Fasting May Complement Endocrine Therapy

Periodic fasting or a fasting-mimicking diet (FMD) may enhance standard endocrine therapy for hormone receptor–positive (HR+) breast cancer, besides reducing common side effects and reversing treatment resistance. These findings, although not conclusive, support further investigations into how fasting may complement breast cancer therapies (Nature 2020;583:620–4).

The researchers, led by co–senior author Valter Longo, PhD, of the Longevity Institute at the University of Southern California in Los Angeles, reported that, in mice, both fasting and FMD—a plant-based diet low in calories, sugar, and protein, and proportionally high in unsaturated fat—enhanced the activity of tamoxifen and fulvestrant by lowering levels of IGF1, insulin, and leptin, a growth factor for HR+ breast cancer cells. These changes, in turn, upregulated the tumor suppressors EGR1 and PTEN, the researchers found, with consequent inhibition of the PI3K–AKT–mTOR pathway, a known factor in endocrine therapy resistance. Adiponectin, which has antitumor effects, increased too.

Longo and his group also showed that periodic cycles of FMD were as effective as the CDK4/6 inhibitor palbociclib (Ibrance; Pfizer) in delaying resistance to fulvestrant. Combining all three—fulvestrant, FMD, and palbociclib—in mice not only suppressed tumor growth for more than 5 months but also led to sustained tumor regression. Shrinkage occurred even in tumors that had become resistant to fulvestrant plus palbociclib when FMD cycling was administered.

Although fasting or FMD led to the suppression of PI3K–AKT–mTOR signaling, rebound hyperglycemia and hyperinsulinemia—side effects associated with pharmacologic inhibitors of this pathway—were not seen. The dietary interventions also prevented two of tamoxifen' s frequent side effects: endometrial hyperplasia and uterine enlargement.

The team then evaluated the utility of FMD among 36 patients enrolled in two clinical trials who were receiving endocrine therapy and/or palbociclib for HR+ breast cancer. In addition to treatment, they underwent 5 days of FMD every 3 or 4 weeks. Between FMD cycles, they received nutritional counseling and amino acid supplements.

The metabolic changes observed among these patients seemed similar to those observed preclinically, says Longo. “Normal cells understand how to respond to conditions of starvation, but cancer cells do not thrive in these conditions,” he says. “By changing different factors, including IGF1, leptin, and insulin, the fasting diet appears to be a nontoxic wild card, creating a complex environment that makes it difficult for cancer cells to survive.” Importantly, clinical outcomes so far show some promise: Two patients receiving cancer therapy and on FMD—one for nearly 2 years and the other for nearly 3—still have controlled disease; the overall median progression-free survival is 9 months.

Currently, the NCI is interested in how fasting may affect cancer treatment response and outcomes, notes Marian Neuhouser, PhD, of Fred Hutchinson Cancer Research Center in Seattle, WA, who was not involved with the study. The topic is included in the agency' s Provocative Questions Initiative for R01 and R21 grant applications. She thinks Longo' s findings, although preliminary, provide a biological rationale for additional research.

Larger future trials should continue to investigate the effects of caloric intake, times of meal consumption, and overall diet quality, says Neuhouser, who worries that study participants might not have received enough nutrients. Thus, she adds that clinical trials involving dietary restrictions “should be monitored to ensure that patients are receiving sufficient macro- and micronutrients needed for health.”

Both Neuhouser and Longo stress that fasting or FMD has potential to enhance, not replace, established therapeutic regimens for HR+ breast cancer.

“The data in mice is very strong, but in terms of human trials, we are just at the beginning,” says Longo. –Janet Colwell

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