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Developmental Biology - Breast Cancer|
A Fasting Diet Could Boost Breast Cancer Therapy
In collaboration with the IFOM Cancer Institute in Milan and with the University of Genova, Italy - a fasting-mimicking diet reduced blood insulin, insulin-like growth factor 1 (IGF1) and leptin in mice.
These effects appear to increase the power of the cancer hormone drugs tamoxifen and fulvestrant, delaying any resistance to them. However, results from just 36 women treated with the hormone therapy and fasting-mimicking diet maybe promising, but, it was still too early to confirm the effects without large-scale clinical trials. Initial research results were published October 2018 in the journal Nature.
"Our newest study suggests that a fasting-mimicking diet together with endocrine therapy for breast cancer, has the potential to not only shrink tumors but also reverse resistant tumors in mice. We also have data that for the first time suggests a fasting-mimicking diet works by changing at least three different factors: IGF1, leptin and insulin."
The researchers explained how the two small clinical trials acted as feasibility studies showing promising results, but were in no way conclusive. They believed those results supported further clinical study of intermittent fasting — also known as intermittent energy restriction (an umbrella term for various meal timing schedules that cycle between voluntary fasting or reduced calorie intake).
The earlier research contributed to a recent clinical study of 129 breast cancer patients conducted with the University of Leiden.
These results, published last month in Nature Communications, show increased efficacy of chemotherapy in patients receiving a combination of chemotherapy and a fasting-mimicking diet.
In the two new small clinical trials - one of which was directed by the study co-corresponding author Alessio Nencioni - patients with hormone-receptor-positive breast cancer receiving estrogen therapy along with cycles of a fasting-mimicking diet, seemed to experience metabolic changes similar to those observed in mice.
These changes included a reduction in insulin, leptin and IGF1 levels, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. Further studies in humans are needed.
"Some patients followed monthly cycles of the fasting-mimicking diet for almost two years without any problems, suggesting that it is a well-tolerated intervention. We hope this means that this nutritional program which mimics fasting, could one day represent a weapon to better fight cancer in patients receiving hormone therapy without serious side effects."
The data also suggests that in mice, the fasting-mimicking diet appears to prevent tamoxifen-induced endometrial hyperplasia, a condition where the endometrium (the lining of the uterus) becomes abnormally thick.
For this reason, study authors believe the potential use of the fasting diet should be explored — given the tamoxifen side effect and limited options for preventing endometrial thickening.
Approximately 80% of all breast cancers express estrogen and/or progesterone receptors.
The most common forms of hormone therapy for these breast cancers work by blocking hormones from attaching to receptors on cancer cells or by decreasing the body's hormone production. Endocrine therapy is frequently effective in these hormone-receptor-positive tumors, but long-term benefits are often hindered by treatment resistance.
Several clinical trials, including one at USC on breast cancer and prostate patients, are now investigating the effects of fasting-mimicking diets in combination with different cancer-fighting drugs.
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 benefit1,2. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet3,4,5 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.
Irene Caffa, Vanessa Spagnolo, Claudio Vernieri, Francesca Valdemarin, Pamela Becherini, Min Wei, Sebastian Brandhorst, Chiara Zucal, Else Driehuis, Lorenzo Ferrando, Francesco Piacente, Alberto Tagliafico, Michele Cilli, Luca Mastracci, Valerio G. Vellone, Silvano Piazza, Anna Laura Cremonini, Raffaella Gradaschi, Carolina Mantero, Mario Passalacqua, Alberto Ballestrero, Gabriele Zoppoli, Michele Cea, Annalisa Arrighi, Patrizio Odetti, Fiammetta Monacelli, Giulia Salvadori, Salvatore Cortellino, Hans Clevers, Filippo De Braud, Samir G. Sukkar, Alessandro Provenzani, Valter D. Longo and Alessio Nencioni.
This work was supported in part by the Associazione Italiana per la Ricerca sul Cancro (AIRC; IG#17736 and #22098 to A.N.; IG#17605 and IG#21820 to V.D.L.; AIRC Fellowship #22457 to G.S. and V.D.L.; IG#21548 to A.P.; and MFAG#22977 to C.V.), the Fondazione Umberto Veronesi (to A.N., I.C., F.P. and V.D.L.), the Italian Ministry of Health (GR-2011-02347192 to A.N.), the 5 × 1000 2014 Funds to the IRCCS Ospedale Policlinico San Martino (to A.N.), the BC161452 and BC161452P1 grants of the Breast Cancer Research Program (US Department of Defense; to V.D.L. and to A.N., respectively), the US National Institute on Aging–National Institutes of Health (NIA–NIH) grants AG034906 and AG20642 (to V.D.L.), and the Associazione Italiana contro le Leucemie-linfomi e Mieloma (AIL), Sezione Liguria. We thank the High Throughput Screening Facility of the University of Trento (Italy) and T. Bonfiglio (Department of Internal Medicine and Medical Specialties, University of Genoa) for their technical support.
Valter D. Longo is the founder of and has an ownership interest in L-Nutra; the company’s food products are used in studies of the fasting-mimicking diet. Longo’s interest in L-Nutra was disclosed and managed per USC’s conflicts-of-interest policies. USC has an ownership interest in L-Nutra and the potential to receive royalty payments from L-Nutra. USC’s financial interest in the company has been disclosed and managed under USC’s institutional conflict of interest policies.
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In mouse models of breast cancer, periodic fasting or fasting-mimicking diet (FMD) enhances endocrine therapy, helping delay or even reverse acquired resistance to it. In patients with breast cancer, the FMD promotes metabolic changes analogous to those observed in mice.