Association between Homologous Recombination Repair Defect Status and Long-Term Prognosis of Early HER2-Low Breast Cancer: A Retrospective Cohort Study

Author:

Chen Jiayi12,Zhu Yingying3,Wu Wei12,Xu Yaqi12,Yang Wenqian12,Ling Li4,Lin Qun12,Jia Shijie12,Xia Yuan12,Liu Zihao5,Yang Yaping12,Gong Chang12

Affiliation:

1. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou , People’s Republic of China

2. Department of Breast Surgery, Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou , People’s Republic of China

3. Division of Clinical Research Design, Clinical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University , Guangzhou , People’s Republic of China

4. Department of Medical Statistics, School of Public Health, Sun Yat-Sen University , Guangzhou , China

5. Department of Breast Surgery, Department of General Surgery, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, the First Affiliated Hospital of Southern University of Science and Technology , Shenzhen, Guangdong , People’s Republic of China

Abstract

Abstract Background As a newly identified subtype of HER2-negative tumors associated with a less favorable prognosis, it remains crucial to evaluate potential prognostic and predictive factors, particularly non-invasive biomarkers, for individuals with human epidermal growth factor 2 (HER2) low early-stage breast cancer (EBC). Multiple investigations have highlighted that HER2-negative patients with EBC exhibiting high homologous recombination deficiency (HRD) scores display lower rates of pathological complete response (PCR) to neoadjuvant chemotherapy (NAC). Nevertheless, no study to date has explored the correlation between HRD and the long-term prognosis in HER2-low patients with EBC. Patients and methods This retrospective observational study focuses on primary EBC sourced from The Cancer Genome Atlas dataset (TCGA). It reveals the gene mutation landscape in EBC with low HER2 expression and elucidates the tumor immune landscape across different HRD states. Utilizing bioinformatics analysis and Cox proportional models, along with the Kaplan-Meier method, the study assesses the correlation between HRD status and disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI). Subgroup analyses were conducted to identify potential variations in the association between HRD and prognosis. Results In the patients with HER2-low breast cancer, patients with homologous recombination related genes (HRRGs) defects had an HRD score about twice that of those without related genes mutations, and were at higher risk of acquiring ARID1A, ATM, and BRCA2 mutations. We also found that most immune cell abundances were significantly higher in EBC tumors with high HRD than in EBC tumors with low HRD or HRD-medium, particularly plasma B-cell abundance, CD8 T-cell abundance, and M1 macrophages. In addition, these tumors with HRD-high also appear to have significantly higher tumor immune scores and lower interstitial scores. Then, we analyzed the relationship between different HRD status and prognosis. There was statistical significance (P = .036 and P = .046, respectively) in DSS and PFI between the HRD-low and HRD-high groups, and patients with HRD-high EBC showed relatively poor survival outcomes. A medium HRD score (hazard ratio, HR = 2.15, 95% CI: 1.04-4.41, P = .038) was a significant risk factor for PFI. Hormone receptor positivity is an important factor in obtaining medium-high HRD score and poor prognosis. Conclusion Higher HRD scores were associated with poorer PFI outcomes, particularly in people with HR+/HER2-low. Varied HRD states exhibited distinctions in HRRGs and the tumor immune landscape. These insights have the potential to assist clinicians in promptly identifying high-risk groups and tailoring personalized treatments for patients with HER2-low EBC, aiming to enhance long-term outcomes.

Funder

Natural Science Foundation of China

Publisher

Oxford University Press (OUP)

Reference58 articles.

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3. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study;Swain,2020

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