Key Takeaways & Executive Findings
- •• HRD is present in about 25% of lung cancers, more common in adenocarcinoma and TP53-mutant tumors. • HRD-positive tumors show higher genomic instability, mutation burden, and immune infiltration. • HRD status predicts improved response to platinum chemotherapy and immune checkpoint inhibitors. • Assessment of HRD could guide personalized treatment strategies in lung cancer.
Abstract
Background: Homologous recombination repair deficiency (HRD) is a key genomic instability phenotype that has been implicated in the pathogenesis and therapeutic response of various cancers, including lung cancer. However, the clinical significance of HRD in lung cancer remains incompletely understood. Methods: We conducted a comprehensive analysis of HRD in lung cancer using genomic and transcriptomic data from public databases and our own cohort. We evaluated the prevalence of HRD, its association with clinicopathological features, genomic alterations, and immune microenvironment, as well as its predictive value for response to platinum-based chemotherapy and immune checkpoint inhibitors. Results: HRD was detected in approximately 25% of lung cancer cases, with higher frequency in lung adenocarcinoma and in tumors with TP53 mutations. HRD-positive tumors exhibited increased genomic instability, higher mutation burden, and enhanced immune infiltration. In our cohort, HRD status was significantly associated with improved progression-free survival in patients receiving platinum-based chemotherapy and with higher response rates to immune checkpoint inhibitors. Conclusions: HRD is a prevalent and clinically relevant biomarker in lung cancer, with potential utility in guiding treatment decisions. Our findings support the integration of HRD assessment into clinical practice for personalized therapy.
1. Introduction
Lung cancer remains the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Despite advances in targeted therapies and immunotherapies, the overall prognosis for lung cancer patients remains poor, underscoring the need for novel biomarkers to guide treatment decisions. Homologous recombination repair (HRR) is a critical DNA repair pathway that maintains genomic stability by accurately repairing double-strand breaks. Deficiencies in HRR, often due to mutations in genes such as BRCA1/2, lead to genomic instability and have been exploited therapeutically in breast and ovarian cancers using PARP inhibitors. However, the role of HRD in lung cancer is less well defined.
Recent studies have suggested that HRD may be present in a subset of lung cancers and could influence tumor behavior and response to therapy. For instance, HRD has been associated with increased sensitivity to platinum-based chemotherapy and immune checkpoint inhibitors in various tumor types. Nevertheless, comprehensive analyses of HRD in lung cancer are lacking, and its clinical significance remains controversial. In this study, we aimed to characterize HRD in lung cancer using multi-omics data, investigate its association with clinical outcomes, and evaluate its potential as a predictive biomarker for treatment response.
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Y. Zhang, L. Wang, H. Li, J. Chen, X. Liu, M. Zhao, Q. Sun, R. Yang, S. Wu, T. Zhou (2026). Homologous recombination repair deficiency and its clinical significance in lung cancer. Chinese Journal of New Drugs. https://doi.org/10.1007/s00520-024-08912-3
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Frequently Asked Questions
What is homologous recombination repair deficiency (HRD)?
HRD is a condition where cells are unable to accurately repair DNA double-strand breaks via homologous recombination, leading to genomic instability. It is often caused by mutations in genes like BRCA1/2 and can make tumors more sensitive to certain therapies.
How common is HRD in lung cancer?
Our study found HRD in approximately 25% of lung cancer cases, with higher prevalence in lung adenocarcinoma and tumors with TP53 mutations.
What is the clinical significance of HRD in lung cancer?
HRD status is associated with improved response to platinum-based chemotherapy and immune checkpoint inhibitors, suggesting it could be used as a predictive biomarker to guide treatment decisions.
How is HRD detected?
HRD can be detected through genomic assays that assess loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions, or by identifying mutations in HRR genes.
Can HRD be targeted therapeutically?
Yes, tumors with HRD may be sensitive to PARP inhibitors, which exploit the DNA repair defect. This approach is already used in breast and ovarian cancers and is being investigated in lung cancer.
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