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In preclinical experiments, cyclic fasting-mimicking diets (FMDs) showed broad anticancer effects in combination with chemotherapy. Among different tumor types, triple-negative breast cancer (TNBC) is exquisitely sensitive to FMD. However, the antitumor activity and efficacy of cyclic FMD in TNBC patients remain unclear. Here, we show that a severely calorie-restricted, triweekly, 5-day FMD regimen results in excellent pathologic complete response (pCR) rates (primary endpoint) and long-term clinical outcomes (secondary endpoints) when combined with preoperative chemotherapy in 30 patients with early-stage TNBC enrolled in the phase 2 trial BREAKFAST. Bulk and single-cell RNA sequencing analysis revealed that highly glycolytic cancer cells, myeloid cells, and pericytes from tumors achieving pCR undergo a significant, early downmodulation of pathways related to glycolysis and pyruvate metabolism. Our findings pave the wave for conducting larger clinical trials to investigate the efficacy of cyclic FMD in early-stage TNBC patients and to validate early changes of intratumor glycolysis as a predictor of clinical benefit from nutrient restriction. This study was registered at Clinicaltrials.gov (NCT04248998)., Competing Interests: Declaration of interests The authors declare the following competing interests: G.V.B., speaker/advisory board: Novartis, Eli Lilly, Daichi/Astrazeneca, Roche, MSD, and Seagen; G.P., consulting fees: Roche, Bayer, and Astra Zeneca; C.V., consulting fees/advisory board: Novartis, Pfizer, Eli Lilly, Daiichi Sankyo, and Menarini Stemline; C.V., honoraria as speaker: Novartis, Eli Lilly, Istituto Gentili, Accademia Nazionale di Medicina, MSD, Research grant: Roche; F.d.B., consulting fees/advisory board: Roche, EMD Serono, NMS Nerviano Medical Science, Sanofi, MSD, Novartis, Incyte, BMS, Menarini, Astra Zeneca, Pierre Fabre, Mattioli 1885, MCCann Health, Taiho; F.d.B., IQVIA Speaker Bureau: BMS, Healthcare Research & Pharmacoepidemiology, Merck Group, MSD, Pfizer, Servier, Sanofi, Roche, AMGEN, Incyte, Dephaforum, Seagen, Nadirex, BMS, Ambrosetti, and Itanet; and F.d.B., research grant/funding: Novartis, F.Hoffmann-LaRoche Ltd, BMS, Ignyta Inc., Merck Sharp & Dohme Spa, Kymab, Pfizer, Tesaro, MSD, MedImmune LCC, Exelixis Inc., LOXO Oncology Inc., DAICHI SANKIO Dev. Ltd, Basilea Pharmaceutica International AG, Janssen-Cilag International NV, and Merck KGAA. C.V. and F.d.B. are co-inventors of the FMD regimen used in this study. The Italian patent (no. 102019000009954) has been released and was first deposited on June 24(th), 2019, with an extension granted under PCT WO 2020/261131 on June 24(th), 2020. The European patent (no. 207403399), Canadian patent (no. 2144217), and USA patent are pending., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Metastatic tumors remain lethal due to primary/acquired resistance to therapy or cancer stem cell (CSC)-mediated repopulation. We show that a fasting-mimicking diet (FMD) activates starvation escape pathways in triple-negative breast cancer (TNBC) cells, which can be identified and targeted by drugs. In CSCs, FMD lowers glucose-dependent protein kinase A signaling and stemness markers to reduce cell number and increase mouse survival. Accordingly, metastatic TNBC patients with lower glycemia survive longer than those with higher baseline glycemia. By contrast, in differentiated cancer cells, FMD activates PI3K-AKT, mTOR, and CDK4/6 as survival/growth pathways, which can be targeted by drugs to promote tumor regression. FMD cycles also prevent hyperglycemia and other toxicities caused by these drugs. These data indicate that FMD has wide and differential effects on normal, cancer, and CSCs, allowing the rapid identification and targeting of starvation escape pathways and providing a method potentially applicable to many malignancies., Competing Interests: Declaration of interests V.D.L. is a scientific advisor and has equity interest in L-Nutra, a company that develops medical food. V.D.L. and G.S. have submitted a patent related to this work. C.V. is an inventor of an FMD regimen (patent pending)., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)