The potential antitumor effect of metformin (M) in breast cancer is being explored by several clinical studies, in early disease. In this phase II randomised study, we compare the efficacy of M plus first line chemotherapy (CT) versus CT in metastatic breast cancer (MBC).
126 non-diabetic women (ITT 122) with stage IV, HER2 negative BC, untreated with CT, were randomized to Arm A: AC (non-pegylated liposomal doxorubicin 60 mg/m2 + cyclofosfamide 600mg/m2, x 8 Q21 + metformin 2,000 mg pos daily until progression) vs Arm B: AC. The primary endpoint was progression free survival (PFS); 98 PFS events were required for 80% power. Secondary endpoints were overall survival (OS), safety and outcome by insulin resistance status (HOMA Index ≥2.5).
122 patients are evaluable for primary endpoint. HOMA Index was > 2.5 in 57 patients (46.7%). At 39.6 months' median follow-up (range 1-71 months), 111 PFS events and 70 deaths had been observed. Median PFS was 9.4 months (95%CI 7.8-10.4) in Arm A (CT + M) and 10.1 (95%CI 7.7-11.5) in Arm B (CT), p= 0.61. 12 month PFS rate was 28.6% (95%CI: 17.4%-40.8%) in Arm A vs 37.1% (95%CI: 25.2%-49.0%) in Arm B. Overall, median PFS was 10.7 months (95%CI 9.6-12.8) in patients with HOMA Index
The present study does not provide evidence in support of an antitumor activity of M in combination with first line CT in MBC. Noteworthy, a significantly shorter PFS was observed in insulin-resistant patients (HOMA ≥2,5), without significant interaction with M. Further development of M in this setting is not warranted, while the adverse prognostic impact of insulin resistance needs to be addressed further.
Clinical trial identification
Eudract number 2009-014662-26 .Protocol version:13 May 2009 Amendment 1: 18/11/2010
Legal entity responsible for the study
IRST Meldola (FC), Italy
TEVA, Italian Association for Cancer Research (AIRC)
All authors have declared no conflicts of interest.