Metformin does not improve outcomes in early breast cancer
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Metformin did not improve outcomes for most patients with early breast cancer, according to study results presented at San Antonio Breast Cancer Symposium.
Results of the Canadian Cancer Trials Group MA.32 trial showed no improvement in invasive DFS, OS or other outcomes among patients with moderate- or high-risk ER/PR-positive or ER/PR-negative breast cancer, suggesting metformin should not be used as breast cancer treatment for those populations.
“Because [individuals with diabetes] were not included in MA.32, this recommendation against the use of metformin should not be extrapolated to the use of metformin to treat diabetes [among patients with breast cancer],” Pamela Goodwin, MD, MSc, FRCPC, professor of medicine and director of Marvelle Koffler Breast Centre at University of Toronto/Mount Sinai Hospital, said during a presentation.
Results of an exploratory analysis of patients with HER2-positive disease suggested a beneficial effect of metformin on invasive DFS and OS among those with at least one C allele of the rs11212617 single nucleotide polymorphism. However, that finding requires additional validation, researchers concluded.
Obesity is linked to poorer breast cancer outcomes, according to study background. Insulin levels are higher among obese patients and may have an even greater effect on breast cancer outcomes.
Goodwin and colleagues conducted the multi-institutional phase 3 MA.32 trial to examine the effect of adjuvant metformin vs. placebo on breast cancer outcomes.
Researchers selected metformin because it promotes modest weight loss and reduces insulin by approximately 15% to 20% among breast cancer survivors without diabetes. Prior window-of-opportunity studies showed the agent may reduce Ki67 expression in breast cancer cells, and preclinical research showed it slowed breast cancer growth.
In addition, observational studies suggested using metformin to treat diabetes among people with breast cancer may be linked to improved breast cancer outcomes, according to study background.
The MA.32 study included 3,649 patients aged 18 to 74 years who had been diagnosed with invasive breast cancer (T1c-T3, N0-3, M0) within the previous year and had undergone excision with negative margins. Those with T1c, N0 disease had additional adverse features. No patients had diabetes.
Researchers randomly assigned patients 1:1 to standard breast cancer therapy plus either metformin dosed at 850 mg twice daily for 5 years or placebo. The metformin regimen included a 4-week ramp-up of 850 daily.
Researchers stratified by ER/PR status, BMI, HER2 status and chemotherapy receipt.
Invasive DFS served as the primary outcome measure. Secondary objectives included other breast cancer outcomes, including OS, breast cancer-free interval and contralateral breast cancer; new diagnosis of diabetes mellitus or cardiovascular hospitalization or death; rates of grade 3 or higher adverse events; and BMI and circulating metabolic factors.
Researchers also conducted correlative analyses of fasting blood and tissue.
An interim analysis conducted in 2016 revealed futility among patients with hormone receptor-negative breast cancer. Follow-up continued for patients with hormone receptor-positive disease.
The primary analysis included 2,553 patients with hormone receptor-positive breast cancer regardless of HER2 status. The metformin and placebo groups were balanced with regard to median age (52 years vs. 53 years), BMI (29 kg/m2 vs. 28.6 kg/m2, menopausal status (postmenopausal, 62.1% vs. 60.2%), race (white, 92.1% vs. 91.2%) and ECOG performance status (0 to 2, 80.9% vs. 80%). Most patients received adjuvant chemotherapy, radiation and hormone therapy.
Results showed metformin did not improve invasive DFS (HR = 1.01; 95% CI, 0.84-1.21) or OS (HR = 1.1; 95% CI, 0.86-1.41) in this population. Researchers reported similar results for distant DFS, breast cancer-free interval and invasive breast cancer-free survival.
Follow-up analysis of the futility result in hormone receptor-negative patients regardless of HER2 status continued to show no benefit with metformin on invasive DFS (HR = 1.01; 95% CI, 0.79-1.3) or OS (HR = 0.89; 95% CI, 0.64-1.23).
Goodwin and colleagues conducted an exploratory analysis of 620 patients with HER2-positive breast cancer (ER/PR-positive, 69.2%; ER/PR-negative, 20.8%). The majority received chemotherapy (99.4%) and trastuzumab (Herceptin, Genentech; 96.5%).
Results showed metformin-treated patients experienced longer invasive DFS (HR = 0.64; 95% CI, 0.43-0.95) and OS (HR = 0.53; 95% CI, 0.3-0.98).
Researchers observed a significant interaction between SNP and the impact of metformin on invasive DFS (any C allele, HR = 0.51; 95% CI, 0.31-0.83; AA genotype, HR = 1.32; 95% CI, 0.58-2.96). They reported a similar pattern for OS (any C allele, HR = 0.35; 95% CI, 0.17-0.73; AA genotype, HR = 2.15; 95% CI, 0.56-8.36).
“No P value ‘spend’ was allocated to this comparison,” Goodwin said. “As a result, it requires replication in a prospective trial focusing on the HER2-positive population.”
Metformin appeared associated with a modest and nonsignificant increase in grade 3 or higher toxicity. Most of the excess adverse events were due to gastrointestinal events such as nausea, vomiting, bloating and diarrhea, Goodwin said.
Perspective
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Stephanie Bernik, MD, FACS
It has long been known that obesity, which often correlates with diabetes, increases a woman’s risk for breast cancer. This study tried to show that using a medication that helps control insulin levels, even among those without diabetes, might decrease one’s risk for breast cancer. 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.
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Goodwin PJ, et al. Abstract GS1-08. Presented at: San Antonio Breast Cancer Symposium; Dec. 7-10, 2021; San Antonio.
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