Diabetes, Metformin, and Breast Cancer: Lilac Time?
Authors: Pamela J. Goodwin, Alastair M. Thompson, Vuk Stambolic
Journal: Journal of Clinical Oncology (2012)

In recent years, there has been increasing evidence that a complex relationship may exist between diabetes, diabetes treatments, and cancer. An article by Chlebowski et al in Journal of Clinical Oncology reports the results of an exploration of these associations in the Women’s Health Initiative (WHI) clinical trials data sets. Their research has many strengths. The WHI clinical trials program involves more than 68,000 postmenopausal women who were observed prospectively; 11,290 had diabetes at study entry or developed it during follow-up, and 3,273 developed invasive breast cancer after study entry. Detailed information was available on breast cancer risk factors including body mass index (a potential confounder in the associations being studied), thereby allowing adjustment for these factors. Additionally, annual mammographic screening was protocol specified, thereby reducing detection bias; centrally coded (but not centrally validated) information was available on estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2), allowing investigation in breast cancer subsets; and analyses were conducted using time-dependent exposure variables, thereby reducing effects of survival biases and allowing more precise examination of associations. Despite these strengths, screening for the presence or absence of diabetes was not standardized (a validated self-report method was used to ascertain the presence of diabetes), and some cases were likely missed. Furthermore, the use of metformin, a biguanide derived from French lilac, to treat diabetes was not randomly assigned, thus introducing a potential allocation bias. The WHI investigators reported many baseline imbalances in breast cancer risk factors in women with diabetes versus those without diabetes. Many of these imbalances reflected poorer health status of diabetic women (eg, greater obesity and physical inactivity, poorer self-reported health); however, diabetic women were also more likely to be Hispanic, less likely to consume alcohol, and more likely to have had early menarche and menopause and to have undergone a hysterectomy but less likely to have used hormone replacement therapy; they also had lower Gail breast cancer risk scores than nondiabetic women. The frequency of mammography was comparable in women with and without diabetes, although it was somewhat greater in diabetic women who received metformin compared with those who did not. After adjustment for imbalances in these key factors, breast cancer risk did not differ in women with diabetes as compared with those without diabetes (hazard ratio [HR], 0.99; 95% CI, 0.85 to 1.14 for invasive disease; HR, 0.99; 95% CI 0.73 to 1.36 for ductal carcinoma in situ). As noted by the authors, this finding differs from traditional wisdom (based on results of earlier epidemiologic studies using a variety of designs), which holds that diabetes is associated with an increased breast cancer risk. A recent meta-analysis of such studies yielded an HR of 1.25 (95% CI 1.20 to 1.29). However, two recent population-based studies found no evidence of an overall increased risk of breast cancer in women with diabetes, although both identified a modestly increased breast cancer risk in a window shortly after breast cancer diagnosis, consistent with a detection bias that would have occurred if women diagnosed with diabetes were more likely to undergo breast cancer screening. Both of these recent studies included only incident cases of diabetes; women who had been diagnosed with cancer before the diagnosis of diabetes were excluded. How can these divergent results be interpreted? One possible view is that there is no association between diabetes and breast cancer risk in postmenopausal women. Alternatively, the relationship between diabetes and breast cancer may be more complex than previously appreciated. There is growing evidence that insulin contributes to the development and progression of many cancers, including breast cancer. Insulin receptors, notably the fetal form, are frequently overexpressed in breast cancer and precursor lesions; binding of insulin to these receptors can stimulate signaling pathways that enhance proliferation and reduce apoptosis. Furthermore, the dysglycemia that is present before and after diabetes diagnosis may provide a substrate for the Warburg effect. This effect involves metabolism of glucose via aerobic glycolysis in rapidly proliferating cells, such as cancer cells. This is a less energy-efficient process than the oxidation phosphorylation that is used in most normal cells, but it yields substrates needed for cell replication in these rapidly proliferating cells. Clinically, insulin resistance, reflected by higher insulin levels and dysglycemia in the absence of frank diabetes, has been associated with increased breast cancer risk and poor breast cancer prognosis. Together, these observations suggest the time of greatest breast cancer risk may occur during a period of insulin resistance that is typically present for up to 10 years before diagnosis of type 2 diabetes, a period not examined in the WHI study or the two recent epidemiologic reports. Lipscombe et al examined the issue of timing using a population-based postmenopausal sample and reported that an elevated breast cancer risk was present before the diagnosis of diabetes. However, even if there is an increased breast cancer risk before diabetes diagnosis, it cannot be concluded that this relationship is causal, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 23 AUGUST 1