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

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). [Display omitted] • Cyclic FMD plus anthracycline-taxane CT resulted in excellent responses in early TNBC • The experimental treatment was safe, and patient compliance was excellent • Early downmodulation of glucose metabolism in cancer cells predicts pCR to FMD In brief, Vernieri et al. conducted a pilot, randomized phase 2 trial showing that cyclic FMD plus preoperative chemotherapy results in excellent pCR rates in stage I–III TNBC patients. In tumors achieving pCR, bulk and single-cell RNA-seq analysis revealed early downmodulation of glucose metabolism in TNBC cells and in glycolytic intratumor cells. [ABSTRACT FROM AUTHOR]