Abstract PD03-01: Significant Reduction of Triple-Negative Breast Cancers in Diabetic Women on Metformin

Abstract

Background: Diabetes is an increasingly prevalent chronic disease. Many of these patients may develop breast cancer (BC). A meta-analysis by Larsson (2007)demonstrated that diabetic women have an increased risk (RR: 1.2) of BC particularly for estrogen receptor positive (ER+) subtypes (RR: 1.22). However, a recent study by Bodmer (2010) showed that women on long-term metformin have a reduced incidence of BC (OR 0.44, 95% CI 0.24-0.82). Metformin has antiproliferative effects on BC based on studies using proliferative marker Ki67. BC patients on metformin have better cancer-specific survival based on Landman (2010). We hypothesize that when compared to other diabetic medications; including exogenous insulin and other oral hypoglycemics; metformin specifically reduces the incidence of triple negative BCs (TNBC or ER-/PR-/Her2-). Methods: We conducted a retrospective chart review of an unselected cohort of patients who underwent surgical interventions for their primary BC to correlate the history of pre-existing diabetes and metformin use to the BC subtypes based on the immunohistochemistry of the surgical specimens. P-values were calculated using Chi-square and Fisher exact tests. Results: There were 99 TNBC in the 1005 patients reviewed. Of the 90 diabetic patients, none of the 44 patients took metformin had TNBC, compared to 7 of the 46 diabetic patients not taking metformin had TNBC (0% vs. 15.2% p=0.007). Discussion: Studies that examined the incidence of BC in diabetics were not able to differentiate the effects of various diabetic treatments on the subtypes of BC. The reported increase in ER+ BC in diabetics is likely multifactorial but may be attributed to the proliferative effects of hyperinsulinemia. Interesting, of all the diabetic medications, Bodmer (2010) reported only metformin reduced the incidence of BC. In this study, we reported a statistical significant reduction in the incidence of TNBC. In fact, in our study population, there was no TNBC in patients who took metformin. Hirsch (2009) reported a selective inhibition of BC stem cells with metformin. Of interest, many studies have shown that BC stem cells were ER-/PR-/Her2-. This study supports the view that the phenotype of the BCs can be influenced by drug. At this point, we cannot differentiate if metformin can “protect” patients from developing TNBC, or “convert” TNBC to other subtypes of BC, further study is underway to address this question. Figure available in online version. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD03-01.

The effect of metformin on breast cancer outcomes in patients with type 2 diabetes

“…It is unclear whether metformin influences the development of specific histologic features or alters the clinical presentation of BC, although metformin use among diabetics has been associated with BCs that are less frequently triple negative . Overall, we did not observe a difference in any histopathologic features or hormone receptor status between users and nonusers of metformin.…”

Metformin in cancer: translational challenges

“…frequently progesterone receptor (PgR) positive (Berstein et al 2010a) and less frequently triple negative (Meiers et al 2010), whereas in lung cancer, metformin use has been associated with a higher frequency of adenocarcinomas (vs other histologies; Mazzone et al 2010, Tan et al 2011.…”

Metformin Induces Apoptosis and Downregulates Pyruvate Kinase M2 in Breast Cancer Cells Only When Grown in Nutrient-Poor Conditions

“…These observations have been validated by a recent study showing a 31% reduction in cancer incidence and mortality when metformin is administered in the treatment of diabetes [ 8 ]. Moreover, because of decreasing insulin levels, metformin-treated patients present a reduced risk of developing obesity related tumors, such as breast and colorectal cancers [ 9 ].…”