotherapy cycles administered in this study, grade 3 or 4 neutropenia was the most frequently reported toxicity (28% of cycles). Additionally, metformin-associated diarrhea was reported in 9% of patients in Arm A.

Overall, the results of this study do not provide evidence of metformin-associated antitumor activity when administered in combination with first-line chemotherapy in metastatic breast cancer. Nevertheless, it should be noted that a significantly shorter PFS was observed in insulin-resistant patients (HOMA ≥2.5). Although this study does not support the further development of metformin in this setting, the adverse prognostic impact of insulin resistance should be further addressed.

Gennari A, et al. ESMO 2016. Abstract 230PD.