The Benefits of Adding Metformin to Tamoxifen to Protect the Endometrium: A Randomized Placebo-Controlled Trial

Davis, S. R. et. al. Clin Endocrinol 2018;89(5):605-612
Source: https://doi.org/10.1111/cen.13830

One of tamoxifen’s uses is to reduce the risk of breast cancer recurrence among women with estrogen receptor (ER)-positive disease. A known risk of taking the medication is endometrial cancer. This risk leads many women to decide against taking the drug.

Tamoxifen acts as an antagonist in the breast, meaning that it hinders cellular growth. However, in the endometrium (lining of the uterus), it works as an agonist and promotes growth. This leads to thickening of the endometrium and can result in polyps, hyperplasia or cancer. As tamoxifen is now recommended for use for up to 10 years, its side effects and risks are of increasing concern.

The endometrial thickening caused by tamoxifen is due to a particular cellular pathway. It is this same pathway that is blocked by metformin, an antidiabetic medication. The investigators sought to determine if metformin actually had a clinically significant effect upon the endometrium.

Just over 100 women in Australia were included in this study. They were all under 75 years of age and had been prescribed tamoxifen as part of their ER-positive breast cancer treatment. They were randomized between daily metformin and placebo. Transvaginal ultrasounds were performed to assess endometrial thickness prior to starting metformin/placebo as well as 52 weeks later.

For the women who remained eligible for study at the 52-week timepoint, endometrial thickness was significantly lower among the women who used metformin. More women who took placebo had endometrial ultrasound findings that led to endometrial sampling. No hyperplasia, polyps or cancer were identified in either group. Hyperplasia is an abnormal increase in volume of a tissue or organ caused by the formation and growth of new normal cells.

This study shows that metformin may counteract the endometrial side effects of tamoxifen in women with ER-positive breast cancer. More evaluations, over longer periods of time, are needed to determine if the risk of endometrial cancer would be reduced with the drug. Moreover, there are other effects of metformin that would need to be evaluated. Nonetheless, this study provides promising information about counteracting a scary risk of tamoxifen.