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Background: Preclinical data suggest that metformin may reduce breast cancer incidence and improve cancer prognosis. However, the current evidence in observational studies is inconclusive. A systematic review and meta-analysis was conducted to assess the effect of metformin on the incidence of breast cancer and all-cause mortality in patients with type II diabetes (T2D). Methods: A literature search was performed on Medline, EMBASE, and the Cochrane library from inception to November 2016. Outcomes were incidence of breast cancer and all-cause mortality. Risk of bias and overall certainty of evidence was assessed using the Newcastle-Ottawa Scale and Grading of Recommendations Assessment, Development, and Evaluation (GRADE), respectively. Meta-analyses were performed using the most fully adjusted ORs or HRs and 95% confidence intervals (95% CI) as effect measures. Results: A total of 12 observational studies were included for breast cancer incidence and 11 studies for all-cause mortality. No significant association was found between metformin exposure and incidence of breast cancer (OR = 0.93; 95% CI, 0.85–1.03; I2 = 35%). A 45% risk reduction was observed for all-cause mortality (HR = 0.55; 95% CI, 0.44–0.70; I2 = 81%). Presence of publication bias is strongly suspected for both outcomes using Egger's funnel plots. Conclusions: The use of metformin may improve overall survival in patients with T2D and breast cancer. No effect of metformin on the incidence of breast cancer was observed. Interpretation of results is limited by the observational nature of the studies and resulting biases. Impact: Clinical trials are warranted to determine the role of metformin in breast cancer risk reduction and prognosis. Cancer Epidemiol Biomarkers Prev; 27(6); 627–35. ©2018 AACR.

Background: Endogenous sex hormone levels have been associated with increased breast cancer risk in postmenopausal women in several prospective studies. However, it remains unclear to what extent serum hormone-breast cancer associations differ with receptor status. Methods: Associations between serum sex hormone levels and breast cancer risk were assessed in a nested case-control study on postmenopausal women of the ORDET cohort. After a median follow-up of 13.5 years, 165 women developed breast cancer. Relative risks of developing breast cancer were estimated by conditional logistic regression. Results: Total and free testosterone levels were directly associated with breast cancer risk [relative risk, 3.28 (95% confidence interval, 1.93-5.55) and 2.86 (95% confidence interval, 1.66-4.94), respectively, for highest versus lowest quartile]. When relations between hormone level and risk of breast cancer expressing various receptor combinations were assessed, high total testosterone was significantly associated with increased risk of estrogen receptor–positive cancers, irrespective of progesterone receptor status. High total testosterone was also associated with increased risk of both human epidermal growth factor receptor 2 (HER2)–negative (HER2−) and HER2+ cancers. High estradiol tended to be associated with increased risk of HER2− cancer and inversely associated with HER2+ cancer, with significant (P = 0.027) heterogeneity between HER2+ and HER2− cancers. However, there were relatively few HER2+ cases. Conclusions: This study provides further evidence that high levels of circulating testosterone increase the risk of developing breast cancer in postmenopausal women. The cancers that develop are mainly estrogen receptor positive. Although HER2+ and HER2− breast cancers were both associated with high total testosterone, they showed opposing associations with estrogen. (Cancer Epidemiol Biomarkers Prev 2009;18(1):169–76)

Catalase, a ubiquitous heme enzyme, catalyzes conversion of hydrogen peroxide to water and molecular oxygen, protecting cells from oxidative stress. A C/T polymorphism in the promoter region of the CAT gene (rs1001179) affects transcriptional activity and RBC catalase levels. Oxidative stress may explain the observed increased postmenopausal breast cancer risk associated with hormone replacement therapy (HRT). We examined CAT genotype, HRT, and postmenopausal breast cancer risk in the Western New York Exposures and Breast Cancer case-control study. Cases (n = 616) were women with primary, incident, pathologically confirmed breast cancer. Randomly selected controls (n = 1,082) were frequency matched to cases on age and race. Genotype was assayed by matrix-assisted laser desorption ionization time-of-flight mass spectrometry. Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) adjusted for potential confounders. CAT genotype alone was not associated with breast cancer risk. Ever use of HRT was associated with increased risk (OR, 1.39; 95% CI, 1.11-1.75). The increase with ever use was more pronounced among those with variant CT or TT CAT genotype (OR, 1.88; 95% CI, 1.29-2.75) than among those with CC (OR, 1.15; 95% CI, 0.86-1.54). Similarly, risk associated with ≥5 years of HRT use was greater among those with at least one variant T allele (OR, 2.32; 95% CI, 1.50-3.59). Increased risk was limited to estrogen receptor–positive tumors. Our findings suggest that CAT genotype modifies the effect of HRT use on breast cancer risk and that HRT may affect risk by affecting oxidative stress. (Cancer Epidemiol Biomarkers Prev 2008;17(5):1082–7)

Specific fatty acids may have differential effects on breast cancer etiology. Animal studies have suggested that conjugated linoleic acids (CLA), a group of fatty acids found predominantly in dairy products and the meat of ruminants, have potent anticarcinogenic properties. We examined breast cancer risk and dietary CLA intake among 1,122 women with primary, incident, histologically confirmed breast cancer and 2,036 controls frequency matched to cases by age, race, and county of residence. Diet was assessed with a self-administered 104-item food frequency questionnaire and other relevant data were collected by detailed in-person interviews. We examined risk with intake of total CLAs and the 9c,11t-18:2 isomer of CLA (9,11 CLA). Odds ratios and 95% confidence intervals were estimated by unconditional logistic regression, adjusting for age, the residual of fat adjusted for energy, and other breast cancer risk factors. No association was observed between intakes of total CLA or 9,11 CLA and overall risk of premenopausal or postmenopausal breast cancer. We observed little association between CLA intakes and risk of estrogen receptor (ER)–negative or ER-positive tumors, although, compared with premenopausal women in the lowest quartile of 9,11 CLA intake, those in the highest quartile had a marginally significant reduction in risk of having an ER-negative tumor (odds ratio, 0.40; 95% confidence interval, 0.16–1.01). Our findings suggest that, although CLA intake was not related to overall breast cancer risk, there may be associations with tumor biology at least among premenopausal women.

To the Editor: We read with great interest the article by Cazzaniga et al. ([1][1]) on the potential use of the insulin sensitizing agent metformin for therapeutic and chemopreventive purposes in breast cancer. We found that the safety profile of metformin was inadequately elicited and poorly