Exercise training decreases Neuregulin-1 concentrations in HER2-positive breast cancer patients undergoing adjuvant trastuzumab: the CARDAPAC study

Document Type

Article

Publication Date

2-4-2026

Institution/Department

Center for Molecular Medicine

Journal Title

Breast cancer research and treatment

MeSH Headings

Humans; Female; Breast Neoplasms (blood, drug therapy, therapy, pathology, metabolism); Trastuzumab (adverse effects, therapeutic use, administration & dosage); Erb-b2 Receptor Tyrosine Kinases (metabolism); Neuregulin-1 (blood); Middle Aged; Chemotherapy, Adjuvant; Adult; Aged; Antineoplastic Agents, Immunological (adverse effects, therapeutic use); Exercise Therapy (methods); Cardiotoxicity; Exercise

Abstract

PURPOSE: Trastuzumab used for the treatment of patients with HER2-positive breast cancer induces cardiotoxicity. The NRG1/HER pathway plays a central role in human cardiovascular physiology; however, the link between exercise, NRG1, and cardiotoxicity is unclear. METHODS: Patients were randomized to receive adjuvant trastuzumab in combination with a training program (TG) or trastuzumab alone (CG). The aim of this study was to assess the effect of a 12-week supervised exercise training on the circulating level of NRG1. Secondary objectives were to assess the correlation between NRG1 level and cardiotoxicity. RESULTS: 89 patients were randomized (TG; n = 46; CG; n = 43), 76 have a NRG1 concentration available at baseline. After the exercise program, plasma levels of NRG1 decreased significantly in the TG (mean difference -0.20 ng/ml; 95% CI, -0.32, - 0.07) whereas they remained stable in the CG (mean difference - 0.05 ng/ml; 95% CI, - 0.20, 0.10). Notably, baseline NRG1 concentrations were higher in the TG group. However, no correlation between NRG1 changes and either cardiorespiratory fitness (V̇O max) and left ventricular ejection fraction (LVEF) was observed (R = 0.087, p = 0.53; R = -0.157, p = 0.26; and R = -0.131, p = 0.33, respectively). CONCLUSIONS: A 12-week interval training program significantly decreased NRG1 concentration in HER2-positive patients with breast cancer treated with adjuvant trastuzumab therapy, despite the trained group presenting higher baseline NRG1 values compared to the control group. In addition, this change was neither associated with V̇O max nor with LVEF. TRIAL REGISTRATION: This trial was registered with ClinicalTrials.gov under the number NCT02433067.

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