Phase II randomized trial of neoadjuvant metformin plus letrozole versus placebo plus letrozole for estrogen receptor positive postmenopausal breast cancer (METEOR)

Metformin, which is commonly used to treat type 2 diabetes, is a relatively safe drug with known pharmacokinetics and manageable toxicities. In addition, numerous experimental, epidemiologic, observational, and clinical studies have shown that metformin has anti-tumor effects [1]. For example, in a preclinical mouse xenograft model, metformin reduced the effective dosages of standard chemotherapeutic drugs and had preferential effects on tumorigenic cells [2]. A retrospective clinical study showed that patients taking metformin during neoadjuvant chemotherapy had a higher pathologic complete response (pCR) rate than diabetic patients not taking metformin or non-diabetes patients (24% vs 8% vs 16%, p = 0.02) [3, 4]. Two potential mechanisms of anti-cancer action of metformin have been suggested. First, metformin may directly activate adenosine monophosphate kinase (AMPK), resulting in the downstream inhibition of mTOR signaling and the consequent suppression of cell proliferation [5‐7]. Second, metformin-induced decreases in circulating insulin and insulin-like growth factor (IGF) concentrations may reduce the activation of the IGF-receptor signaling axis, resulting in decreases in growth promotion and mitogenesis [8‐10]. Thus, the anti-cancer effects of metformin are mediated through a systemic improvement in metabolic profile and by directly targeting tumor cells [11, 12].

Questions remain, however, about the clinical benefits of metformin as an anti-cancer agent in patients with breast cancer. Although one large-scale, phase III trial of adjuvant metformin has been initiated in women with breast cancer (NCIC CTG MA.32) [1], the accrual and treatment process is still ongoing, and several years of follow-up are needed to determine survival benefits. In addition, little is known about the effects of metformin on different subtypes of breast cancer or on the synergy between metformin and concurrently administered systemic agents. In addition, the optimal dosage of metformin that shows maximal anti-tumor effects with acceptable toxicities has not been determined. In this context, neoadjuvant treatment is the most efficient setting to assess the short-term in vivo effects of drug therapy in breast cancer patients. Neoadjuvant endocrine therapy results in a comparable response but lower toxicity compared with neoadjuvant chemotherapy in women with ER-positive breast cancer [13]. In postmenopausal women, aromatase inhibitors are associated with higher response rates than tamoxifen [14, 15]. A recent phase II trial found that neoadjuvant treatment with everolimus, an mTOR inhibitor, plus letrozole resulted in a better response rate than letrozole alone [16]. In addition, neoadjuvant metformin was shown to lower Ki67 level [17]. These results suggested that metformin may be effective, when combined with letrozole, in postmenopausal women with ER-positive breast cancer. We therefore designed and initiated a phase II clinical trial evaluating the anti-tumor effect of neoadjuvant metformin in postmenopausal women with ER-positive breast cancer by comparing treatment with letrozole plus metformin or placebo.

The maximum effective dose of metformin to treat hyperglycemia in patients with type 2 diabetes is 1000 mg twice daily. However, the metformin dose that yields the maximal anti-tumor effect is unclear. Results from two xenograft models reported that the human equivalent of 1500–2250 mg/day was needed to inhibit tumorigenesis [21‐23]. A preoperative window of opportunity trial in breast cancer patients utilized a dose of 2000 mg/day [24], whereas the ongoing NCIC CTG MA32 phase III clinical trial is testing the effect of adjuvant metformin, is utilizing a dosage of 1700 mg/day. To use the maximum dose of metformin in this neoadjuvant setting, as well as to ensure patient safety, the dose is gradually increased over the first few weeks of treatment, and doses may be adjusted in response to toxicities/adverse events. The results of this trial will provide important information on the optimally effective and safest dose of metformin in non-diabetic breast cancer patients.

This study was designed to evaluate the direct anti-tumor effects of metformin in human breast cancer cancers. We expect that metformin will show a synergy with neoadjuvant letrozole in ER-positive breast cancer patients similar to that of the mTOR inhibitor, everolimus. Parallel translational research may provide a better understanding of the mechanism of action of metformin in cancer and may reveal biomarkers predictive of response to metformin.