4138 Background: CAGAC is an aggressive malignancy with poor prognosis where chemotherapy and immunotherapy provide a limited benefit. There have been clinical trials investigating the benefit of PARP inhibitors in biliary tract cancers. HRDsig positivity in other types of cancer have shown to predict sensitivity to PARP inhibitors. We explored the genomic characteristics of CAGAC patients according to the HRDsig status using a large real-world genomic dataset. Methods: Comprehensive genomic profiling was performed on 2,423 cases of CAGAC to assess all types of genomic alterations (GA), including base substitutions, short insertions and deletions, copy number changes, rearrangements, and fusions. Microsatellite instability (MSI) status, tumor mutational burden (TMB), genomic ancestry, and trinucleotide signatures were determined from the sequencing data. PD-L1 was determined with the DAKO 22C3 IHC assay. HRDsig status was determined by measuring large scale copy number changes and DNA repair errors. Patients were grouped into HRDsig positive (HRDsig+) and negative (HRDsig-) based on results. Genes with GA ≥5% in either population were included in the analysis. Results: Among 2,423 total cases, 152 (6.3%) were HRDsig+. Between MRDsig+ and MRDsig-, there was no significant difference in gender (female 76.3% vs 69.1%, p = 0.061), age (median 66.5 vs 68.0 yrs; p = 0.065), genomic ancestry (EUR 67.6% vs 63.7%, p = 1.0), MSI-H status (0.0% vs 1.3%, p = 0.468), PD-L1 expression (Low 34.0% vs 23.4%, p = 0.529. High 1.9% vs 5.4%, p = 0.946). Median GA per tumor was the same between groups (median 5 vs 5, p = 0.723), but the proportion of TMB≥10 mut/Mbp were higher in HRDsig+ (12.5% vs 4.7%, p = 0.001). HRDsig+ had more frequent alterations in BRCA1 (9.2% vs 1.4%, p < 0.001), BRCA2 (21.7% vs 1.9%; p < 0.001), PALB2 (11.2% vs 0.4%; p < 0.001), NF1 (9.9% vs 4.4%; p = 0.018), PIK3R1 (5.9% vs 2.5%; p = 0.05), and PTEN (11.8% vs 5.3%; p = 0.015). HRDsig- had more frequent alterations in ERBB2 (5.9% vs 19.0%, p < 0.001), KRAS (5.9% vs 14.9%, p = 0.007), and MDM2 (3.3% vs 9.4%, p = 0.024). Conclusions: HRDsig positivity comprised approximately 6% of all CAGAC cases. HRDsig+ were associated with a higher proportion of mutations related to homologous recombination repair (HRR) genes and mTOR pathway, whereas HRDsig- demonstrated a higher proportion of common driver mutations such as ERBB2 and KRAS. Notably, there were cases with discordant HRDsig and HRR mutation status, which may be attributed to factors such as epigenetic alterations or mono-allelic alterations. These cases may represent the role of HRDsig complementing HRR mutation status and potentially have clinical implications in predicting response to PARP inhibitors.
Nam et al. (Wed,) studied this question.