Alex Buga, David G. Harper, Teryn N. Sapper, Parker N. Hyde, Brandon Fell, Ryan Dickerson, Justen T. Stoner, Madison L. Kackley, Christopher D. Crabtree, Drew D. Decker, Bradley T. Robinson, Gerald Krystal, Katherine Binzel, Maryam B. Lustberg, Jeff S. Volek
Ketogenic diets may positively influence cancer through pleiotropic mechanisms, but only a few small and short-term studies have addressed feasibility and efficacy in cancer patients. The primary goals of this study were to evaluate the feasibility and the sustained metabolic effects of a personalized well-formulated ketogenic diet (WFKD) designed to achieve consistent blood beta-hydroxybutyrate (βHB) >0.5 mM in women diagnosed with stage IV metastatic breast cancer (MBC) undergoing chemotherapy.
Women (n = 20) were enrolled in a six month, two-phase, single-arm WFKD intervention (NCT03535701). Phase I was a highly-supervised, ad libitum, personalized WFKD, where women were provided with ketogenic-appropriate food daily for three months. Phase II transitioned women to a self-administered WFKD with ongoing coaching for an additional three months. Fasting capillary βHB and glucose were collected daily; weight, body composition, plasma insulin, and insulin resistance were collected at baseline, three and six months.
In 2020, breast cancer became the most diagnosed cancer worldwide–with an estimated 2.3 million new cases–surpassing lung cancer . Early detection and treatment have improved breast cancer survival rates to almost 90% , however, approximately only one in three women with stage IV metastatic breast cancer (MBC) survive past five years . Previous dietary interventions, exploring MBC outcomes, focused on low-fat/high-carbohydrate regimens that produced disappointing results [4–6] indicating limited efficacy. Observational studies examining the role of fat in breast cancer have also demonstrated mixed results [7, 8]. The ambient dietary carbohydrate intake is likely to be an important consideration in how dietary fat is metabolized, which in turn might explain inconsistent associations between fat consumption and cancer risk. We previously demonstrated that in the context of a carbohydrate-restricted well-formulated ketogenic diet (WFKD), increased consumption of saturated fat does not lead to increased levels of circulating saturated fat; in fact, blood saturated fat usually decreases [9–12]. Beyond positively influencing saturated fat metabolism, a WFKD is associated with broad-spectrum health benefits, many of which might have favorable impact on breast cancer  treatment and outcomes.
Participants were recruited through the Stefanie Spielman Comprehensive Breast Center at The Ohio State University from October 2017 to September 2019. Data collection and last the last follow-up ended in March 2020. The goal was to enroll 20 women with diagnosed MBC, currently undergoing standard-of-care anticancer therapies, into a WFKD intervention. A summary of patients’ specific disease subtypes (i.e., hormone phenotype), anatomical sites of metastases, and treatment regimens are summarized in Table 1. Detailed drug descriptions are summarized in the supplement (S1 Table). To maximize recruitment and sample size requirements, the trial did not limit participants to specific histological subtypes and/or treatment regimen. A list of inclusion and exclusion criteria are presented in Table 2. The study was registered on ClinicalTrials.gov (NCT03535701) prior to commencing data collection. Approvals for the clinical protocols and clinical oversight were provided by The Ohio State University Institutional Review Board (IRB; #2017C0020) and the Clinical Scientific Review Committee (CSRC; OSU-16289) at the OSU Comprehensive Cancer Center. Written informed consent was obtained from all individual participants included in the study, prior to commencing data collection, and in accordance with the Declaration of Helsinki 2013. A detailed CONSORT diagram depicts the study enrolment (Fig 1).
Enrollment and participant characteristics
Out of the 20 enrolled participants, 5 dropped out during Phase I, and 6 prior to completing Phase II. Thus, 15 participants completed Phase I and 9 participants completed both Phase I and II. Baseline characteristics, disease subtype, study duration, chemotherapy regimen, and brief rationale for withdrawal are presented in Fig 4. In no instance was the primary reason for subject withdrawal attributed to the WFKD. There were also no adverse events associated with the adoption or maintenance of the WFKD.
We demonstrated that a three-month highly supervised WFKD, followed by a three-month self-administered WFKD, was a well-tolerated and sustainable dietary approach for most women with MBC undergoing chemotherapy. Nutritional ketosis was achieved in all the women who completed the first three months, facilitated by using prepared/procured food and frequent nutrition coaching guided by daily monitoring of fasting βHB and glucose. After three months participants received less intense coaching, but maintained nutritional ketosis, improved body weight, body composition, glucose, and insulin sensitivity. To our knowledge, this is the first study to demonstrate that nutritional ketosis can be safely sustained with proper nutritional guidance and monitoring in women with MBC undergoing chemotherapy over six-months.
Women with MBC undergoing chemotherapy were motivated to participate in a ketogenic intervention trial. Most of them transitioned successfully to a WFKD and demonstrated improved metabolic health consistent with responses observed in non-cancer populations. The WFKD was well tolerated by women who demonstrated high adherence as confirmed by daily capillary blood ketone monitoring and had no adverse diet-related events. After three months, women with MBC experienced significant improvements in fasting blood glucose, insulin, insulin resistance, body weight, and body composition, effects that have been observed in healthy individuals. These beneficial metabolic outcomes were sustained in a subset of women who completed six months of the WFKD. Given these positive outcomes, future research studies should explore the use of a similarly designed WFKD as an adjunct therapy in women with MBC, with emphasis on examining a larger cohort, including a control group, and possibly identifying key characteristics in responders and non-responders. Future studies should also consider including a follow-up protocol that assesses long-term benefits to metabolic health, quality of life, and progression-free survival.
The authors would like to thank the participants, oncologists, research volunteers, and metabolic kitchen staff for their invaluable time and efforts that guaranteed this project’s success.
Citation: Buga A, Harper DG, Sapper TN, Hyde PN, Fell B, Dickerson R, et al. (2024) Feasibility and metabolic outcomes of a well-formulated ketogenic diet as an adjuvant therapeutic intervention for women with stage IV metastatic breast cancer: The Keto-CARE trial. PLoS ONE 19(1): e0296523. https://doi.org/10.1371/journal.pone.0296523
Editor: Rainer J. Klement, Leopoldina Hospital Schweinfurt, GERMANY
Received: September 5, 2023; Accepted: December 13, 2023; Published: January 2, 2024
Copyright: © 2024 Buga et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Data described in the manuscript will be made available immediately upon manuscript acceptance on the Ohio State Dryad database at: https://doi.org/10.5061/dryad.kh18932d4.
Funding: Grant Recipient: JV Grant Award #: AWD-102893 Grant Organization: Lotte and John Hecht Memorial Foundation Grant Website: https://www.hecht.org/ The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: JSV receives royalties from book sales; is a founder and has equity in Virta Health; and is a science advisor for Simply Good Foods and Cook Keto. MBL has received consulting fees from AstraZeneca, Biotheranostics, Novartis, Pfizer and PledPharma. The remaining authors have no relevant financial or non-financial interests to disclose. This does not alter our adherence to PLOS ONE policies on sharing data and materials.