Mutational Portrait of Lung Adenocarcinoma in Brazilian Patients: Past, Present, and Future of Molecular Profiling in the Clinic.

Objectives:Approximately 60% of lung adenocarcinomas (LAs) carry mutations that can guide treatment with tyrosine-kinase inhibitors (TKI) and other targeted therapies. Data on activating mutations inEGFRand other tyrosine-kinase receptor (TKR) genes in highly admixed populations, such as that of Brazil, are scarce. In this study, we comprehensively analyzed the actionable alteration profile of LA in Brazilian patients. Materials and Methods:EGFRdriver mutation data were collected from a large Brazilian LA cohort covering an 8-year period of molecular testing in a single institution. Tests were performed using three distinct methods, and demographic and histopathological data were analyzed. For a subset of patients, driver mutations inKRAS, NRAS, andBRAFand gene fusions involving TKR genes (before TKI treatment) andEGFRT790M (after TKI treatment) were assessed. Results:EGFRmutations were detected in 25% of 1,316 LAs evaluated, with exon 19 deletions and exon 21 L858R TKI sensitizing mutations representing 72.5% of all mutations. Mutation rates were higher in women and non-smokers (p< 0.001). Next-generation sequencing was very sensitive, with a lower rate of inconclusive results compared with Sanger sequencing and pyrosequencing.EGFR/RAS/BRAFhotspot gene panels were applied in 495 LA cases and detected oncogenic mutations in 51.3% of samples, most frequently inEGFR(22.4%) andKRAS(26.9%). In subgroups of 36 and 35 patients, gene fusions were detected in 11.1% of tumors andEGFRT790M resistance mutations were detected in 59% of plasma samples from patients previously treated with TKI, respectively. Conclusion:This report provides the first comprehensive actionable alteration portrait of LA in Brazil. The high rate of actionable alterations inEGFRand other driver genes in LA reinforces the need to incorporate TKI guided by molecular diagnostics into clinical routines for patients in both public and private healthcare systems.