Many women consider botanical dietary supplements (BDSs) as safe alternatives to hormone therapy for menopausal symptoms. However, the effect of BDSs on breast cancer risk is largely unknown. In the estrogen chemical carcinogenesis pathway, P450 1B1 metabolizes estrogens to 4-hydroxylated catechols, which are oxidized to genotoxic quinones that initiate and promote breast cancer. In contrast, P450 1A1 catalyzed 2-hydroxylation represents a detoxification pathway. The current study evaluated the effects of red clover, a popular BDS used for women’s health, and its isoflavones, biochanin A (BA), formononetin (FN), genistein (GN), and daidzein (DZ), on estrogen metabolism. The methoxy estrogen metabolites (2-MeOE1, 4-MeOE1) were measured by LC-MS/MS, and CYP1A1 and CYP1B1 gene expression was analyzed by qPCR. Nonmalignant ER-negative breast epithelial cells (MCF-10A) and ER-positive breast cancer cells (MCF-7) were derived from normal breast epithelial tissue and ER+ breast cancer tissue. Red clover extract (RCE, 10 μg/mL) and isoflavones had no effect on estrogen metabolism in MCF-10A cells. However, in MCF-7 cells, RCE treatments downregulated CYP1A1 expression and enhanced genotoxic metabolism (4-MeOE1/CYP1B1 > 2-MeOE1/CYP1A1). Experiments with the isoflavones showed that the AhR agonists (BA, FN) preferentially induced CYP1B1 expression as well as 4-MeOE1. In contrast, the ER agonists (GN, DZ) downregulated CYP1A1 expression likely through an epigenetic mechanism. Finally, the ER antagonist ICI 182,780 potentiated isoflavone-induced XRE-luciferase reporter activity and reversed GN and DZ induced downregulation of CYP1A1 expression. Overall, these studies show that red clover and its isoflavones have differential effects on estrogen metabolism in “normal” vs breast cancer cells. In breast cancer cells, the AhR agonists stimulate genotoxic metabolism, and the ER agonists downregulate the detoxification pathway. These data may suggest that especially breast cancer patients should avoid red clover and isoflavone based BDSs when making choices for menopausal symptom relief.

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Background: Physical limitations and disability among older cancer patients can lead to suboptimal treatment and surveillance for secondary cancers. Our objective was to evaluate the effects of poor physical health-related quality of life (PQOL) and physical functioning (PF) on contralateral breast cancer (CBC) risk among older women diagnosed with unilateral breast cancer (UBC). Methods: We performed a nested case-control study within a cohort from the Surveillance, Epidemiology and End Results Medicare Health Outcomes Survey (MHOS) database. Women were required to have first primary UBC without prophylactic contralateral mastectomy. Among 2,938 women ages 65 years and older with stages I-III UBC between 1997 and 2011, we identified 100 subsequent CBC cases and 915 controls using incidence density sampling without replacement matched on age, race, and quarter-year of diagnosis. PQOL and PF were determined from survey responses to the Medical Outcomes Trust Short Form 36 component scores. Conditional logistic regression models were used to estimate relative risks (RR) and 95% confidence intervals (CI) for metachronous CBC. Results: Cases and controls were similar with respect to comorbidities, stage, surgery and radiation treatments but differed by hormone receptor status (ER/PR-negative, cases 23% and controls 11%). Cases had lower mean PQOL (-1.8; 95% CI -4.3, 0.7) and PF (-2.2, 95% CI -4.9, 0.5) component scores, but these differences were not statistically significant. In multivariable models, estimates suggest increased CBC risk for women in the lowest quartile of PQOL compared to those in the upper quartile (RR=1.8; 95% CI 0.8, 4.3). Compared to women in the upper quartile of physical functioning scores, women in the lower three quartiles had a 2.6-fold (95% CI 1.2, 5.9) increased risk of CBC. Conclusions: Our findings indicate that low physical health-related quality of life is common among older women diagnosed with breast cancer, and poor physical functioning is related to risk of CBC. Efforts to understand and minimize declines in physical functioning post-breast cancer diagnosis may help optimize treatment strategies to reduce the risk of this adverse outcome. Citation Format: Nita Mukand, Nadia Nabulsi, Ali Alobaidi, Alemseged Asfaw, Brian C. Chiu, Naomi Y. Ko, Gregory S. Calip. The association between physical health-related quality of life, physical functioning and risk of contralateral breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5749.