In this prospective cohort of postmenopausal women, the incidence of invasive breast cancer was lower in women with diabetes treated with metformin compared with women without diabetes. Fewer cancers that were positive for both ER and PR and fewer cancers that were HER2 negative were diagnosed in metformin users.
The predominance of prior observational studies2,3,33
have associated diabetes with higher incidence of breast cancer. However, this association has recently been challenged in two large population-based cohort analyses.4,5
In the first, the British Columbia Linked Health Database covering 99% of the British Columbia population of about 4.8 million residents was used to generate a retrospective cohort. With 2,381 patients, incidence of breast cancer was not associated with diabetes status (HR, 1.01; 95% CI, 0.92 to 1.10; P
In the second, the Danish National Diabetes Register and Cancer Registry were linked to perform a cohort analyses of the entire Danish population. In that setting, although incidence of several cancers, including those of the liver, pancreas, and lung, were significantly associated with diabetes, incidence of breast cancer was not (P
In addition, time-varying analyses found evidence of potential detection bias, suggestive of increased cancer surveillance soon after diabetes detection.4,5,34
Similar to women in these recent contemporary cohort reports, women with diabetes in our WHI cohort did not have a higher incidence of breast cancer compared with women without diabetes, a finding potentially influenced by the relatively high frequency of metformin use in these women.
Until recently, observational studies19,20
examining metformin use and incidence of breast cancer were limited and were mixed with two of four studies22,23
reporting significantly lower incidence of breast cancer for women with diabetes who used metformin. Ruitter et al21
have just reported findings from analyses that used the Dutch National Medical Register (a drug-dispensing database) to generate a cohort of 85,289 women. In this setting, a statistically significantly lower incidence of breast cancer was seen in women who used metformin compared with those who used sulfonylurea derivatives (HR, 0.95; 95% CI, 0.91 to 0.98).21
The metformin results in this study add to such analyses by comprehensively adjusting for breast cancer risk factors, including BMI, physical activity, smoking, and frequency of mammography.
Although some preclinical work suggested predominant metformin influence on triple-negative cancers,35
our review found only one prior study that examined metformin influence on breast cancer subtypes. In 90 women with diabetes and breast cancer, the incidence of PR-positive tumors was higher in metformin users.24
Further studies are clearly needed in this area.
Women with diabetes present with a more advanced stage of breast cancer.36–38
but not all42
studies find lower mammographic screening rates in women with diabetes. In the WHI clinical trials, mammograms were mandated by protocol. Consequently, mammogram frequency was comparable in women with and without diabetes, and no significant difference in cancer stage was seen comparing women with diabetes who were not users of metformin with women without diabetes. Women with diabetes who were metformin users had a somewhat higher frequency of mammography compared with nonusers. Metformin nonusers were more commonly receiving insulin and therefore more likely to be under subspecialty care. Because providers of subspecialty care are described as less likely to order screening procedures,43
a difference in screening could result. In any event, analyses were adjusted for mammography frequency.
Clinical studies also support a metformin influence on cancer. In a preoperative study,44
women without diabetes with invasive breast cancer randomly assigned to metformin for 2 weeks had reduced Ki-67, a measure of tumor proliferation,45
compared with nonusers. In a retrospective neoadjuvant therapy analysis, patients with breast cancer who had diabetes and used metformin had a higher frequency of complete response (24%) than patients who had diabetes and did not use metformin (8%) and patients without diabetes (16%; P
Finally, in retrospective analyses, patients with diabetes and HER2-positive breast cancer who used metformin had better clinical outcome that nonusers.47
In post hoc analyses in an adjuvant setting, use of metformin was not associated with improved survival in patients with triple-negative breast cancer, but there was a trend for decreased distant recurrence compared with women without diabetes.48
An inhibitory influence of metformin on breast cancer is biologically plausible but the potential mediating mechanism is not understood. Proposed mechanisms include indirect insulin-mediated effects and direct effects on cancer cells via influence on the AMPK pathway with resultant inhibition of the mammalian target of rapamycin (mTOR) pathway.15,49
We have previously presented metformin findings with similar trends but with less strong associations that were based on the entire WHI population, including participants in both clinical trials and observational studies.50
Our analyses included only participants in the clinical trials because medication information in the observational study was available only through year 3 compared with through year 9 in the clinical trials.
Diagnoses of diabetes were not based on medical record review; rather, they were determined by ongoing direct query and review of the use of antidiabetic medication. As described in Patients and Methods, this approach has been evaluated,27
and the associations seen compare favorably with the commonly used International Classification of Disease, Ninth Revision (ICD-9) clinical modification codes51
; confirmation studies suggest 72% sensitivity and 96% specificity for identification of diabetes.52
The strengths of our study include the prospective cohort design; the large, diverse population well characterized for risk of breast cancer; serial assessment of mammography; breast cancer verification via review of pathology reports; and information on diabetes and the use of diabetes medication updated throughout. This database allowed for time-dependent, exposure-related analyses of use of diabetes medication and risk of breast cancer. Limitations of our study include lack of information on the severity of diabetes and reliance on local laboratory assessment of hormone receptor and HER2 status, precluding information on quality control. Especially noteworthy are the substantial differences in baseline characteristics of women with and without diabetes for factors including obesity and physical activity that could result in residual confounding despite adjustment in analyses for many breast cancer risk factors.
Our findings are of most direct relevance to women with diabetes, most of whom were overweight or obese. However, consideration of the totality of available evidence does provide support for the ongoing clinical studies of metformin,53
including a prospective, full-scale, multicenter adjuvant trial54
and proof of principal studies in prevention settings.55
In a large population of postmenopausal women, use of oral metformin was associated with lower incidence of invasive breast cancer. The influence of metformin on breast cancer subtypes requires further study. Our results inform future studies evaluating use of metformin in the management and prevention of breast cancer.