Evidence Still Cloudy for Anticancer Effects with Metformin
Observational studies have suggested that the antidiabetes agent metformin (Glucophage) may have anticancer effects. New studies have attempted to confirm this, but the results and their meaning still remain unclear.
Reviewing several studies presented at the meeting, Michael N. Pollak, MD, the Alexander Goldfarb Research Chair in Cancer Research and the Director, Division of Cancer Prevention, Department of Oncology, McGill University, Montreal, Canada, said that there are many unanswered questions, but that “some of those questions have become clearer.”
The rationale for investigating antitumor effects that may be attributed to metformin stemmed first from the observation that diabetic patients receiving the drug were less likely to develop breast cancer than diabetic patients who did not receive metformin. Laboratory studies have pointed to multiple mechanisms by which metformin may inhibit tumor growth or proliferation, but preclinical models do not accurately reflect the metformin concentrations achieved in humans, Dr Pollak said.
In a study presented at the meeting, Italian investigators evaluated cancer-cell apoptosis in 88 patients with breast cancer who were randomized to metformin or to placebo for 4 weeks before surgery for early breast cancer. Apoptosis was similar between the groups at baseline, but it increased significantly in both arms before surgery. An interaction was seen between apoptosis (by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling [TUNEL] assay) and homeostasis model assessment, a measure of insulin resistance.
Patients who were not insulin resistant had a TUNEL level of 10% with metformin versus 6% with placebo (P = .05). In contrast, women with insulin resistance had a median TUNEL value of 6% with metformin and 9% with placebo (P = .3). Proliferation by Ki67 was also correlated with TUNEL at baseline and surgery, according to Giancarlo Pruneri, MD, Assistant Professor, Division of Pathology, European Institute of Oncology, Milan School of Medicine, Italy.
A small presurgical study from Columbia University showed no effect of metformin on tumor proliferation. The mean Ki67 values did not change significantly according to metformin exposure.
Positive Effects of Metformin in Breast Cancer
However, a small Canadian study showed metformin to be potentially beneficial in 38 nondiabetic women with early breast cancer who took the drug for 2 weeks or longer before diagnostic core biopsy. The neoadjuvant use of metformin was associated with a significant reduction in Ki67 activity (P = .016) and with a significant increase in TUNEL (P = .037).
Other markers of tumor proliferation were also reduced significantly, according to Ryan J. O. Dowling, PhD, Division of Signalling Biology, Ontario Cancer Institute, Canada, and colleagues, who noted that changes in insulin levels and Akt signaling suggest that metformin has clinically important insulin-dependent effects on tumor growth.