DOI: 10.1177/17588359261456794 ISSN: 1758-8359

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

Shu-Jie Zhang, Jian-Fei Fu, Cui-Cui Li, Lan Wang, Xin Zhao, Xin-Yu Zhu, Zi-Liang Qian, Wen-Yong Sun, Lin-Feng Zheng, Xiang-Yi Chen, Xiang Lu, Wen-Ming Cao
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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.

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