Adding metformin to standard chemotherapy for non-diabetic breast cancer patients did not improve invasive disease-free survival, according to the Phase III MA.32 trial
Metformin added to breast cancer chemotherapy in women with non-metastatic, high-risk operable breast cancer, does not significantly improve invasive disease-free survival according to the findings of a randomised trial conducted by researchers in Canada, Switzerland and the UK.
It has been found that diabetic patients who develop cancer have a 40% higher mortality risk than non-diabetics. Furthermore, the presence of type 2 diabetes may be associated with 10-20% excess relative risk of breast cancer. Metformin is a biguanide used in the treatment of type 2 diabetes and works by decreasing gluconeogenesis and increases peripheral utilisation of glucose. A 2015 meta-analysis of 11 studies comparing the outcomes of breast cancer therapy in diabetic patients with and without metformin concluded that use of metformin in standard cancer therapy might improve both overall and cancer-specific survivals of diabetic patients. However, other studies have produced opposing results, with one analysis of over 2300 women with breast cancer, concluding that the study failed to show an association between improved survival and increased cumulative metformin use in breast cancer patients who had recent-onset diabetes. In contrast, a 2012 retrospective analysis found that diabetic patients with breast cancer who received metformin and neoadjuvant chemotherapy had a higher pathologic complete response rate than those not receiving the drug.
As the above data was derived from observational studies, which are subject to several forms of bias, for the present study, the researchers conducted a randomised, placebo-controlled trial, focusing specifically on metformin to determine whether the use of the drug in breast cancer patients without diabetes, positively impacted on treatment outcomes.
Adult women without diabetes who received standard therapy for a T1 to T3, No to N3, MO breast cancer were recruited and stratified as either oestrogen and/or progesterone receptor positive (ER/PgR +) or negative (ER/PgR -). Enrolled participants were then randomised 1:1, to 850 mg of metformin once daily or matching placebo for 4 weeks and the dosage was then increased to twice daily for 5 years. The primary endpoint of the trial was invasive disease-free survival. Secondary outcomes included overall survival and the incidence rates for death.
Metformin use and invasive disease-free survival
A total of 3649 women with a mean age of 52.4 years of whom, 2533 were ER/PgR + were recruited. However, futility was declared for the ER/PgR- group and so the analysis was restricted to the 2533 women who were ER/PgR +.
After a median follow-up of 96.2 months, 18.4% of women had invasive disease-free survival (234 in the metformin group vs 231 in the placebo arm), giving an incidence rate of 2.78 per 100 patient-years in the metformin group and 2.74 in the placebo group (hazard ratio, HR = 1.01, 95% CI 0.84 – 1.21, p = 0.93). Similarly, the risk of death was not significantly different (HR = 1.10, 95% CI 0.86 – 1.41, p = 0.47). Although futility was declared for those with ER/PgR-, among the patients who were followed up for a median of 94.1 months, there was also no difference in the level of invasive disease-free survival (HR = 1.01, 95% CI 0.79 – 1.30, p = .082). There were also no significant differences in any of the secondary outcomes.
The authors concluded that despite the evidence from observational studies, use of adjunctive metformin did not improve invasive disease-free survival in women with breast cancer without diabetes.
Goodwin PJ et al. Effect of Metformin vs Placebo on Invasive Disease–Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial JAMA 2022