Landscape of pathogenic germline variants in patients with lung cancer.

Abstract

388570 Background: Few studies have aimed to investigate the prevalence and spectrum of pathogenic germline variants (PGVs) in patients diagnosed with lung cancer. Given the growing opportunities for precision therapies based on PGVs in DNA damage-repair (DDR)/homologous recombination-repair (HRR) genes and the importance of identifying PGVs to inform future cancer screening and cascade testing, we investigated the prevalence and potential clinical implications of PGVs in individuals with lung cancer. Methods: Deidentified data were retrospectively reviewed for 7,788 individuals diagnosed with lung cancer for whom germline DNA sequencing and exon-level copy number analysis were performed between 2014-2022 at a commercial diagnostic laboratory. The diagnosis of lung cancer was based on ICD-10 codes or language on the test requisition suggesting a primary lung cancer diagnosis. Individuals with requisitions suggesting lung metastases, neuroendocrine tumors or sarcomas as the basis for testing were excluded. Number of genes tested varied per ordering clinician preference. Clinically actionable PGVs were defined as those associated with clinical management recommendations or trial eligibility per current, standard of care guidelines. Descriptive statistics were utilized. Results: The cohort was predominantly female (71.1%), White (64.5%), and most had a history of > 1 cancer (71.1%). A median of 79 genes (range 1-159) were tested. Testing identified 1,503 PGVs in 81 known cancer-risk genes in 1,161/7,788 (14.9%) patients; an additional 229 (2.9%) patients carried a single PGV in a gene associated with autosomal recessive inheritance. PGV rates stratified by self-reported ancestry: Black/African American, 11.8%; Asian or Pacific Islander, 11.8%; Hispanic, 14.5%; White, 15.4%. Among genes with >1,000 individuals tested, PGVs were most common in BRCA2 (2.8%), CHEK2 (2.1%), ATM (1.9%), TP53 (1.3%), BRCA1 (1.2%), and EGFR (1.0%). Of 1,161 individuals, 712 (61.3%) had a PGV in a DDR/HRR gene, making them potentially eligible for a clinical treatment trial, and 1,104/1,161 (95.1%) had a PGV that was potentially clinically actionable. Conclusions: From this large cohort of individuals with lung cancer, 14.9% had PGVs, nearly all of which were clinically actionable. Notably, HRR PGVs were common (64%). Currently, the U.S. Food and Drug Administration has approved and the National Comprehensive Cancer Network Guidelines endorse targeted therapies for patients with breast, pancreatic, prostate, and ovarian cancers who carry HRR PGVs. Recently, the NCCN Guidelines panel recommended germline testing be considered for all patients diagnosed with colorectal cancer. Given the profound implications for both patients and their families that result from identifying PGVs, our results suggest that all patients with lung cancer also be considered for germline genetic testing.