In observational studies, the use of metformin in patients with type 2 diabetes has been inconsistently associated with beneficial effects on BC prognosis. However, it is unclear whether metformin confers any protective effect in patients with BC who do not have diabetes. The purpose of this study was to determine whether the administration of adjuvant metformin in BC patients without diabetes improves outcomes.
MA.32 was an international phase III, randomized, placebo-controlled, double-blind trial that involved high-risk operable BC patients who did not have metastatic disease. Patients were eligible for enrollment in the study if they were aged 18 to 74 years, had received standard treatment for T1-T3, N0-N3, M0 BC between August 2010 and March 2013, had a fasting blood glucose of <126 mg/dL, had undergone complete resection of their BC, and had completed neoadjuvant chemotherapy. The use of adjuvant therapy, radiation, targeted therapy and biologicals, and bisphosphonates were permitted.
Specific criteria were available for those with T1cN0 BC based on histologic grade, lymphovascular invasion, hormone receptor status, and Oncotype Recurrence Scores. Inclusion criteria were subsequently modified to mandate triple-negative status for patients with T1cN0 disease as well as the presence of one or more adverse consequences for those with T2N0 tumors.
Patients were excluded if they had a history of diabetes or lactic acidosis, were currently on medications for diabetes, had a BC recurrence or had previous invasive cancer, consumed three or more alcoholic beverages daily, or if they had marked hepatic, renal, or cardiac dysfunction.
Those in the intervention group received 850 mg of metformin once daily for 4 weeks, then twice daily for 5 years. Dosage reductions were permitted if adverse effects occurred.
The primary endpoint was invasive disease-free survival (IDFS). Secondary endpoints included overall survival (OS), distant relapse-free survival (DRFS), and BC-free interval as well as a new diabetes diagnosis, cardiovascular hospitalization, quality of life, diet, and physical activity; however, these noncancer secondary endpoints were not reported on in this paper.
A total of 3,649 patients were enrolled in the study with a mean age of 52.4 years. Almost all of the patients (99.8%) were women. Patients were stratified based on hormone receptor–positivity status, BMI, ERBB2 (formerly HER2)–positivity status, and use of chemotherapy. In 2016, a futility analysis at 37 months revealed no benefit in patients with estrogen receptor/progesterone receptor (ER/PR) receptor–negative disease, and these patients were excluded from the final primary analysis data, which included 2,533 patients with ER/PR–positive disease. Of these, 1,268 patients were randomized to metformin and 1,265 received placebo.
After a median follow-up of 96.2 months, 18.4% of those with ER/PR–positive disease had IDFS events. The incidence rates for IDFS were 2.78/100 patient-years in the metformin group and 2.74 per 100 patient-years in the placebo group (P = .93). Further, in this group, 76% of deaths (190 out of 250) were related to BC.
Metformin did not offer a significant survival benefit. The metformin group had 1.46 deaths per 100 patient-years versus 1.32 deaths per 100 patient-years in the placebo group (P = .47). Metformin also did not have an effect on DRFS or BC-free interval. There was no difference in survival based on rs11212617 single nucleotide variation (SNV), which has been found in some earlier studies.
These findings were similar for ER/PR–negative patients. However, metformin use in those who were ERBB2+ BC who had any C allele of the rs11212617 SNV was associated with longer IDFS and longer OS. Metformin did not affect IDFS or OS in patients with ERBB2- BC. By the final year of treatment, 64.3% on metformin and 70.9% of those on placebo had discontinued treatment. The most common grade 3 or higher adverse events were hypertension, irregular menses, and diarrhea.
With all of the emphasis on deprescribing these days, pharmacists can utilize the information from this study to advise against the use of metformin for BC recurrence prevention in patients without a history of diabetes.
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