Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit 1,2 . Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet 3-5 enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.Growth factor signalling through the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAP kinase) axes enhances oestrogen receptor activity and frequently underlies endocrine resistance in breast tumours 1,2,6 . Water-only fasting or plant-based diets that are simultaneously low in calories, sugar and protein and proportionally high in fat (fasting-mimicking diets (FMDs)) reduce circulating growth factors such as insulin and IGF1 2,6,7 . Therefore, we hypothesized that these dietary interventions could be used to enhance the activity of oestrogen therapy (ET) and delay endocrine resistance.Low-serum, low-glucose cell culture conditions designed to mimic the effects of fasting or FMD (referred to as short-term starvation, STS) increased the anti-tumour activities of tamoxifen and fulvestrant in HR + /HER2breast cancer (BC) cell lines, and similar results were obtained in mouse xenografts of the same cell lines subjected to weekly cycles of fasting or FMD (Fig. 1a, Extended Data Figs. 1, 2a, b). STS also increased the anti-tumour activity of tamoxifen in tumour organoids from patients with HR + BC 8 , and weekly FMD cycles prevented acquired resistance to tamoxifen in mice (Extended Data Fig. 2c, d). Enhancement of ET activity through STS was dependent on the reduction in serum, but not glucose, as adding back glucose to the growth medium did not affect the observed potentiation (Extended Data Fig. 3a).In mice, besides increasing β-hydroxybutyrate levels (Extended Data Fig. 3b) and lowering blood glucose (from 6.3 ± 0.6 mmol l −1 to 4.1 ± 0....

In preclinical studies, fasting was found to potentiate the effects of several anticancer treatments, and early clinical studies indicated that patients may benefit from regimes of modified fasting. However, concerns remain over possible negative impact on the patients’ nutritional status. We assessed the feasibility and safety of a 5-day “Fasting-Mimicking Diet” (FMD) as well as its effects on body composition and circulating growth factors, adipokines and cyto/chemokines in cancer patients. In this single-arm, phase I/II clinical trial, patients with solid or hematologic malignancy, low nutritional risk and undergoing active medical treatment received periodic FMD cycles. The body weight, handgrip strength and body composition were monitored throughout the study. Growth factors, adipokines and cyto/chemokines were assessed by ELISA. Ninety patients were enrolled, and FMD was administered every three weeks/once a month with an average of 6.3 FMD cycles/patient. FMD was largely safe with only mild side effects. The patients’ weight and handgrip remained stable, the phase angle and fat-free mass increased, while the fat mass decreased. FMD reduced the serum c-peptide, IGF1, IGFBP3 and leptin levels, while increasing IGFBP1, and these modifications persisted for weeks beyond the FMD period. Thus, periodic FMD cycles are feasible and can be safely combined with standard antineoplastic treatments in cancer patients at low nutritional risk. The FMD resulted in reduced fat mass, insulin production and circulating IGF1 and leptin. This trial was registered on Clinicaltrials.gov in July 2018 with the identifier NCT03595540.

In recent years, scientific interest in the use of the ketogenic diet (KD) as a complementary approach to the standard cancer therapy has grown, in particular against those of the central nervous system (CNS). In metabolic terms, there are the following differences between healthy and neoplastic cells: neoplastic cells divert their metabolism to anaerobic glycolysis (Warburg effect), they alter the normal mitochondrial functioning, and they use mainly certain amino acids for their own metabolic needs, to gain an advantage over healthy cells and to lead to a pro-oncogenetic effect. Several works in literature speculate which are the molecular targets of KD used against cancer. The following different mechanisms of action will be explored in this review: metabolic, inflammatory, oncogenic and oncosuppressive, ROS, and epigenetic modulation. Preclinical and clinical studies on the use of KD in CNS tumors have also increased in recent years. An interesting hypothesis emerged from the studies about the possible use of a ketogenic diet as a combination therapy along with chemotherapy (CT) and radiotherapy (RT) for the treatment of cancer. Currently, however, clinical data are still very limited but encouraging, so we need further studies to definitively validate or disprove the role of KD in fighting against cancer.