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Oral Hypoglycemics for Breast Cancer?

Diabetic patients who received metformin plus neoadjuvant chemotherapy achieved higher pathologic complete response rates than those who received chemotherapy alone.

Population-based studies have demonstrated that use of metformin — a drug commonly prescribed as first-line therapy for type 2 diabetes — is associated with diminished incidence of cancer. Also, in vitro studies have shown that metformin has antiproliferative effects against a wide variety of cancer cells, including breast cancer cells. To support these findings with clinical data, investigators conducted a retrospective study involving 2529 patients who received neoadjuvant chemotherapy for early-stage breast cancer.

The study cohort consisted of 68 diabetic patients who received metformin, 87 diabetic patients who did not receive metformin, and 2374 nondiabetic patients. All patients received 3 to 6 cycles of an anthracycline-based chemotherapy regimen. Additional taxane therapy (paclitaxel or docetaxel) was administered to 75% of patients; other therapies (adjuvant endocrine therapy and radiation therapy) were administered as clinically appropriate. Diabetic patients were older and more likely to be postmenopausal, overweight, and obese than nondiabetic patients. Diabetic patients also were more likely than nondiabetic patients to receive neoadjuvant taxane therapy (87% vs. 75%; P=0.01).

The pathologic complete response (pCR) rate (defined as no tumor in the breast or lymph nodes) was 24% in the metformin group, 8% in the nonmetformin group, and 16% in the nondiabetic group (P=0.02). Pairwise comparisons of pCR rates were significant between the metformin and nonmetformin groups (P=0.007) and between the nonmetformin and nondiabetic groups (P=0.04) but not between the metformin and nondiabetic groups (P=0.10).

Comment: Should patients receive metformin with their chemotherapy? No! But the apparent enhanced benefit associated with metformin is interesting and, as editorialists note, might be biologically based. Metformin inhibits transcription of key gluconeogenesis genes in the liver and increases glucose uptake in skeletal muscle, thereby reducing circulating glucose levels, increasing insulin sensitivity, and reducing hyperinsulinemia associated with insulin resistance. These actions all have been implicated in breast cancer prognosis. The key molecular pathway that seems to explain metformin's many actions is activation of adenosine monophosphate–activated protein kinase. Such activation phosphorylates and stabilizes the protein product of the tuberous sclerosis complex tumor suppressor gene, an inhibitory process that effects the mammalian target of rapamycin (mTOR) pathway. Activation of mTOR has pleiotropic effects including proliferation, drug resistance, protein translation, and cell growth. Although the results of this study are intriguing, a much larger prospective adjuvant clinical trial has been proposed to evaluate the effects of metformin on clinical outcomes in patients with early-stage breast cancer.

— William J. Gradishar, MD

Published in Journal Watch Oncology and Hematology August 11, 2009

Citation(s):

Jiralerspong S et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 2009 Jul 10; 27:3297.

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• Medline abstract (Free)

Goodwin PJ et al. Metformin in breast cancer: Time for action. J Clin Oncol 2009 Jul 10; 27:3271.

• Original article (Subscription may be required)
• Medline abstract (Free)