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SAN ANTONIO -- Metformin did not improve outcomes in patients with early breast cancer, regardless of estrogen receptor (ER) or progesterone receptor (PR) status, according to results from the phase III CCTGMA.32 trial.

However, an exploratory analysis suggested that metformin may have a beneficial effect in HER2-positive breast cancer, said Pamela J. Goodwin, MD, MSc, of Mount Sinai Hospital/Lunenfeld-Tanenbaum Research Institute at the University of Toronto, during a presentation at the San Antonio Breast Cancer Symposium.

Of the 620 patients with HER2-positive breast cancer analyzed, invasive disease-free survival (IDFS) was improved in those who received metformin (HR 0.64, 95% CI 0.43-0.95, P=0.03), as was overall survival (OS; HR 0.53, 95% CI 0.30-0.98, P=0.04).

Goodwin explained that this exploratory analysis was informed by the results of the , in which the pathologic complete response rate more than doubled when neoadjuvant metformin was added to anthracycline/taxane-based chemotherapy and trastuzumab in HER2-positive patients who had at least one C allele of a prespecified ATM-associated single-nucleotide polymorphism (SNP).

"The presence of any C allele of this SNP is associated with metformin benefit in diabetes," she pointed out.

"Importantly, there was a significant interaction by SNP (P=0.05) on the effect of metformin on IDFS, with those with any C allele having a hazard ratio of 0.51 (95% CI 0.31-0.83, P=0.0067)," the researchers reported. "Whereas those with the AA genotype had no evidence of a benefit with metformin (HR 1.32, 95% CI 0.58-2.96, P=0.51)."

A similar interaction was seen for OS. The 601 patients with any C allele had a reduction in death (HR 0.35, 95% CI 0.17-0.73, P=0.003), while those with the AA genotype showed no evidence of a metformin benefit (HR 2.15, 95% CI 0.56-8.36, P=0.26).

The randomized, placebo-controlled CCTGMA.32 trial enrolled 3,649 patients ages 18 to 74 with T1-3 N0-3 M0 breast cancer and no evidence of distant metastases from 2010 to 2013. All patients were treated with standard therapy and were randomized to receive metformin 850 mg twice daily for 5 years or placebo.

In 2016, futility was declared in ER/PR-negative patients and the intervention was stopped in that group, with blinding and follow-up continuing. Thus, the study's primary analysis focused on the 2,533 ER/PR-positive patients (mean age 52.7, mean BMI 28.8).

At a median follow-up of 96.2 months, 234 IDFS events occurred in the metformin arm versus 321 in the placebo arm, 75.6% of which were due to breast cancer (HR 1.01, 95% CI 0.84-1.21, P=0.92). There were 131 deaths in the metformin arm and 119 in the placebo arm, with 75.8% of deaths related to breast cancer (HR 1.10, 95% CI 0.86-1.41, P=0.47).

Similar results for other breast cancer outcomes were observed, including distant disease-free survival (HR 0.99, 95% CI 0.80-1.23, P=0.94) and breast cancer-free interval (HR 0.98, 95% CI 0.80-1.20, P=0.87).

In a follow-up to the futility results in the 1,116 patients with ER/PR-negative breast cancer at a median follow-up of 96 months, there was no benefit seen with metformin for either IDFS (HR 1.01, 95% CI 0.79-1.30, P=0.92) or OS (HR 0.89, 95% CI 0.64-1.23, P=0.46).

"Subjects with HER2-positive breast cancer -- notably those with at least one C allele of the ATM-associated rs11212617 SNP -- experienced improved IDFS and overall survival with metformin," Goodwin concluded. "However, no P value 'spend' was allocated to this comparison. As a result, it requires replication in a prospective trial focusing on the HER2-positive population."

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