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Concurrent Driver Gene Mutations as Negative Predictive Factors in EGFR Positive Non-Small Cell Lung Cancer
15 Pages Posted: 8 Jan 2019
More...Abstract
Background: Tyrosine kinase inhibitors (TKIs) are clinically effective in non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) oncogene mutations. However, the genetic factors other than EGFR mutations that may predict the disease progression and efficacy of TKI treatment needs to be define.
Methods: Four hundred and twenty three consecutive patients with advanced NSCLC and EGFR 19del or 21L858R mutations were retrospectively screened. A total of 71 patients whose progression free survivals (PFS) were longer than 24 months or shorter than 6 months were included and stratified into two groups. Pretreatment specimens of tumor tissue were collected and next generation sequencing (NGS) was performed. Genetic background discrepancy was analyzed in the two groups.
Findings: Sensitive EGFR mutations of 19del or 21 L858R were detected by NGS in all of the 71 patients. The 21L858R mutation was the major EGFR mutation type. Complex EGFR mutations were found in 22 (31%) patients. The most frequent accompany somatic mutations were TP53 (42/59%), followed by RB1 (14%), MAPK2K (8%), and ERBB2 (7%). Concurrent resistant mutation of T790M was found in both groups while ALK fusion, MET amplification, and BRAF V600E were only found in short PFS group. The T790M ratio to EGFR mutation was higher in short PFS group. Patients in short PFS group had significantly more resistant mutations than patients in long PFS group (P=0*018). The number of contaminate somatic mutations, the number of EGFR pathway related mutation and tumor mutation burden (TMB) were not significant different between the two groups.
Interpretion: Preexisting driver gene mutations and a high T790M ratio to EGFR mutation were most important negative predictive factors of TKI therapy in EGFR-mutated patients receiving TKI treatment. This study also highlights the importance of exploring resistance genomic alterations as well as driver mutations before the initiation of EGFR-TKIs.
Funding: National Natural Science Foundation of China (Grant No. 81702292).
Declaration of Interest: No potential conflicts of interest were disclosed.
Ethical Approval: This study was approved by the Peking Union Medical College Hospital review board.
Keywords: non-small cell lung cancer, epidermal growth factor receptor tyrosine kinase inhibitor, predictive factor, co-occurring mutations
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