Study suggests an elevated risk for other breast ca subtypes

Having type 2 diabetes (T2D) or taking metformin to treat it had no effect on breast cancer risk although both the disease itself and its treatment influenced the development of specific subtypes of breast cancer, a nationwide, prospective cohort study has shown.

Out of 44,541 participants in the Sister Study, there was no association between T2D and overall breast cancer risk at a Hazard Ratio (HR) of 0.99 (95% CI, 0.85-1.13), Dale Sandler, chief, epidemiology branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina and colleagues reported in the Annals of Oncology.

On the other hand, having T2D increased the risk of developing triple-negative breast cancer by 40% at a HR of 1.40 (95% CI, 0.90-2.16), they added.

Compared with women who did not have T2D, having T2D and being treated with metformin did not increase the risk of breast cancer either at a HR of 0.98 (95% CI, 0.83-1.15), Sandler and colleagues noted, but having T2D and using metformin slightly attenuated estrogen receptor (ER)-positive breast cancer risk at a HR of 0.86 (95% CI, 0.70-1.05), especially among women who took metformin for 10 or more years, where the risk of ER-positive breast cancer was 38% lower at a HR of 0.62 (95% CI, 0.38-1.01; P=0.09).

Compared with not having T2D, T2D with metformin use increased the risk of developing an ER-negative breast cancer by 25% at a HR of 1.25 (95% CI, 0.84-1.88) while the risk of developing triple negative breast cancer was 74% higher at a HR of 1.74 (95% CI, 1.06-2.83).

“Metformin may help reduce breast cancer risk by improving insulin sensitivity and correcting hyperinsulinemia through reduction in circulating insulin and insulin-like growth factor concentrations,” Sandler and colleagues explained. “Our findings suggest that associations between T2D and breast cancer may differ by hormone receptor status and that associations between T2D and ER-positive breast cancer may be reduced by long-term metformin use.”

Sister Study

The Sister Study enrolled women from 35 to 74 years of age whose sisters or half-sisters had been diagnosed with breast cancer.

“During follow-up (median 8.6 years), 2,678 breast cancers were diagnosed at least 1 year after enrollment,” the authors noted. Some 7.2% of the cohort had prevalent T2D—meaning they had diabetes on study enrollment—while 5.3% of them developed incident T2D over the course of the study interval. The majority of both groups at 61% had at some point been treated with metformin.

In an analysis confined to women with incident T2D, developing T2D and receiving treatment with an anti-diabetic medication other than metformin more than doubled the overall risk of breast cancer at a HR of 2.04 (95% CI, 1.17-3.57) compared with not having T2D as well as ER-positive breast cancer, which was increased by over 2.5-fold at a HR of 2.62 (95% CI, 1.46-4.70).

“The associations between metformin use and breast cancer were not appreciably changed after adjusting for duration of diabetes,” Sandler and colleagues observed.

Stratifying results for T2D and metformin use based on a number of demographic variables, analyses showed that the risk of breast cancer was significantly increased by 50% at a HR of 1.50 (95% 1.02-2.19) in ethnicities other than non-Hispanic white or black (P=0.05).

As the authors observed, it is not clear what mechanisms explain the increased risk of ER-negative as well as triple negative breast cancer among women with T2D who took metformin.

Indeed, “some biological evidence has supported anticancer effects of metformin on ER-negative breast cancer and TNBC (triple negative breast cancer),” the authors pointed out. However, given that the benefits of metformin were largely confined to ER-positive breast cancer, “it is possible that it is the underlying diabetes that is associated with the increased risk for ER-negative breast cancer in the absence of any protection from metformin use,” they noted.

Editorial Commentary

Commenting on the findings, Ana Lohmann, MD, University of Western Ontario, London, Ontario and Pamela Goodwin, MD, University of Toronto, Toronto, Ontario, pointed out that the association between T2D and its treatment and breast cancer risk is “biologically plausible” given the many metabolic perturbations seen in T2D that may have an effect on cancer risk.

On the other hand, several other recent studies have examined the association of diabetes with breast cancer risk in relation to breast cancer subtypes and none of these studies found that the association between diabetes and overall breast cancer risk was statistically significant, the editorialists pointed out.

In contradistinction, diabetes was significantly associated with a 22% greater risk of ER-positive breast cancer at a HR of 1.22 (95% CI, 1.01-1.47) in the Nurses’ Health study, but not ER-negative breast cancer.

The risk of breast cancer was also significant when stratified by treatment—metformin versus non-metformin (P=0.04)—in the Women’s Health Initiative.

“Thus, the evidence linking T2D to risk in relation to BC (breast cancer) subtypes is inconsistent, as is the evidence regarding potential effects of T2D treatment (including metformin) on BC risk,” Lohmann and Goodwin observed.

The editorialists also pointed out that despite the large number of women enrolled in the Sister Study, only 277 breast cancers were diagnosed in women with T2D over the study interval including 25 triple negative breast cancers, among whom 177 women with any breast cancer received metformin as did 20 women with triple negative breast cancer.

“The significant association of T2D with risk of TNBC (triple negative breast cancer) in the subgroup treated with metformin (n=20) may have reflected chance and/or uncontrolled bias and confounding,” Lohmann and Goodwin cautioned. “The report by [Sandler] adds to the growing evidence linking T2D and its treatment to BC risk but definitive conclusions regarding those associations are not yet possible.”

  1. Type 2 diabetes in and of itself did not affect the overall risk of breast cancer in a nationwide cohort of women whose sisters or half sisters had been diagnosed with breast cancer.

  2. Both the disease itself as well as treatment with metformin appeared to influence the risk of different subtypes of breast cancer, especially long-term use of metformin which significantly reduced the risk of estrogen receptor-positive breast cancer.

Pam Harrison, Contributing Writer, BreakingMED™

This research was supported by the Intramural Research Program of the NIH.

The authors had no conflicts of interest to declare.

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