Prevalence of incidental pathogenic germline variants detected in cfDNA in patients with oncogene-driven non-small cell lung cancer.

Abstract

10569 Background: Preliminary data has highlighted inherited predisposition to lung cancer (LC) related to certain pathogenic germline variant (PGV) in cancer predisposing genes, including patients (pts) with tumors harboring somatic driver oncogene alterations (alt); however, the frequency of PGV in LC is unknown. Liquid biopsy assays may be able to identify incidental PGV (iPGV) in pts with solid tumors at scale. Here, we report the prevalence of iPGV in genes predisposing to cancer in pts with advanced non-small cell LC (aNSCLC) relative to driver alt status. Methods: Genomic results were retrospectively queried from 31126 pts with aNSCLC who had Guardant360 testing as part of routine clinical care from 10/2020-12/2021. iPGVs were defined as being non-synonymous, non-VUS alt in selected genes known to increase lifetime cancer risk (Table) with variant allele frequency (VAF) >30% and pathogenicity defined by a proprietary bioinformatics pipeline. Clinical factors such as age, gender, histology, and diagnosis status (new/progressing) were extracted from test requisition forms. The driver group included guideline-recommended and emerging somatic mutations (m) in EGFR/KRAS/BRAF/MET/HER2, fusions (f) in ALK/ROS1/RET/NTRK1-3 and amplifications (a) in HER2/MET. Results: Out of 31126, 720 (2.3%) of pts had predicted iPGV, of whom 54% were female, with a median age of 64 (22-100); most pts were newly diagnosed (66%). Among them, 92% of pts had iPGVs identified in the homologous recombination and repair (HRR) pathway, 3% in mismatch repair (MMR) pathway and 5% EGFR iPGVs. A total of 335 (47%) pts with iPGVs had somatic driver alt (Table): 20% of pts with iPGV had KRASm (n=144/720; 67 G12C), 12% EGFRm (n=87; 28 ex19del, 35 ex21(L858R)), 2.5% BRAFm (n=18), 2.5% METm ex14 skip (n=18), 0.1% HER2m (n=1), 0.8% ALKf (n=6), 0.1% ROS1f (n=1), 0.1% RETf (n=1), 0.1% HER2a (n=1), and 0.4% METa (n=3). ATM iPGVs were enriched in pts with driver alt. (45% driver vs 27% non-driver, p<0.0001) while BRCA1 iPGVs were more frequently observed in pts without driver alt. (17% vs 8%, p<0.0001). Distribution of other iPGVs was similar across driver/non-driver groups. Conclusions: In this large cohort, 2.3% of pts with aNSCLC were iPGV-carriers; 47% of pts had oncogene-driven tumors, particularly with KRAS, EGFR, BRAF and MET alt. iPGV and lung carcinogenesis need further evaluation to define the role of genetic predisposition in LC risk and to determine the highest risk individuals to explore screening and therapeutic strategies, such as in pts with other solid tumors. [Table: see text]