In preclinical experiments, cyclic fasting-mimicking diets (FMDs) showed broad anticancer effects in combination with chemotherapy. Among different tumor types, triple-negative breast cancer (TNBC) is exquisitely sensitive to FMD. However, the antitumor activity and efficacy of cyclic FMD in TNBC patients remain unclear. Here, we show that a severely calorie-restricted, triweekly, 5-day FMD regimen results in excellent pathologic complete response (pCR) rates (primary endpoint) and long-term clinical outcomes (secondary endpoints) when combined with preoperative chemotherapy in 30 patients with early-stage TNBC enrolled in the phase 2 trial BREAKFAST. Bulk and single-cell RNA sequencing analysis revealed that highly glycolytic cancer cells, myeloid cells, and pericytes from tumors achieving pCR undergo a significant, early downmodulation of pathways related to glycolysis and pyruvate metabolism. Our findings pave the wave for conducting larger clinical trials to investigate the efficacy of cyclic FMD in early-stage TNBC patients and to validate early changes of intratumor glycolysis as a predictor of clinical benefit from nutrient restriction. This study was registered at Clinicaltrials.gov (NCT04248998).

中文翻译：

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肿瘤糖酵解的早期下调可预测三阴性乳腺癌患者对模拟禁食饮食的反应


在临床前实验中，循环模拟禁食饮食 （FMD） 与化疗联合使用显示出广泛的抗癌作用。在不同的肿瘤类型中，三阴性乳腺癌 （TNBC） 对 FMD 非常敏感。然而，周期性 FMD 对 TNBC 患者的抗肿瘤活性和疗效仍不清楚。在这里，我们表明，在 30 名参加 2 期试验 BREAKFAST 的早期 TNBC 患者中，严重限制卡路里、每三周一次、为期 5 天的 FMD 方案与术前化疗联合时，可产生出色的病理完全缓解 （pCR） 率（主要终点）和长期临床结果（次要终点）。大量和单细胞 RNA 测序分析显示，来自达到 pCR 的肿瘤的高度糖酵解癌细胞、髓系细胞和周细胞经历了与糖酵解和丙酮酸代谢相关的途径的显着早期下调。我们的研究结果为进行更大规模的临床试验铺平了浪潮，以研究周期性 FMD 对早期 TNBC 患者的疗效，并验证肿瘤内糖酵解的早期变化作为营养限制临床获益的预测因子。这项研究在 Clinicaltrials.gov （NCT04248998） 注册。