Charles Shapiro, MD

Charles Shapiro, MD, Professor of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, commented on the study findings.

“MA.32 is a large, randomized placebo-controlled trial of metformin in over 3,600 women with invasive breast cancer. The rationale for metformin was sound, and the primary endpoints—invasive disease–free survival and overall survival—were most appropriate. At 8 years of median follow-up, neither the overall results, nor the subsets of estrogen and progesterone receptor–positive or –negative, did not differ statistically from placebo. In an exploratory analysis, a subset of 620 women with HER2-positive breast cancers seemed to benefit from metformin. As with all subset analyses, when the overall trial is negative, subset analyses should be taken with the ‘proverbial grain of salt.’ The authors concluded that more work needs to be done, and rightly so,” Dr. Shapiro said.

“Metformin affects insulin signaling and insulin resistance. Both are still relevant to breast cancer. Definitive negative trials, such as this one, should be presented and published, and the authors congratulated. What works and does not work are both equally important. The trial was ‘cutting edge’ for its time, and the correlative studies have yet to be presented. Perhaps, if the trial collected tumors, genomic profiling identifying mutations or immunophenotyping of the tumor microenvironment will lead to some benefits of metformin in yet unidentified subsets. Likewise, if plasma was collected, it may be possible to assay circulating DNA to identify ESR1, PI3 kinase, and other mutations. I hope sufficient funding for the correlative studies exists,” he continued.

“The trial began accrual in 2010 and was designed in earlier years. A deeper understanding of the biology of the breast cancer subsets now exists, and a new generation of therapeutics such as poly (ADP-ribose) polymerase inhibitors in BRCA-mutation carriers, CDK4/6 inhibitors, immunotherapy, and antibody-drug conjugates are in routine clinical practice. None of these agents existed when the trial was first designed. We are making incremental progress in the treatment of breast cancer, and it is a good thing for women and health-care providers,” Dr. Shapiro noted. 

DISCLOSURE: Dr. Shapiro has received royalties from UptoDate and has served as a consultant for 2nd MD and Anthenum.