The genomic landscape of young and old lung cancer patients highlights age‐dependent mutation frequencies and clinical actionability in young patients.

The aim of the study was to investigate age‐dependent tendency of genomic alterations in lung cancer, and also to examine mutational profiles and its association with clinical treatment outcomes in young adenocarcinoma patients. By studying 7858 lung cancer samples using targeted‐gene sequencing, we investigated genomic differences and clinical on‐treatment time (OTT) to different therapies between young (≤ 45 years) and old (> 45 years) patients. The age‐dependent trend test for genomic alterations in all patients revealed steady increases in tumor mutation burden and alterations in a number of genes with age, including KRAS, MET, CDKN2A, PIK3CA and MDM2, while the frequencies of ALK, ROS1 and RET fusions and ERBB2 mutations were decreasing. The highest rate of EGFR alterations was observed in the 45 ~ 50 years age group. Comparisons of young and old adenocarcinoma patients found that young patients were characterized by a higher prevalence of ALK, ROS1 and RET fusions, and ERBB2 exon‐20 insertions and EGFR exon‐19 deletions. Actionable mutations were highly prevalent in young adenocarcinoma patients, with 88% of patients harboring at least one actionable genetic alteration. First‐line therapies in EGFR‐positive patients (n = 979) by EGFR tyrosine kinase inhibitors or chemotherapy resulted in similar OTT between young and old patients. Somatic interaction analyses implied that young EGFR‐positive patients were more likely to also have PIK3CA, MET, TP53 and RB1 mutations than old patients. Lung cancer in young patients, and especially those with adenocarcinoma, exhibited different clinical features and genomic attributes compared to old patients, which should be considered for therapeutic decision‐making purposes. What's new? Young patients with lung cancer represent a sub‐group with distinct clinical features compared to older patients. This large retrospective cohort study with a targeted sequencing panel covering over 400 cancer‐related genes suggests that young adenocarcinoma patients (≤45 years) have a different spectrum of driver mutations and a higher ratio of actionable genetic alterations compared to older patients. Over a third of young patients have multiple drivers, and the co‐mutation rate of EGFR with other oncogenes is high. These findings highlight genetic differences between young and older patients that possibly associate with different treatment outcomes. [ABSTRACT FROM AUTHOR]