• Masayuki Takeda, Kazuko Sakai, Hidetoshi Hayashi, Kaoru Tanaka, Koji Haratani, Takayuki Takahama, Ryoji Kato, Kimio Yonesaka, Kazuto Nishio, and Kazuhiko Nakagawa.
• Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka-Sayama, Osaka, Japan. Electronic address: takeda_m@med.kindai.ac.jp.
• Lung Cancer. 2020 Jan 1; 139: 28-34.

ObjectivesThe T790M secondary mutation of epidermal growth factor receptor gene (EGFR) is the most common mechanism of acquired resistance to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). We investigated the association between gene mutation profile in EGFR mutation-positive non-small cell lung cancer (NSCLC) before EGFR-TKI treatment and T790M status after EGFR-TKI treatment.Materials And MethodsA total of 57 EGFR mutation-positive NSCLC patients who had undergone a repeat biopsy (tissue or liquid) after failure of treatment with a first- or second-generation EGFR-TKI and who had sufficient tumor tissue available from before treatment for genetic analysis was enrolled. The gene mutation profile of tumor tissue obtained before EGFR-TKI treatment was evaluated by next-generation sequencing with a comprehensive cancer gene panel (409 genes). The number of potentially damaging nonsynonymous mutations was predicted with PolyPhen-2 software.ResultsProgression-free survival during EGFR-TKI treatment did not differ significantly between patients who developed T790M-mediated resistance and those who developed T790M-independent resistance. The predicted number of damaging nonsynonymous mutations in pretreatment tumor tissue was significantly lower in patients who developed T790M-mediated resistance than in those with T790M-independent resistance (P =  0.049).ConclusionsCoexisting mutations in tumor tissue before EGFR-TKI treatment may contribute to the emergence of cell clones responsible for development of T790M-dependent or T790M-independent TKI resistance in patients with EGFR-mutated NSCLC. Multiplex genomic testing of pretreatment tumor tissue may thus provide a means of identifying patients likely to develop T790M-mediated TKI resistance and therefore inform treatment selection.Copyright © 2019 Elsevier B.V. All rights reserved.

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