Posted December 8, 2020

Valter Longo, Ph.D., University of Southern California
Alessio Nencioni, Ph.D., University of Genoa

Hormone-receptor-positive (HR⁺) breast cancers comprise roughly 75% of all breast cancer diagnoses. While endocrine therapy, which blocks the production of or removes hormones from the body, has shown clinical success for HR⁺ breast cancers, endocrine resistance remains a problem for breast cancer patients and disease progression often occurs. Resistance to endocrine therapy is mediated through signaling of various growth factors (e.g., insulin, insulin-like growth factor 1 [IGF1], and leptin) that enhance estrogen receptor activity within tumor cells. Fasting or fasting-mimicking diets (FMDs; i.e., diets that are plant-based, low-calorie, high-fat, sugar- and protein-restricted) reduce the level of circulating growth factors, suggesting that these dietary interventions could be used to prevent estrogen receptor activation in tumor cells and potentially delay endocrine resistance. With support from a Fiscal Year 2016 Breast Cancer Research Program Breakthrough Award – Funding Level 2, Dr. Longo and Dr. Nencioni sought to examine whether periodic fasting or FMD could enhance endocrine therapy and demonstrate long-lasting, beneficial clinical outcomes. 

In a recent article published in Nature, Dr. Longo and Dr. Nencioni, together with their research team, evaluated HR⁺ breast cancer mouse models to assess whether fasting or FMD enhance the activity of the endocrine therapies tamoxifen and fulvestrant, which block estrogen activity. While weekly cycles of fasting or FMD alone reduced the levels of serum C-peptide (a proxy of endogenous insulin production) and IGF1, the combination of either dietary intervention with tamoxifen or fulvestrant also reduced levels of leptin, a hormone secreted by fat cells that behaves as a growth factor for HR⁺ breast cancer cells and may promote resistance to endocrine therapy. In mice bearing HR⁺ tumors that had been treated with fulvestrant plus FMD, reintroduction of insulin, leptin, and IGF1 (collectively referred to as fasting-reduced factors [FRFs]) resulted in increased tumor growth, indicating a reversal to the benefit of adding FMD to potentiate fulvestrant activity. Withdrawal of FRFs after three cycles of FMD restored tumor sensitivity to fulvestrant.

The research team next assessed whether combining FMD with endocrine therapy plus palbociclib, an inhibitor of cyclin-dependent kinase (CDK) 4/6, would provide an improved therapeutic effect for mice with HR⁺ breast cancer tumors. CDK4/6 plays an important role in normal cell cycle progression, and CDK4/6 inhibitors, like palbociclib, are widely used together with endocrine therapy in patients with HR⁺ breast cancer. While the combination of fulvestrant and FMD or fulvestrant and palbociclib delayed tumor growth compared to treatment with any single agent, either combination did not prevent the development of fulvestrant resistance, as evidenced by a resurgence in tumor volume after 90 days of treatment. However, combining FMD, palbociclib, and fulvestrant not only prevented tumor growth for more than 160 days, it also led to slow, but steady tumor shrinkage. Moreover, tumors in mice that had previously developed resistance to fulvestrant plus palbociclib treatment could be resensitized to this combination treatment after periodic cycles of FMD. Importantly, when the research team assessed the effects of periodic FMD on disease control and circulating FRFs in 36 HR⁺ breast cancer patients receiving endocrine therapy (NCT03595540 and NCT03340935), they noted metabolic changes analogous to those observed in the mouse experiments. Notably, some of the metabolic changes observed in mice and humans were long-lasting, suggesting that periodic FMD provides effects that continue after a normal diet is resumed.

Dr. Longo and Dr. Nencioni’s work provides early evidence that FMD not only increases the anti-cancer activity of the estrogen-blocking endocrine therapeutics tamoxifen and fulvestrant, but also inhibits endocrine resistance through a reduction in FRFs that persists beyond the FMD period. Furthermore, FMD, when used in combination with fulvestrant and palbociclib, causes tumor regression and reverses acquired resistance to these two drugs. The results of this study provide rationale for larger clinical trials of FMD as an adjuvant to endocrine therapy to improve clinical outcomes in patients with HR⁺ breast cancers.

Publication:

Caffa I, Spagnolo V, Vernieri C, et al. 2020. Fasting-mimicking diet and hormone therapy induce breast cancer regression. Nature. https://doi.org/10.1038/s41586-020-2502-7

Link:

Public and Technical Abstracts: Periodic Fasting-Mimicking Diet as a Strategy to Increase the Effectiveness of Hormone Therapies in Estrogen Receptor-Positive Breast Cancer

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