Wang H, Ou Q, Li D, et al. - In this retrospective analysis of 61 patients who underwent surgical resection of primary non–small cell lung cancer (NSCLC) and brain metastases (BMs), researchers carried out comprehensive genomic profiling of primary NSCLC and matched BMs using next-generation sequencing targeting 416 cancer-relevant genes, to understand the molecular mechanisms behind increased BM risk so that effective interventions may be developed. Between primary NSCLC and matched BMs, a high concordance for mutations of major drivers, including EGFR, KRAS, TP53, and ALK, was reported, whereas discordance was indicative of the unique genomic evolution and oncogenic mechanisms of NSCLC BMs. Higher levels of copy number variations were shown by BMs vs primary NSCLC. In NSCLC patients, PI3K signaling significantly correlated with increased metastatic risk. Significantly shorter BM-free survival was experienced by patients with activated PI3K signaling in their primary NSCLC. Trending of mutated TP53 or an activated WNT pathway, through CTNNB1, APC, and AXIN2 mutations, toward shorter BM-free intervals but not significantly so, was also reported.