The addition of metformin, a drug commonly used to treat type 2 diabetes, to standard adjuvant treatment failed to improve invasive disease–free survival or overall survival for hormone receptor–positive or –negative breast cancer, according to the results of a large landmark trial led by the Canadian Cancer Trials Group (CCTG) and the Breast International Group (BIG).¹ Exploratory analyses suggest that metformin might have a benefit in HER2-positive breast cancers, but this requires further study.

In the primary analysis, no difference in invasive disease–free survival was observed in the primary analysis group consisting of patients with estrogen receptor–positive and/or progesterone receptor–positive disease between the metformin and placebo arms. Findings were similar in those with hormone receptor–negative breast cancer.

“The results tell us that metformin does not improve invasive disease–free survival, overall survival, or other breast cancer outcomes in high-risk early-stage breast cancer, and any off-label use of this drug for the treatment of these common types of breast cancer should be stopped. Although metformin is not beneficial for use in the most common breast cancers, exploratory analyses suggest it may be beneficial in HER2-positive breast cancer,” said lead author Pamela Goodwin, MD, MSc, FRCPC, FASCO, Professor of Medicine at the University of Toronto and Mount Sinai Hospital, speaking at the 2021 San Antonio Breast Cancer Symposium.

Pamela Goodwin, MD, MSc, FRCPC, FASCO

“These results [related to HER2-positive breast cancer] would need to be replicated in future studies before metformin is used as a breast cancer treatment for HER2-positive breast cancer. The MA.32 exploratory findings in this subset will not change practice,” she added. Dr. Goodwin noted that contemporary practice has changed, and more patients are being treated with neoadjuvant therapy and dual HER2 blockade. Thus, metformin would have to be studied in that context.

Metformin is a biguanide drug used to treat hyperglycemia and diabetes. Breast cancer is associated with obesity, which is in turn associated with inflammation. Metformin can promote weight loss and lower insulin levels. Previous observational and preclinical studies suggested that metformin may have an anticancer effect by slowing proliferation of cell growth.

Study Details

The randomized, double-blind, placebo-controlled CCTG.MA.32 trial is the largest study to evaluate the addition of metformin to standard treatment for breast cancer, with more than 3,600 patients with breast cancer enrolled in North America, Switzerland, and the United Kingdom. Patients were randomly assigned to metformin at 850 mg twice daily (n = 1,824) vs placebo (n = 1,825).

Eligibility criteria included a diagnosis of invasive breast cancer within 1 year and negative surgical margins; tumors were staged as T1c to T3 and N0 to N3, with T1cN0 requiring additional adverse features. All patients had standard-of-care primary treatment, and none had type 2 diabetes.

The primary analysis was performed in patients with estrogen receptor– and progesterone receptor–positive breast cancer after the intervention was stopped for futility in estrogen receptor– and progesterone receptor–negative breast cancer at an interim analysis conducted at 29.6 months’ median follow-up. Baseline characteristics were comparable across the two study arms. In both arms, the median patient age was about 52, and about 61% were postmenopausal. About 53% had stage T2 disease, and the majority of tumors were grade 2 or 3. Additionally, about 17% of patients had HER2-positive disease, with 97% treated with trastuzumab.

Invasive disease–free survival rates were almost identical in both study arms: 18.5% and 18.3% in patients receiving metformin and placebo, respectively. Rates of distant, local/regional, and contralateral invasive recurrence as well as new primary cancer were similar between groups.

Death rates were similar in both arms: 131 patients (10.3%) in the metformin arm died vs 119 (9.9%) in the placebo arm. Causes of death in the metformin arm included breast cancer (7.8%), other primary malignancies (1.2%), cardiovascular disease (0.3%), and other factors (1.0%) and were similar in the placebo group.

Grade 3 or higher adverse events were reported in 21.5% of patients in the metformin arm compared with 17.5% in the placebo arm. Common adverse events were nausea, vomiting, bloating, and diarrhea.

In the estrogen receptor–/progesterone receptor–negative population, there were a total of 172 invasive disease–free survival events at the time the intervention was stopped for futility. At 96 months of follow-up, there were 245 invasive disease–free survival events in 1,116 patients, with no benefit observed for the use of metformin on invasive disease–free or overall survival with longer follow-up.

HER2-Positive Exploratory Subset

An exploratory analysis was conducted in patients with HER2–positive breast cancer to explore a previously reported finding that patients with HER2-positive breast cancer whose tumors had at least one C allele of a prespecified single nucleotide polymorphism (ie, ATM-associated rs11212617) had a higher pathologic complete response rate with metformin than those who did not have this allele.² According to Dr. Goodwin, the presence of a C allele in patients with diabetes is associated with a metformin benefit on glucose control.

Among the 620 patients with HER2-positive disease, 99.4% were treated with chemotherapy and 96.5% received trastuzu-mab. There were 99 invasive disease–free survival events and 47 overall survival events. In the overall HER2-positive subpopulation, the metformin-treated patients had fewer invasive disease–free survival events compared with the placebo arm. There were fewer patient deaths with metformin.

A significant interaction was found between patients with at least one C allele of the rs11212617 single nucleotide polymorphism and invasive disease–free survival in the metformin-treated patients (P = .007), which was not seen with other genotypes. Overall survival was also significantly better for those with the single nucleotide polymorphism on treatment with metformin (P = .003) vs the AA genotypes. 

DISCLOSURE: Dr. Goodwin reported no conflicts of interest.

REFERENCES

1. Goodwin PJ, Chen BE, Gelmon KA, et al: CCTG.MA.32, a phase III randomized double-blind placebo controlled adjuvant trial of metformin vs placebo in early breast cancer: Results of the primary efficacy analysis. 2021 San Antonio Breast Cancer Symposium. Abstract GS1-08. Presented on December 7, 2021.

2. Cuyàs E, Buxó M, Iglesias MJF, et al: The C Allele of ATM rs11212617 associates with higher pathological complete remission rate in breast cancer patients treated with neoadjuvant metformin. Front Oncol 9:193, 2019.