Metformin disappoints in early breast cancer

Adjuvant treatment with metformin does not improve outcomes in most patients with early breast cancer in a phase III study, suggesting that metformin should not be used as a breast cancer treatment in these patients.

This was the key finding of the Canadian Cancer Trials Group MA.32 study presented at SABCS 2021.

In the primary analysis of 2,553 patients with hormone receptor-positive breast cancer regardless of HER2 status,  there was no improvement in invasive disease-free survival (IDFS), overall survival (OS), or other outcomes among those treated with metformin on top of standard therapy.

IDFS events occurred in 18.5 percent of patients receiving metformin vs 18.3 percent in those on placebo, with 75.6 percent of events due to breast cancer. There was no advantage with metformin even in distant disease-free survival (hazard ratio [HR], 0.99; p=0.94) and breast cancer-free interval (HR, 0.98; p= 0.87).

However, the exploratory analysis of 620 women with HER2-positive disease suggested that metformin may have a beneficial effect, particularly among those with at least one C allele of the rs11212617 single nucleotide polymorphism, reported lead author Dr Pamela Goodwin, director of Marvelle Koffler Breast Centre at the University of Toronto and Mount Sinai Hospital in Toronto, Canada. In this subset of patients, IDFS events were improved in those treated with metformin (HR, 0.64; p=0.03) vs placebo and so was OS (HR, 0.53; p=0.04).

“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,” she added.

MA.32 population had no diabetes

MA.32 study included 3,649 patients (age 18–74 years) with T1-3, N0-3, M0 invasive breast cancer, who were randomly assigned to standard breast cancer therapy plus metformin 850 mg twice daily for 5 years or placebo.  None of them had diabetes. [SABCS 2021, abstract GS1-08]

Invasive DFS was the primary outcome while secondary outcomes included OS, breast cancer-free interval and contralateral breast cancer, a new diagnosis of diabetes or cardiovascular hospitalization or death, rates of grade 3 or higher adverse events, BMI, and circulating metabolic factors.

The study sprang from preclinical studies demonstrating that metformin had some anticancer effects. “In some window of opportunity neoadjuvant studies, metformin was able to reduce Ki67 in breast cancer cells,” she shared. “ In preclinical in vitro and in vivo research, metformin also slowed breast cancer growth.”

Observational studies also suggested that metformin use in diabetes patients with breast cancer may be associated with better outcomes.

More research needed

“The investigators tried to show that using a medication that helps control insulin levels might decrease one’s risk for breast cancer even among those without diabetes,” commented Dr Stephanie Bernik, Chief of Breast Service at Mount Sinai West and associate professor of surgery at the Icahn School of Medicine, Mount Sinai, New York City, New York, who is unaffiliated with the study. “Unfortunately, metformin had no effect on outcomes in this study even though it has shown promise in other studies.”

“As [patients with diabetes] were not included in MA.32, the recommendation against the use of metformin should not be extrapolated to the use of metformin to treat diabetes [in patients with breast cancer],” cautioned Goodwin.

More studies are warranted to identify which mechanisms of action might be helpful to combat cancer in patients with or without diabetes.