The emergence of various genetic alterations mediated the Osimertinib resistance of a patient harboring heterozygous germline EGFR T790M: a case report.

Epidermal growth factor receptor () T790M is the major mechanism mediating resistance to first- and second-generation EGFR tyrosine kinase inhibitors. Despite the high frequency of activating mutations among East Asian lung cancer patients, germline T790M has been the subject of very little research. Questions remain as to whether germline T790M develops resistance to Osimertinib and if so, through which mechanisms. This study examined a patient harboring germline T790M who acquired resistance to Osimertinib therapy. After the failure of first-line icotinib therapy, which was administered for only 3 months, targeted next-generation sequencing of plasma samples collected at icotinib progression and the re-analysis of the baseline tissue biopsy sample revealed T790M with allelic frequencies approximating 50%. Lymphocyte genomic deoxyribonucleic acid (DNA) sequencing confirmed the germline heterozygous status of the T790M mutation. In addition to the T790M, a concurrent L858R was detected from the baseline tissue sample. Osimertinib therapy was initiated resulting in a partial response within 1 month of the commencement of the therapy. After 15.2 months of Osimertinib therapy, disease progression was evaluated due to the presence of pleural effusion. The targeted sequencing of plasma and pleural effusion samples revealed the emergence of G719A, tumor protein p53 () Q136X, and the co-amplification of Cyclin D1, fibroblast growth factor () 19, , and This case highlights the importance of conducting next-generation sequencing-based molecular testing during both diagnostic and disease progression assessments to reveal sensitizing mutations and mutations that could mediate primary and acquired resistance to targeted therapeutics.