Impact of coexisting gene mutations in EGFR-mutated non-small cell lung cancer before treatment on EGFR T790M mutation status after EGFR-TKIs.,Lung Cancer

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Impact of coexisting gene mutations in EGFR-mutated non-small cell lung cancer before treatment on EGFR T790M mutation status after EGFR-TKIs.
Lung Cancer ( IF 5.3 ) Pub Date : 2019-11-03 , DOI: 10.1016/j.lungcan.2019.10.028
Masayuki Takeda ₁ , Kazuko Sakai ₂ , Hidetoshi Hayashi ₁ , Kaoru Tanaka ₁ , Koji Haratani ₁ , Takayuki Takahama ₁ , Ryoji Kato ₁ , Kimio Yonesaka ₁ , Kazuto Nishio ₂ , Kazuhiko Nakagawa ₁

Affiliation

OBJECTIVES The 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 METHODS A 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. RESULTS Progression-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). CONCLUSIONS Coexisting 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.

更新日期：2019-11-03

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