HRD status and genomic characteristics of Chinese NSCLC patients.

Abstract

e20507 Background: Homologous recombination deficiency (HRD) is a condition marked by dysfunction in homologous recombination repair (HRR), leading to genomic instability and increased mutations. This study aims to clarify the HRD status and genomic characteristics of Chinese non-small cell lung cancer (NSCLC) patients. Methods: We analyzed formalin-fixed paraffin-embedded (FFPE) samples from 523 Chinese NSCLC patients using next-generation sequencing (NGS). The HRD score was determined based on genomic markers: loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST). Of these, 105 patients also had PD-L1 immunohistochemistry results. Results: The median age of the cohort was 63 years (range 27-87), with 54.3% male. The median HRD score was 9 (range 0-66), and the upper quartile value was 20, establishing HRD positivity at ≥20. Notably, HRD positive patients were older (64 years vs. 62.5 years, p=0.046) and had a higher male proportion (67.3% vs. 49.2%, p<0.01). Tumor mutational burden (TMB) was markedly elevated in HRD positive patients (8.1 vs. 4.47 Muts/Mb, p<0.01), whereas PD-L1 positivity rates were comparable (22% vs. 23%). In terms of somatic copy number variations (SCNVs), HRD positive patients exhibited a higher median number (4 vs. 2, p<0.01). The five genes with the most notable differences between HRD positive and HRD negative patients included MTAP loss (10.4% vs. 0.8%), SOX2 gain (8.2% vs. 0.3%), and FGFR1 gain (7.5% vs. 0.3%), all with p-values <0.01. Additionally, MET gain (11.2% vs. 2.1%) and EGFR gain (17.2% vs. 5.9%) were more prevalent in the HRD positive group (p<0.01), while HER2 gain (1.5% vs. 0.5%) did not differ significantly between groups. For somatic mutations, RAD51B (3.0% vs. 0%, p=0.004) and BRCA2 (6.7% vs. 1.8%, p=0.007) were notably more prevalent in HRD positive patients, whereas other HRR pathway mutations were similar across groups. The mutation rates of driver genes, including EGFR, KRAS, BRAF, HER2, and FGFR1-4, were not significantly different between HRD positive and HRD negative patients. Fusion events showed no substantial difference (HRD negative vs. HRD positive: 10.6% vs. 6.8%, p=0.18), with HRD negative patients exhibiting a higher prevalence of ALK fusions (5.6% vs. 0.7%, p=0.012). BRAF, ROS1, NRG1, and MET fusions were exclusively identified in HRD negative patients. Conversely, there was a trend suggested a higher incidence of FGFR1/3 fusions in HRD positive patients (2.1% vs. 0.3%, p=0.05). Conclusions: This study identifies distinct HRD status and genomic features in Chinese NSCLC patients. HRD positive patients have higher TMB and SCNV counts, with increased mutations in BRCA2 and RAD51B. In contrast, HRD negative patients show more fusion events, especially ALK fusions. These results suggest that PARP inhibitors and targeted therapies for PIK3CA, AKT, and MET may be effective for HRD positive NSCLC patients.