Genomic profiling of lung adenocarcinoma patients reveals therapeutic targets and confers clinical benefit when standard molecular testing is negative

Background: Identification of clinically relevant oncogenic drivers in advanced cancer is critical in selecting appropriate targeted therapy. Using next-generation sequencing (NGS)-based clinical cancer gene assay, we performed comprehensive genomic profiling (CGP) of advanced cases of lung adenocarcinoma. Methods: Formalin-fixed paraffin-embedded tumors from 51 lung adenocarcinoma patients whose tumors previously tested negative for EGFR/KRAS/ALK by conventional methods were collected, and CGP was performed via hybridization capture of 4,557 exons from 287 cancer-related genes and 47 introns from 19 genes frequently rearranged in cancer. Results: Genomic profiles of all 51 cases were obtained, with a median coverage of 564x and a total of 190 individual genomic alterations (GAs). GAs per specimen was a mean of 3.7 (range 0-10). Cancer genomes are characterized by 50% (80/190) non-synonymous base substitutions, 15% (29/190) insertions or deletion, and 3% (5/190) splice site mutation. TP53 mutation was the most common GAs (15%, n= 29/190), followed by CDKN2A homozygous loss (5%, n= 10/190), KRAS mutation (4%, n= 8/190), EGFR mutation (4%, n= 8/190) and MDM2 amplification (2%, n= 5/190). As per NCCN guidelines, targetable GAs were identified in 16 patients (31%) (BRAF mutation [n= 1], EGFR mutation [n= 8], ERBB2 mutation [n= 4], MET amplification [n= 1], KIF5B-RET rearrangement [n= 2], CCDC6-RET rearrangement [n= 1], CD74-ROS1 rearrangement [n= 1], EZR-ROS1 rearrangement [n= 5], and SLC34A2-ROS1 rearrangement [n= 1]). Conclusion: Fifty eight percent of patients wild type by standard testing for EGFR/KRAS/ALK have GAs identifiable by CGP that suggest benefit from target therapy. CGP used when standard molecular testing for NSCLC is negative can reveal additional avenues of benefit from targeted therapy.