Age-related variation in heart rate variability across receptor-defined breast cancer groups, with distinct patterns in triple-negative disease: a cross-sectional study

Breast cancer (BC) is the most common malignancy among women worldwide, and growing evidence suggests that autonomic nervous system (ANS) activity modulates tumor biology and the tumor microenvironment. Heart rate variability (HRV), a non-invasive index of ANS balance, is influenced by age, menopausal status, body composition, and physical fitness. However, whether receptor-defined BC groups and patient-related characteristics jointly shape autonomic regulation prior to treatment remains unclear. This study compared HRV across receptor-defined BC groups and examined whether patient-related factors, particularly age, are associated with cardiac autonomic modulation. In this cross-sectional study, registered in the Brazilian Registry of Clinical Trials (ReBEC; RBR-2pmkjw7; UTN code: U1111-1296-9924; registration date: February 17, 2024; URL: https://ensaiosclinicos.gov.br/rg/RBR-2pmkjw7 ), 39 women with histologically confirmed BC were evaluated before treatment initiation. Tumors were classified by immunohistochemistry as hormone receptor–positive/HER2-negative, HER2-positive (irrespective of hormone receptor status), or triple-negative breast cancer (TNBC). HRV indices (Mean RR, SDNN, RMSSD, LF, HF, LF/HF) were derived from a stationary 5-min resting segment. Multivariate general linear models assessed differences across tumor groups while adjusting for age, menopausal status, cardiorespiratory fitness, muscular strength, body fat percentage, and lean mass. Secondary exploratory analyses examined tumor group × age interactions using age as a continuous variable. HRV indices did not differ independently across receptor-defined tumor groups (Pillai’s Trace = 0.851, p = 0.398). Age emerged as the strongest determinant of HRV, showing inverse associations with RMSSD ( p = 0.043) and a borderline association with SDNN ( p = 0.052). Exploratory analyses revealed a significant tumor group × age interaction (Pillai’s Trace = 1.013, p = 0.015), indicating that age-related associations with HRV varied across tumor groups. Women with TNBC exhibited numerically steeper age-related declines in vagally mediated indices compared with other groups. Cardiac autonomic modulation in BC appears to be primarily influenced by age, while receptor-defined tumor group alone did not independently explain HRV variability — a null finding that, given the modest sample size, warrants cautious rather than definitive interpretation. Exploratory findings suggest that age-related autonomic trajectories may differ across receptor-defined tumor groups, with TNBC showing numerically steeper age-related declines in selected HRV indices. These patterns reflect variation in age-dependent autonomic remodeling rather than static between-group differences. Longitudinal studies are needed to determine the clinical relevance of these differential aging trajectories.