Targeting host and tumor metabolic factors in patients with high-risk early breast cancer: the NEOMET project

Pathological complete response (pCR) is a predictor of survival in early breast cancer (BC), establishing neoadjuvant chemotherapy (NACT)—alone or combined with anti-HER2 agents or immunotherapy—as the standard of care in aggressive BC subtypes1 . Among the investigational approaches to increase pCR, targeting host and cancer metabolism is gaining momentum due to recent discoveries. Physical exercise and dietary interventions have been associated with pCR after NACT2 , and with reduced recurrence risk in BC survivors3 . The efficacy of these interventions may be partly attributed to the reactivation of antitumor immunity. The first trial assessing a 5 day cyclic fast-mimicking diet in patients with solid tumors showed significant effects on both circulating immune cells and the tumor immune microenvironment (TME), demonstrating a strong interplay between host metabolism, systemic immunity and resident immunity4 . Lifestyle interventions may also have a direct effect on tumor metabolism. In a small cohort of patients undergoing the same fast-mimicking diet before surgery for early BC, the reduction in IGF-1 levels in plasma were associated with a consensual reduction in the expression of the IGF-1 receptor on the tumor at sugery4 . This suggests that host and tumor metabolism are interconnected, and that targeting the former can directly impact the latter. These compelling findings open several questions. First, host and tumor metabolic factors influencing BC outcomes remain largely unknown. Second, it is currently unknown how systemic metabolic interventions (other than fasting mimicking diet) reshape tumor metabolism. To address these questions, we started a randomized trial (NEOMET) assessing the addition of physical exercise and dietary supplementation in patients with early BC undergoing NACT. We propose to use the NEOMET trial, together with an additional in-house patient cohort, as a platform to assess how host and tumor metabolic factors can impact early BC outcomes, and to investigate the pharmacodynamic activity of lifestyle interventions at the host and tumor level.