Insulin resistance and diabetes play a role in the pathogenesis of endometrial cancer and are also potential side effects of its treatment. Research has been conducted to determine whether metformin improves outcomes in patients with endometrial cancer.

The insulin-like growth factor (IGF) system is significant in endometrial cancer, and women with diabetes or insulin resistance are at higher risk for endometrial cancer. Metformin works by increasing the uptake of insulin into cells, so molecularly it makes sense that it could be helpful. We did a phase 0 window-of-opportunity study at MD Anderson that enrolled patients with newly diagnosed endometrial cancer who were surgical candidates designated to receive oral metformin prior to surgery. Women received metformin for 7 to 30 days, depending on the timing of their surgery. We looked at growth pathways at baseline and at the time of surgery, and we saw that, even with a short exposure to metformin, there was a downregulation of serum insulin and IGF-1. A similar study had been done previously in patients with endometrial cancer and obesity that showed consistent findings.

In a large, randomized, phase 2/3 NRG Oncology/GOG Foundation study on advanced endometrial cancer, patients received standard-of-care chemotherapy (carboplatin and paclitaxel) with either placebo or metformin to see if it would improve progression-free survival. Unfortunately, the study stopped data accrual early because no treatment benefit was shown.

One of the side effects of the mTOR inhibitor everolimus is hyperglycemia. So, in a phase 2 trial evaluating everolimus and letrozole in patients with hormonally driven recurrent endometrial cancer, we started metformin in those who had developed hyperglycemia, and several other patients were already receiving metformin for that indication. The response rate of patients on metformin was 56% compared with 23% for those not on metformin.

We did a small, follow-up, single-arm, phase 2 study looking at the combination of all 3 drugs. Small studies are not always directly comparative, but when we treated patients with metformin, everolimus, and letrozole, the response rate was 28%, although it was hard to conclude whether adding metformin actually made a significant improvement. When patients receive hormonally driven therapies such as mTOR inhibitors and antiestrogens, I do not give everyone metformin because you do not want to add a drug that has toxicity unless there is a clear benefit. But, certainly, in patients who develop hyperglycemia or diabetes, I think that metformin is the go-to drug because it helps control blood sugar and may have some benefit in managing endometrial cancer as well.