Landscape of Concomitant Driver Alterations in Classical <i>EGFR</i>-Mutated Non-Small Cell Lung Cancer.

Abstract

Next-generation sequencing (NGS) has enabled the detection of concomitant driver alterations in non-small cell lung cancer (NSCLC). However, the magnitude and clinical relevance of concomitant drivers remain to be explored. We profiled concomitant driver alterations of <i>EGFR</i>+ NSCLC by using targeted NGS. The associated genomic and clinical features were analyzed and validated in an independent The Cancer Genome Atlas cohort of patients with <i>EGFR</i>+ NSCLC. Out of the total patient population, 334 patients had <i>EGFR</i> mutations along with concomitant driver mutations, comprising 3.09% of the entire cohort. The most frequent co-occurring mutations with sensitizing <i>EGFR</i> mutations include <i>KRAS</i> at 53.9%, followed by <i>ERBB2</i> at 24.3%, <i>MET</i> at 16.5%, and <i>BRAF</i> at 3.3%. <i>KRAS</i> mutations in concomitant drivers were frequently hyperexchange mutations (25.6% <i>v</i> 8.2%, <i>P</i> < .001), compared with <i>KRAS</i> single drivers. <i>EGFR</i>/<i>ERBB2</i> drivers exhibited a higher incidence of <i>ERBB2</i> amplification (40.7% <i>v</i> 16.5%, <i>P</i> < .001) and p.S310F/Y mutations (44.4% <i>v</i> 4.3%, <i>P</i> < .001) compared with <i>ERBB2</i> alone. <i>EGFR</i>/<i>MET</i> drivers had a higher frequency of <i>MET</i> amplification (71.4% <i>v</i> 43.3%) than <i>MET</i> single drivers. At the genomic level, the median number of additional concurrent mutations was four, with <i>TSC2</i> (4%), <i>CD274</i> (1%), and <i>TP53</i> (63%) being the most frequently coaltered genes in concomitant driver tumors. Interestingly, clonality analysis indicated that <i>EGFR</i> mutations were more likely to occur as clonal events, whereas the codrivers were more often subclonal. Patients with concomitant drivers or with concomitant <i>MET</i> amplification exhibited worse prognosis. These findings might aid in the selection of effective therapeutic regimens and facilitate the development of combination therapies.