SAN ANTONIO — Metformin, an old and familiar diabetes drug, might have a future in the prevention and adjuvant therapy of breast cancer.
Accumulating evidence from epidemiologic, cell culture, and animal studies suggests that metformin has an antineoplastic effect. The drug is in ongoing randomized clinical trials with biomarker end points in breast cancer patients. If outcomes prove favorable, larger trials with clinical end points in the prevention and adjuvant settings are likely, Dr. Michael Pollak said at the annual San Antonio Breast Cancer Symposium.
Although metformin is often described as an insulin sensitizer because it reduces hyperinsulinemia in insulin-resistant patients, he and his colleagues have shown that it acts as a growth inhibitor in human epithelial cells, including breast cancer cells, by activating the adenosine monophosphate kinase pathway (Cancer Res. 2006;66:10269–73).
This finding, coupled with the fact that metformin reduces circulating insulin and insulinlike growth factor (IGF) levels, provides mechanisms to explain the observation in epidemiologic studies that women on metformin appear to have a reduced likelihood of developing breast cancer, and that breast cancer patients on metformin have a better prognosis, according to Dr. Pollak, professor of oncology and medicine and director of the Cancer Prevention Program at McGill University, Montreal.
He explained that the classic medical school teaching regarding insulin is incomplete. The conventional wisdom holds that insulin is a product of pancreatic β cells that regulates systemic energy balance by acting on insulin-sensitive liver, fat, and muscle tissues. In reality, insulin is present and regulates cell behavior even in simple organisms without a pancreas. Moreover, both normal and transformed human epithelial cells contain copious receptors for insulin and IGF-1.
Body mass index, caloric intake, physical exercise, birth weight, and the timing of the adolescent growth spurt are all breast cancer risk or prognosis factors. And they have a common underlying theme: All are related to insulin and IGF signaling and other hormonal mediators of energy balance and growth regulation.
Greater BMI means higher circulating insulin and IGF-1 levels, and while higher BMI is only modestly associated with increased breast cancer risk, it is more strongly related to worse mortality in women who have the malignancy. Hence, the increasing prevalence of obesity in North America could begin to erode the substantial improvements in breast cancer mortality seen in the last two decades, the endocrinologist said.
In one recent hypothesis-generating metformin study, Dr. Josie M.M. Evans and coworkers at the University of Dundee (Scotland) evaluated roughly 11,876 patients with newly diagnosed type 2 diabetes, of whom 923 were subsequently diagnosed with cancer. The adjusted relative risk of malignancy in long-term metformin users was reduced by 44%, compared with nonusers (BMJ 2005;330:1304–5).
In another population-based cohort study, investigators at the Institute of Health Economics, Edmonton, Alta., identified 10,309 Saskatchewanians with type 2 diabetes. During an average of 5.4 years of follow-up after their diagnosis, 407 cancer-related deaths occurred. Cancer mortality was 3.5% in metformin users, 5.8% in insulin users, and 4.9% in individuals on sulfonylurea monotherapy. After adjustment in a multivariate Cox regression analysis, cancer-related mortality was 30% greater in sulfonylurea users than in metformin users. In insulin users, it was 90% higher than in metformin users (Diabetes Care 2006;29:254–8).
Dr. Pollak speculated that the subgroup of breast cancer patients most likely to benefit from metformin in terms of reduced recurrence and mortality risks are those with high circulating insulin or C-peptide levels. This would include not only the many patients with a high BMI, but also what he called normal-weight metabolically obese individuals.
“These people have high insulin levels even though they're thin. There are lots of such individuals in affluent societies,” he said.
Even as Dr. Pollak and others focus on metformin as a possible breast cancer agent, more than a dozen pharmaceutical companies are developing drugs targeting the IGF-1 signaling pathway for the treatment of various cancers. The products in the pipeline fall into three strategies: antiligand antibodies, antireceptor antibodies, and small-molecule tyrosine kinase inhibitors. Most are in preclinical or phase I studies.
In contrast, nearly 35 million prescriptions per year are written for the generic version of metformin alone. The drug is well tolerated and its safety profile is thoroughly established.
Patients with high insulin orC-peptide levels may be most likely to benefit from metformin. DR. POLLAK