Adjuvant treatment with metformin did not improve outcomes in most patients with early breast cancer, according to new findings from a randomized controlled trial.
In the primary analysis, the addition of metformin to standard therapy in moderate/high-risk hormone receptor positive or negative breast cancer did not improve invasive disease–free survival (IDFS), overall survival, or other breast outcomes, explained lead author Pamela J. Goodwin, MD, FRCPC, a professor of medicine at the University of Toronto, Canada. “Metformin should not be used as breast cancer treatment in this population.”
However, an exploratory analysis suggested that metformin may have a beneficial effect in women with HER2-positive breast cancer, Goodwin noted.
In this subset, IDFS was improved in patients who received metformin (HR, 0.64; P = .03), as was overall survival (HR, 0.53; P = .04).
The findings were presented at the San Antonio Breast Cancer Symposium (SABCS) 2021.
“This trial arose from the observation that obesity is associated with poor breast cancer outcomes, and insulin levels are higher in obesity and may be more strongly associated with breast cancer outcomes than obesity,” said Goodwin.
Metformin was used because of its ability to promote modest weight loss and lower insulin by about 15% to 20% in nondiabetic breast cancer survivors. It has also shown anticancer effects in preclinical studies. “In some window of opportunity neoadjuvant studies, it has been shown to reduce Ki67 in breast cancer cells,” she said. “And in preclinical in vitro and in vivo research, it slows growth of breast cancer.”
In addition, emerging evidence from observational studies suggests that the use of metformin to treat diabetes in breast cancer patients may be associated with better outcomes, strengthening the rationale for the study.
The negative results in breast cancer follow recent reports of negative findings in lung cancer, when metformin was found to be ineffective when used alongside chemotherapy in locally advanced lung cancer, as reported by Medscape Medical News.
No Benefit Seen
Metformin was compared to placebo in the phase 3 CCTG MA.32 trial, conducted in 3649 patients aged 18 to 74 years with T1-3 N0-3 M0 breast cancer. 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” after a second interim analysis conducted at 29.6 months’ median follow-up, Goodwin noted. The intervention was stopped in that group, although blinding and follow-up continued.
After that, the study’s primary analysis focused on the 2533 ER/PR-positive patients (mean age, 52.7 years; mean BMI, 28.8; approx. 60% postmenopausal).
Just over half of these patients had T2 tumor stage, and most disease was grade 2 or 3.
In addition, 16.5% (of metformin) and 17.4% (of placebo) patients had HER2-positive disease, with the majority (97%) of all HER2 patients receiving trastuzumab.
There was no difference between the two groups in IDFS events, occurring in 18.5% of patients receiving metformin and 18.3% who received placebo, with most (75.6%) events due to breast cancer (HR, 1.01; P = .92).
There were 131 deaths in the metformin arm and 119 in the placebo arm, with most (75.8%) of the deaths related to breast cancer (HR, 1.10; P = .47).
Other breast cancer outcomes had similar results, including distant disease-free survival (HR, 0.99; P = .94) and breast cancer–free interval (HR, 0.98; P = .87), both of which showed no advantage for metformin.
Possible HER2 Advantage
However, the exploratory analysis suggested there may be an advantage for patients with HER2-positive disease, but primarily those who had at least 1 C allele of a prespecified ATM associated rs11212617 SNP. These patients achieved a higher pathologic complete response rate with metformin than those without the allele.
There were 620 patients with HER2-positive disease analyzed, with 99.4% receiving chemotherapy and 96.5% receiving trastuzumab. There were 99 IDFS events, and 47 OS events.
In the entire HER2-positive cohort, patients who received metformin had fewer IDFS events (HR, 0.64; P = .026) compared with the placebo arm. Mortality was also lower with metformin (HR for overall survival, 0.53; P = .038).
“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.”
More Research?
Stephanie Bernik, chief of breast surgery, Mount Sinai West, and associate professor of breast surgery, Icahn School of Medicine at Mount Sinai, New York, was approached by Medscape Medical News for an independent comment.
“It has long been known that obesity, which often correlates with diabetes, increases a woman’s risk of breast cancer,” she commented.
“This study tried to show that using a medication that helps control insulin levels, even in those without diabetes, might decrease one’s risk of breast cancer,” she said. “Unfortunately, using metformin had no effect on outcomes in this study, even though it has shown promise in other studies. Perhaps more research needs to be carried out to try to pinpoint which mechanisms of action, if any, might be helpful to combat cancer in those with and without diabetes.”
The study was funded by the Canadian Cancer Trials Group, Cancer Therapy Evaluation Program, Breast Cancer Researcher Foundation, Susan G. Komen for the Cure, Canadian Cancer Society, Apotex, Swiss Cancer Research, and the Canadian Breast Cancer Foundation. Goodwin has no disclosures
San Antonio Breast Cancer Symposium (SABCS) 2021: Presented December 7, 2021. Abstract GS1-08.
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