Background An individual’s metabolic state plays a critical role in breast cancer (BC) risk, influenced by factors such as obesity and insulin signaling. Hypocaloric diets induce metabolic changes that influence these metabolic factors, thereby potentially influencing BC risk. However, it remains unclear whether metabolic profiles like those induced by such beneficial diets are associated with BC risk.

Methods We compared the impact of a hypocaloric low-carbohydrate ketogenic diet (KD) and a low-fat diet (LFD) on BC risk in two stages. First, we developed metabolomics-based scores representing the metabolic states resulting from these two hypocaloric diets. Plasma metabolomics data of 43 individuals from two controlled dietary interventions were analyzed (N = 31 KD, N = 12 LFD) and a metabolite-based score was generated for both KD and LFD using diet-induced fold-changes. Second, these scores were applied to metabolomics data from a nested case-control study of participants from the Nurses’ Health Study II (NHSII, 1,058 BC cases, 1,054 controls, predominantly premenopausal women). Using multivariable-adjusted models, we assessed the association between the metabolomic scores and BC risk.

Results KD and LFD had similar but distinct metabolic signatures. Both metabolomics scores were positively associated with breast cancer risk in NHSII. Women in the highest quartile of the KD metabolomic score had a 37% increased risk of BC compared to women in the lowest quartile (p=0.021). Similarly, women in the highest quartile of the LFD metabolomic score had a 32% increased BC risk compared to women in the lowest quartile (p=0.008). Similar increases in risk were seen when further adjusting for BMI at age 18 and weight change since age 18. Increased levels of cholesterol esters (CE), particularly CE 22:6, and long-chain polyunsaturated triglycerides were associated with higher risk in both diet scores, while increases in short-chain, more saturated triglycerides were associated with lower risk.

Conclusion Metabolomic profiles resembling those induced by hypocaloric ketogenic and low-fat diets were unexpectedly associated with an increased risk of breast cancer in a predominantly premenopausal cohort. These associations were independent of BMI, highlighting the complex relationship between metabolic states and cancer risk, independent of actual dietary interventions.

M.D.G. holds equity in Faeth Therapeutics and Skye Biosciences; reports consulting or advisory roles with Almac Discovery, Genentech Inc, Faeth Therapeutics, Scorpion Therapeutics, and Skye Biosciences; honoraria from Pfizer Inc.; patents, royalties, and other intellectual property with Weill Cornell Medicine and Faeth Therapeutics. V.M. has institutional grants or contracts with AstraZeneca, Bristol Myers Squibb, Cullinan Oncology, DualityBio, Eisai, Faeth Therapeutics, Karyopharm Therapeutics, Merck, Takeda, and Zymeworks; receives personal meeting/travel support from AstraZeneca; and is an unpaid consultant for Clovis Oncology, Cullinan Oncology, DualityBio, Eisai, Faeth Therapeutics, Jazz Pharmaceuticals, GlaxoSmithKline, Immunocore, iTeos Therapeutics, Karyopharm Therapeutics, Lilly, Merck, Mereo BioPharma, MorphoSys, MSD, Novartis, Regeneron, Sutro Biopharma, and Zymeworks. JK is co-founder and holds equity in iollo and ExactRx and is an advisor to Everfur (Stand Health Inc).

This study was funded by the National Institutes of Health (NIH)/National Cancer Institute (NCI) with the following grants: UM1 CA186107, P01 CA87969, R01 CA49449, R01 CA050385, U01 CA176726, U01 CA260352, R01 CA067262 and Susan G. Komen Foundation. Funding for this study also came from 2020 AACR-The Mark Foundation for Cancer Research "Science of the Patient" (SOP) Grant (20-60-51-GONC), NIH R01CA279561, and Cycle for Survival.

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IRB of Brigham and Women's Hospital gave ethical approval for this work IRB of Harvard T.H. Chan School of Public Health gave ethical approval for this work

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https://github.com/krumsieklab/hypocaloric-diet-bc