Researchers hypothesized that metformin — a medication that helps lower insulin levels in patients with diabetes and is associated with inducing weight loss — might improve breast cancer outcomes.
Treating patients who have early breast cancer with metformin — a drug used to treat and control high blood sugar levels in patients with diabetes — after their initial cancer treatments did not improve invasive disease-free survival (IDFS) or overall survival (OS), regardless of estrogen or progesterone receptor (PR) status.
The results came from the phase 3 CCTG MA.32 trial, which was presented at the 2021 San Antonio Breast Cancer Symposium.
The primary analysis showed that outcomes in patients with estrogen receptor (ER)–positive and PR-positive disease was similar between two groups, where patients received either metformin or a placebo.
“Metformin does not improve IDFS, OS, or other breast cancer outcomes in moderate/high risk estrogen receptor (ER)/PR-positive or ER/PR-negative breast cancer patients and should not be used as breast cancer treatment in those groups,” said Dr. Pamela J. Goodwin, lead study author and professor of medicine at the University of Toronto, during the presentation.
The research team attempted to determine if treatment with metformin could induce better tumor responses based on the association of obesity with poor breast cancer outcomes and the drug’s ability to promote weight loss and lower insulin levels.
Patients were eligible for the study if they had a diagnosis of invasive breast cancer within one year and negative margins following surgery. Tumors had to be staged as T1c to T3 — meaning tumors could range from 2 cm to more than 5 cm — and N0 to N3 (cancer in no lymph nodes to 10-plus lymph nodes), with T1cN0 requiring additional adverse features. All patients must have received standard breast cancer therapy and could not have diabetes.
The primary analysis was in patients with ER/PR–positive breast cancer, with 1,268 patients in the metformin group and 1,265 in the placebo group. They had median ages of 52 and 53 years, respectively, and 62.1% and 60.2% were postmenopausal.
A total of 52.5% and 54.2%, respectively, had T2 tumor stage, and most disease was grade 2 or grade 3. Additionally, 16.5% and 17.4% had HER2-positive disease, with 97% receiving Herceptin (trastuzumab).
Invasive disease-free survival (IDFS) occurred in 18.5% and 18.3% of patients receiving metformin and placebo, respectively. Rates of distant, local/regional and tumors in the opposite breast from diagnosis as well as new primary cancer were similar between groups.
In total, 131 patients (10.3%) in the metformin group died, compared with 119 (9.9%) in the placebo group. Causes of death among those who received metformin were breast cancer (7.8%), other primary malignancies (1.2%) and cardiovascular disease (0.3%) among other factors (1%), with similar rates in the placebo group.
A total of 21.7% of patients in the metformin group experienced grade 3 (severe) or worse side effects, compared with 18.7% in the placebo group. These side effects included nausea, vomiting, bloating and diarrhea.
Results among patients with ER/PR-negative breast cancer showed that futility — or treatment without any benefit for the patient —was established at 29.5 months of follow-up with 172 IDFS events. At the 96-month follow-up, there were 245 IDFS events in 1,116 patients, with no benefit noted with metformin.
The exploratory analysis looked at patients who had human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Interestingly, patients who had at least one C allele — a type of genetic variation — had a higher pathologic complete response rate with metformin than those who had no allele. Goodwin said any presence of a C allele is associated with a metformin benefit on glucose control in diabetes.
A total of 620 patients with HER2-positive cancer were analyzed, with 99.4% receiving chemotherapy and 96.5% receiving Herceptin (trastuzumab).
When looking at the entire HER2-positive population, patients who received metformin had fewer IDFS events than those who were administered placebo. There were also fewer patient deaths with metformin.
“Exploratory analyses in HER2-positive breast cancer suggested a beneficial effect of metformin on IDFS and OS, notably in patients with at least one C allele of the rs11212617 snp. These observations should be replicated in future research,” concluded Goodwin.
A version of this article was originally published on Cancer Network as, “Metformin Does Not Improve Outcomes in Early Hormone Receptor–Positive or –Negative Breast Cancer.”
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