HR-positive breast cancer: Fasting-mimicking diet plus ET causes potentially beneficial metabolic changes
Fasting-mimicking diet (FMD) cycles in combination with endocrine therapy (ET) cause metabolic changes in hormone receptor (HR)-positive breast cancer patients analogous to those observed in animal models, where they are associated with anticancer activity.
“Lifestyle and nutrition are now well-known risk factors in the development of several chronic diseases, including cancer. Obesity alone is estimated to account for 14 percent to 20 percent of all cancer-related deaths in the US, leading to guidelines on nutrition and physical activity for reducing the risk of developing cancer,” said Dr Irene Caffa of the Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy, whilst introducing her research at the AACR 2020 Virtual Annual Meeting I. [N Engl J Med 2003;348:1625-1638; CA Cancer J Clin 2012;62:30-67]
ET is usually effective in oestrogen or progesterone receptor-expressing breast cancer tumours, but primary and acquired resistance limits its long-term benefit. Growth factor signalling through the PI3K/AKT/mTOR pathway enhances oestrogen receptor activity and is a key mechanism underlying endocrine resistance. [Breast Cancer Res Treat 2013;137:397-406]
Fasting forces healthy cells to enter a slow division and highly protected mode, which protects them against the toxicity of anticancer drugs while sensitizing different types of cancer cells to these therapeutics. [Sci Transl Med 2012;4:124ra27; Proc Natl Acad Sci USA 2008;105:8215-8220; Oncotarget 2015;6:11820-11832] In addition, fasting or plant-based, low-calorie, carbohydrate- and protein-restricted FMD reduces circulating growth factors, such as insulin and IGF1. [Ageing Res Rev 2019;53:100910]
“We hypothesized that these dietary interventions could be used to enhance the activity of ET and delay the occurrence of resistance,” said Caffa. “Our in vivo experiments in mouse xenografts of human breast cancer cell lines were conducted in mice treated with ET with or without 48–72 hours of FMD. We found that periodic fasting or FMD enhanced tamoxifen and fulvestrant activity by lowering circulating IGF1, insulin and leptin levels and by blocking AKT-mTOR signalling via EGR1 and PTEN upregulation.” [Caffa I, et al, AACR 2020 Virtual Meeting I, abstract CT075]
“By monitoring tumour growth and mouse survival and collecting tumour masses, we established that periodic FMD cycles added to fulvestrant in combination with the CDK4/6 inhibitor palbociclib promoted long-lasting tumour regressions and reverted acquired resistance. Moreover, both fasting and FMD prevented tamoxifen-induced endometrial hyperplasia,” noted Caffa.
Circulating growth factors and adipo-cytokines were detected in the blood samples of 36 patients with HR-positive breast cancer, who were enrolled in two clinical trials assessing the safety and feasibility of periodic FMD in cancer patients (NCT03595540 and NCT03340935). In HR-positive breast cancer patients receiving ET, FMD cycles caused metabolic changes analogous to those observed in mice, including reduced leptin and IGF1 levels, which were found to remain low for extended periods. “In mice, these long-lasting effects were associated with carryover anticancer activity,” highlighted Caffa.
“Preliminary clinical data indicate good tolerability of FMD in patients undergoing cancer treatment. Overall, our results provide the rationale for conducting further clinical studies of fasting-based dietary strategies as an adjuvant to ET with or without CDK4/6 inhibitors in patients with HR-positive breast cancer,” concluded Caffa. [J Exp Clin Cancer Res 2019;38:209; BMC Cancer 2018;18:476; BMC Cancer 2015;15:652]