Background: Circulating branched-chain amino acid (BCAA) levels reflect metabolic health as well as dietary intake and have been linked to some cancers. Associations with breast cancer are unclear.

Methods: We evaluated the association between circulating BCAA levels and risk of breast cancer by menopausal status at the time of sample collection in a prospective nested case-control study (1,997 cases, 1,997 controls) within the Nurses' Health Study (NHS) and NHSII. Two-thirds of women in NHS (592 cases) donated two blood samples collected 10 years apart. We used conditional logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) of breast cancer risk in multivariable models which included BMI at age 18 and adulthood weight gain, in addition to other risk factors. We conducted an external validation with secondary analyses in the Women's Health Study (WHS) (1,297 cases).

Results: Among NHSII participants (predominantly premenopausal at blood collection), elevated circulating BCAA levels were associated with suggestively lower breast cancer risk (e.g., isoleucine highest vs. lowest quartile, multivariable OR (95% CI)= 0.86 (0.65-1.13), p-trend=0.20), with significant linear trends among fasting samples (e.g., isoleucine OR (95% CI)=0.74 (0.53-1.05), p-trend=0.05). In contrast, among postmenopausal women, proximate measures (within 10y from sample collection) were associated with increased breast cancer risk (e.g., isoleucine highest vs. lowest quartile multivariable OR (95% CI)=1.63 (1.12-2.39), p-trend=0.01), with slightly stronger associations among fasting samples (OR (95% CI)=1.73 (1.15-2.61), p-trend=0.01). Distant measures (10-20y since sample collection) were not statistically significantly associated with risk (OR (95% CI)=1.15 (0.87-1.52), p-trend=0.35). We did not observe significant heterogeneity by ER status or BMI. In the WHS, a suggestive positive association was observed for distant measures of leucine among postmenopausal women: OR (95% CI)=1.31 (0.97-1.75), p-trend=0.05.

Conclusion: Although elevated circulating BCAA levels were associated with lower breast cancer risk among premenopausal NHSII women and higher risk of postmenopausal breast cancer in NHS when assessed within 10 years of diagnosis, independent of established risk factors, including adiposity, results were not validated in WHS. Additional independent studies are needed to reassess and understand the complex relationship between BCAAs, menopausal status and timing, and risk of breast cancer.

Citation Format: Oana A. Zeleznik, Raji Balasubramanian, Yumeng Ren, Deirdre K. Tobias, Bernard A. Rosner, Cheng Peng, Alaina M. Bever, Lisa Frueh, Clary B. Clish, Samia Mora, Frank B. Hu, A. Heather Eliassen. Branched-chain amino acids and risk of breast cancer by menopausal status in three large cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 746.