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Clinical Trial
. 2025 Feb 4;37(2):330-344.e7.
doi: 10.1016/j.cmet.2024.11.004. Epub 2024 Dec 17.

Early downmodulation of tumor glycolysis predicts response to fasting-mimicking diet in triple-negative breast cancer patients

Francesca Ligorio  1 , Andrea Vingiani  2 , Tommaso Torelli  3 , Caterina Sposetti  4 , Lorenzo Drufuca  5 , Fabio Iannelli  6 , Lucrezia Zanenga  7 , Catherine Depretto  8 , Secondo Folli  9 , Gianfranco Scaperrotta  8 , Giuseppe Capri  7 , Giulia V Bianchi  7 , Cristina Ferraris  9 , Gabriele Martelli  9 , Ilaria Maugeri  9 , Leonardo Provenzano  4 , Federico Nichetti  7 , Luca Agnelli  3 , Riccardo Lobefaro  7 , Giovanni Fucà  7 , Giuseppe Fotia  7 , Luigi Mariani  10 , Daniele Morelli  3 , Vito Ladisa  11 , Maria Carmen De Santis  8 , Laura Lozza  8 , Giovanna Trecate  8 , Antonino Belfiore  3 , Silvia Brich  3 , Alessia Bertolotti  3 , Daniele Lorenzini  2 , Angela Ficchì  7 , Antonia Martinetti  7 , Elisa Sottotetti  7 , Alessio Arata  7 , Paola Corsetto  12 , Luca Sorrentino  9 , Mattia Rediti  5 , Giulia Salvadori  5 , Saverio Minucci  13 , Marco Foiani  14 , Giovanni Apolone  15 , Massimiliano Pagani  16 , Giancarlo Pruneri  2 , Filippo de Braud  4 , Claudio Vernieri  17
Affiliations
Clinical Trial

Early downmodulation of tumor glycolysis predicts response to fasting-mimicking diet in triple-negative breast cancer patients

Francesca Ligorio et al. Cell Metab. .

Abstract

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).

Keywords: body composition analysis; bulk RNA-seq analysis; fasting-mimicking diet; neoadjuvant treatment; phase 2 trial; single-cell RNA-seq analysis; triple-negative breast cancer.

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Conflict of interest statement

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.

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