Homologous recombination deficiency correlates with tumor-infiltrating lymphocytes and predicts patient outcomes in hormone receptor-positive/HER2-negative breast cancer.

BACKGROUND

Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer represents the most prevalent molecular subtype but demonstrates pronounced biological and clinical heterogeneity. Homologous recombination deficiency (HRD) and tumor-infiltrating lymphocytes (TILs) have recently emerged as key determinants of prognosis and immune activity, but their interplay in this subtype remains understudied.

OBJECTIVES

To assess the relationship between HRD, TILs, and clinical outcomes in HR+/HER2- breast cancer and validate the prognostic value of HRD.

DESIGN

Retrospective multicenter cohort study.

METHODS

A total of 365 patients (332 with available TILs data) from three institutions were enrolled. HRD was quantified using Shallow HRD algorithm on low-depth whole-genome sequencing (threshold: score ⩾6). TILs were evaluated by the MD Anderson system (⩾10% classified as high). Spearman correlation, Kaplan-Meier survival analysis, and multivariable Cox regression were performed.

RESULTS

HRD scores were inversely correlated with TILs (Spearman rho = -0.13, p = 0.031). HRD-high patients had significantly inferior 10-year survival (invasive disease-free survival (IDFS): 31.0% vs 57.9%, hazard ratio (HR) = 2.36; distant recurrence-free survival (DRFS): 34.1% vs 61.1%, HR = 2.48; overall survival (OS): 48.7% vs 79.0%, HR = 2.79; p < 0.0001). HRD was confirmed as an independent prognostic predictor (IDFS HR = 2.03, DRFS HR = 2.16, OS HR = 2.15; p < 0.01). No significant survival benefit from anthracycline-based chemotherapy was observed in HRD-high tumors (HR = 1.32, p = 0.451). High TILs showed no significant association with survival outcomes in this cohort.

CONCLUSION

HRD represents a reliable independent prognostic biomarker in HR+/HER2- breast cancer in this cohort, with an inverse association with TILs suggesting immune evasion. Its potential impact on prognosis and treatment requires further validation in prospective clinical trials.