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Severe calorie restriction, in the form of cyclic fasting or fasting-mimicking diets (FMDs), boosts the antitumor activity of cytotoxic chemotherapy in mouse models of triple-negative breast cancer (TNBC). This effect is mostly mediated by fasting/FMD-induced reduction of plasma glucose concentration and by a boost in antitumor immunity. However, clinical evidence that cyclic FMD may impact on the outcomes of advanced TNBC (aTNBC) patients is lacking. We compared the overall survival (OS) of 14 aTNBC patients receiving first-line carboplatin-gemcitabine plus cyclic FMD in the context of the NCT03340935 trial with the OS of 76 consecutive aTNBC patients treated with carboplatin-based chemotherapy alone at Fondazione IRCCS Istituto Nazionale dei Tumori. Multivariable Cox regression models were used to adjust the prognostic impact of FMD for other prognostic variables. Patients undergoing cyclic FMD in combination with carboplatin-gemcitabine had better OS when compared to patients receiving chemotherapy alone (median OS 30.3 months, 95% CI 18-NR, vs 17.2 months, 95% CI 15.3-25.1, log-rank P value .041). Multivariable analysis confirmed an association between FMD use and better OS (HR: 0.40; 95% CI: 0.19-0.86; P = .019) also after propensity score-based matching according to patient ECOG PS and the presence of de novo metastatic disease (HR: 0.41; 95% CI: 0.21-0.83; P = .013). Cyclic FMD in combination with first-line chemotherapy may improve clinical outcomes in aTNBC patients. Our study paves the way for conducting phase II trials to investigate if cyclic FMD can increase the antitumor activity/efficacy of chemotherapy or chemoimmunotherapy in patients with early-stage TNBC or aTNBC., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Breast cancers (BCs) arising in carriers of germline BRCA1 and BRCA2 pathogenic variants (PVs) have long been considered as indistinguishable biological and clinical entities. However, the loss of function of BRCA1 or BRCA2 proteins has different consequences in terms of tumor cell reliance on estrogen receptor signaling and tumor microenvironment composition. Here, we review accumulating preclinical and clinical data indicating that BRCA1 or BRCA2 inactivation may differentially affect BC sensitivity to standard systemic therapies. Based on a different crosstalk between BRCA1 or BRCA2 and the ER pathway, BRCA2-mutated Hormone Receptor-positive, HER2-negative advanced BC may be less sensitive to endocrine therapy (ET) plus CDK 4/6 inhibitors (CDK 4/6i), whereas BRCA2-mutated triple-negative breast cancer (TNBC) may be especially sensitive to immune checkpoint inhibitors. If validated in future prospective studies, these data may have relevant clinical implications, thus establishing different treatment paths in patients with BRCA1 or BRCA2 PVs., Competing Interests: Declaration of Competing Interest Prof. G. Pruneri reports personal fees from Roche Foundation One, Bayer, Novartis, and personal fees from Lilly outside the submitted work. Prof. F. de Braud reports an advisory role at Roche, EMD Serono, NMS Nerviano Medical Science, Sanofi, MSD, Novartis, Incyte, BMS, Menarini; speaker role for BMS, Healthcare Research & Pharmacoepidemiology, Merck Group, ACCMED, Nadirex, MSD, Pfizer, Servier, Sanofi, Roche, AMGEN, Incyte, Dephaforum; Principal Investigator for Novartis, F.Hoffmann-LaRoche Ltd, BMS, Ignyta Operating INC, Merck Sharp & Dohme Spa, Kymab, Pfizer, Tesaro, MSD, MedImmune LCC, Exelixis Inc., LOXO Oncology Incorporated, DAICHI SANKIO Dev. Limited, Basilea Pharmaceutica International AG, Janssen-Cilag International NV, Merck KGAA. Dr. C. Vernieri reports an advisory role for Novartis, Pfizer, Eli Lilly and Daiichi Sankyo; travel grants: Lilly, Novartis, Istituto Gentili, Roche, Pfizer; research grants: Roche. All other authors report no competing interests., (Copyright © 2023. Published by Elsevier B.V.)

Background: Platinum-based chemotherapy is widely used in patients with advanced triple-negative breast cancer (TNBC). However, the most effective platinum-based combination in the first-line treatment setting remains unclear., Materials and Methods: We evaluated the efficacy of first-line carboplatin-paclitaxel (CP) or carboplatin-gemcitabine (CG) combinations in advanced TNBC patients treated between April 2007 and April 2021. CP and CG were compared in terms of progression-free survival (PFS), overall survival (OS), and incidence of adverse events (AEs). Multivariable Cox Models were used to adjust the efficacy of CP versus CG for clinically relevant covariates., Results: Of 88 consecutive advanced TNBC patients receiving first-line carboplatin-based doublets, 56 (63.6%) received CP and 32 (36.4%) CG. After adjusting for clinically relevant variables, patients receiving CG had significantly better PFS when compared to CP-treated patients (HR: 0.49 (95% CI, 0.27-0.87), P value 0.014). Of note, CG was associated with better PFS only among patients previously treated with taxanes in the (neo)adjuvant setting (HR: 0.39; 95% CI, 0.21-0.75), but not in patients not exposed to taxanes (HR: 1.20; 95% CI, 0.37-3.88). CG was also independently associated with better OS when compared to CP (HR: 0.31 (95% CI: 0.15-0.64), P value 0.002). Overall, grade 3-4 AEs were more common in patients treated with CG than in patients treated with CP (68.8% vs. 21.4%, P value .009)., Conclusion: CG and CP are effective and well tolerated first-line platinum doublets in advanced TNBC patients. CG could be more effective than CP in patients previous exposed to taxanes despite worse toxicity profile., (Copyright © 2022 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.)