Modulation of systemic and intratumor metabolism predicts response to fasting-mimicking diet plus chemotherapy in patients with early TNBC

BackgroundThe randomized, phase II trial BREAKFAST investigated if severe calorie restriction, in the form of 5-day fasting-mimicking diet (FMD), plus/minus metformin, improves the antitumor activity of neoadjuvant chemotherapy (NACT) in patients (pts) with early-stage triple-negative breast cancer (TNBC). Among exploratory analyses of the trial we evaluated treatment-induced modulation of systemic and intratumor metabolism, and its association with pathologic complete response (pCR) probability.Methods30 pts with stage I-III TNBC were randomized to receive anthracycline plus taxane CT (triweekly AC followed by weekly paclitaxel) in combination with triweekly 5-day FMD cycles (arm A), or CT + FMD + daily metformin (1700 mg) (arm B). Tumor specimens were collected at baseline and after one treatment cycle to study changes of intratumor metabolic transcriptomic profiles through bulk and single cell (sc) RNA-sequencing (RNA-seq) analysis. Metabolic evaluations in blood samples collected before and after the first FMD cycle, and body composition parameters estimated through CT scans performed at baseline and before surgery were used to study systemic metabolism modulation.ResultsThe experimental treatment caused a short-term decrease of blood glucose, insulin and LDH levels. LDH reduction predicted pCR after adjustment for T and N stage, Ki-67 and treatment arm (p=0.04). After six months of treatment, we observed a reduction of total, subcutaneous and visceral adipose tissue, which was more pronounced in patients with higher baseline BMI. Transcriptomic analysis of tumor samples showed a precocious downmodulation of intratumor glycolysis, pyruvate metabolism and TCA cycle, which was only observed in patients who had higher baseline adiposity and underwent pCR. Of note, scRNA-seq analysis revealed that these changes specifically occurred in highly glycolytic cells in the tumor microenvironment, i.e., cancer cells, myeloid cells and pericytes.ConclusionsThe precocious downmodulation of systemic and intratumor glucose metabolism predicts pCR in TNBC pts receiving NACT plus FMD. Glycolysis inhibition is a potentially novel metabolic biomarker of response to FMD-based treatment in TNBC pts.Clinical trial identificationNCT04248998.Legal entity responsible for the studyFondazione IRCCS Istituto Nazionale dei Tumori di Milano.FundingThe Italian Ministry of Health (Ricerca Corrente); the Scientific Directorate of Fondazione IRCCS Istituto Nazionale dei Tumori (Milan, Italy), and the “Associazione Italiana per la Ricerca sul Cancro� (AIRC; MFAG-2019 no. 22977: principal investigator: C. Vernieri).DisclosureF. Ligorio: Financial Interests, Personal, Invited Speaker: Novartis; Other, Travel/accomodation: Eli Lilly, Istituto Gentili. G.V. Bianchi: Financial Interests, Personal, Advisory Board: Novartis, Eli Lilly, Daichi/Astrazeneca, Roche, Seagen, MSD. F.G.M. De Braud: Financial Interests, Personal, Invited Speaker: AMGEN, Ambrosetti, Ambrosetti, BMS, Dephaforum, ESO, Healthcare Research & Pharmacoepidemiology, Incyte, MSD, Merck Group, Nadirex, Pfizer, Roche, Sanofi, Seagen, Servier, Accmed, Dynamicom Education; Financial Interests, Personal, Other, Think Thank: MCCann Health; Financial Interests, Personal, Other, Consultant: Mattioli 1885; Financial Interests, Personal, Other: Novartis; Financial Interests, Personal, Other, Consultant Advisory Board: AstraZeneca, BMS, EMD Serono, Incyte, MSD, Menarini, NMS Nerviano Medical Science, Novartis, Pierre Fabre, Roche, Sanofi; Financial Interests, Personal, Other, Consultant Adv Board: Taiho; Financial Interests, Personal, Coordinating PI: BMS, Basilea Pharmaceutica International AG, Daichi Sankio Dev. Limited, Exelixis Inc, F.Hoffmann-LaRoche Ltd, IQVIA, Ignyta Operating INC, Janssen-Cilag International NV, Kymab, LOXO Oncology Incorporated, MSD, MedImmune LCC, Merck KGAA, Merck Sharp & Dohme Spa, Novartis, Pfizer, Tesaro. G. Pruneri: Financial Interests, Personal, Advisory Board: Roche, Bayer, Astrazeneca. C. Vernieri: Financial Interests, Personal, Advisory Board: Novartis, Pfizer, Lilly, Daiichi Sankyo, Menarini; Financial Interests, Institutional, Funding: Roche; Financial Interests, Personal, Invited Speaker: Novartis, MSD, Accademia Nazionale di Medicina, Istituto Gentili, Lilly. All other authors have declared no conflicts of interest.