Fasting mimicking diet as an adjunct to neoadjuvant chemotherapy for breast cancer in the multicentre randomized phase 2 DIRECT trial

Abstract

Short-term fasting protects tumor-bearing mice against the toxic effects of chemotherapy while enhancing therapeutic efficacy. We randomized 131 patients with HER2-negative stage II/III breast cancer, without diabetes and a BMI over 18 kg m^-2, to receive either a fasting mimicking diet (FMD) or their regular diet for 3 days prior to and during neoadjuvant chemotherapy. Here we show that there was no difference in toxicity between both groups, despite the fact that dexamethasone was omitted in the FMD group. A radiologically complete or partial response occurs more often in patients using the FMD (OR 3.168, P = 0.039). Moreover, per-protocol analysis reveals that the Miller&Payne 4/5 pathological response, indicating 90-100% tumor-cell loss, is more likely to occur in patients using the FMD (OR 4.109, P = 0.016). Also, the FMD significantly curtails chemotherapy-induced DNA damage in T-lymphocytes. These positive findings encourage further exploration of the benefits of fasting/FMD in cancer therapy. Trial number: NCT02126449.

Fig. 1. Consort diagram of the DIRECT study.

This figure shows reasons for exclusion from the study and the numbers of patients included in the PP and ITT analyses. Abbreviations: FMD: fasting mimicking diet, ITT: Intention to treat, PP: Per protocol. * diagnosed the day after randomization.

Fig. 2. Tumor response data for the ITT and PP analysis.

The pathological response was given for Miller and Payne pathological response score 4/5 (90–100% tumor cell loss) vs. 1/2/3 (less than 90% tumor cell loss). The radiological response was scored according RECIST 1.1 and given for complete response + partial response vs. stable disease + progression disease. Abbreviations: FMD: fasting mimicking diet, ITT: Intention to treat, PP: Per protocol, MP: Miller and Payne, CR: complete response, PR: partial response, SD: stable disease, PD: progression disease. Logistic regression was used (2-sided). Source data are provided as a Source Data file.

Fig. 3. EORTC QLQ-C30 global health domain given for 4 timepoints: before therapy (after randomization), halfway therapy, at the end of therapy and at six months follow-up.

Error bars indicate the 95% CI of the mean. Abbreviations: EORTC: European Organization for Research and Treatment of Cancer, FMD: fasting mimicking diet. CI: confidence interval. FMD N = 57 and regular diet N = 54. Armitage’s trend test was used. Source data are provided as a Source Data file.

Fig. 4. Tumor response data per number of cycles completed.

The pathological response was given for Miller and Payne pathological response score 4/5 (90–100% tumor cell loss) vs.1/2/3 (less than 90% tumor cell loss). The radiological response was scored according to RECIST 1.1 and given for complete response + partial response vs. stable disease + progression disease. P-value is given for Armitage’s trend test (2-sided). Abbreviations: FMD: fasting mimicking diet, MP: Miller and Payne, CR: complete response, PR: partial response, SD: stable disease, PD: progression disease. Source data are provided as a Source Data file.

Fig. 5. Metabolic and endocrine parameters before chemotherapy compared between compliant and non-compliant patients halfway therapy of the FMD group and the regular group.

Values are measured on day −1 or day 0 before cycle 1 and halfway therapy. *P-value <0.05, **P-value <0.001 (2-sided). Error bars indicate the standard error of the mean (if data was normally distributed) or the 25% and 75% percentiles of the median (if data was non-normally distributed). Independent t-tests and Mann-Whitney tests were used. Reference values: glucose 3.1–6.4 mmol/L; insulin 0–20 mU/L; IGF-1 5.4–24.3 nmol/L. Abbreviations: FMD: fasting mimicking diet, IGF-1: Insulin-like growth factor 1. Source data are provided as a Source Data file.

Fig. 6. Difference of γ-H2AX intensity in CD45+ CD3+ lymphocytes of each patient before cycle 1 and 3 h after chemotherapy, given as a percentage increase.

Error bars indicate the standard error of the mean. Independent t-tests were used (2-sided). Abbreviations: FMD: fasting mimicking diet. *P = 0.045. Source data are provided as a Source Data file.