Potential cancer susceptibility genes in metastatic lung cancer: A Hong Kong territory–wide genomic study.

e22646 Background: Cancer susceptibility genes (CSGs) are increasingly identified in lung cancer with the widespread adoption of comprehensive genomic profiling (CGP). However, the prevalence of putative CSG variants detected through tumor only sequencing and their associations with molecular and clinical features in Asian patients with metastatic lung cancer remain poorly defined. Methods: This territory wide prospective cohort study included patients with metastatic lung cancer who underwent tumor only comprehensive genomic profiling using FoundationOne CDx as part of the Hong Kong Territory Wide Lung Cancer Genomics Project. Patients reported to harbor putative CSG variants were identified. Clinical characteristics, including age at diagnosis, sex, family history, as well as molecular features including common actionable alterations and PD L1 expression, were compared between patients with and without putative CSG variants. Results: Among 1,324 patients analyzed, 50 patients (3.8%) were reported to harbor putative CSG variants. The most frequent alteration was the MUTYH splice site mutation c.892 2A > G (44% among patients with CSGs), followed by ATM alterations (16%). Alterations in BRCA2 and RAD51D were each observed in 6%, BRCA1 and RAD51C in 4%, and CHEK2, BRIP1, MLH1, TSH2, RET, SDHA, and VHL in 2% each.Median age at diagnosis was similar between patients with and without putative CSG variants (65 vs 66 years, NS), with slight male predominance (74% vs 66%, NS). The overall frequency of family history of cancer was comparable (40% vs 41.6%, NS); however, a numerically higher proportion of patients with putative CSG variants had a family history of lung cancer (16% vs 12.6%, p = 0.21, NS).Patients with putative CSG variants demonstrated a higher proportion of PD L1 positivity (50% vs 37%, p = 0.06) and MET alterations (6% vs 1%, p = 0.0004). The prevalence of EGFR mutations was also higher (44% vs 35%, p = 0.012), while frequencies of ALK (2% vs 1.7%, NS), ROS1 (2% vs 1.5%, NS), and BRAF (2% vs 0.7%, NS) alterations were comparable. Among patients carrying MUTYH mutations, 64% harbored concurrent EGFR mutations, the majority of which were common EGFR variants of exon 19 deletion and L858R mutations (95%). Conclusions: Putative cancer susceptibility gene variants are infrequently identified through tumor only CGP in metastatic lung cancer but are associated with distinct molecular features, including higher rates of EGFR and MET alterations and increased PD L1 expression. While CGP inform therapeutic decision making, it also potentially facilitate prompt referral for genetic counseling on hereditability.