Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype, and is associated with the lowest cure rates in the limited-stage disease setting, as well as with the lowest overall survival in the metastatic setting. Preclinical studies indicate that cycles of fasting or calorie-restricted, low-carbohydrate, low-protein diets, also known as fasting-mimicking diets (FMDs), have synergistic cytotoxic effects when combined with chemotherapy agents, such as doxorubicin or cisplatin, in several in vitro and in vivo tumor models, including murine TNBC models. More recently, intermittent fasting has demonstrated highly synergistic antitumor effects when combined with metformin; of note, these effects are mediated through the concomitant inhibition of glycolysis (via fasting-induced hypoglycemia) and metformin-induced inhibition of mitochondrial oxidative phosphorylation (OXPHOS). Finally, small reports published so far indicate that cyclic fasting and FMDs are well tolerated in cancer patients, and can be safety combined with standard antitumor treatments.

Based on these data, the BREAKFAST trial was designed to investigate the antitumor activity of cyclic FMD, alone or in combination with metformin, in patients with localized TNBC. In this study, 90 patients with stage I-III TNBC will be randomized in a 1:1 ratio to receive approximately 6 months of standard preoperative anthracycline plus taxane chemotherapy in combination with eight triweekly cycles of 5-day FMD (Arm A), or the same chemotherapy-FMD regimen plus daily metformin (Arm B). The primary objective of the study is to demonstrate that one or both experimental treatments increase the rate of pCR from 45% (historical data) to 65%