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Ref Type Journal Article
PMID (31839416)
Authors Zhao J, Lin G, Zhuo M, Fan Z, Miao L, Chen L, Zeng A, Yin R, Ou Y, Shi Z, Yin J, Gao W, Chen J, Zhou X, Zeng Y, Liu X, Xu H, Chen R, Xia X, Carbone DP
Title Next-generation sequencing based mutation profiling reveals heterogeneity of clinical response and resistance to osimertinib.
Journal Vol Issue Date Pages Journal Short Title
Lung cancer (Amsterdam, Netherlands) 141 2020 Mar 114-118 Lung Cancer
URL
Abstract Text The 3rd generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR TKI) osimertinib has shown promising efficacy both in EGFR-mutant, T790M positive non-small cell lung cancer (NSCLC) patients who have become resistant to 1st or 2nd generation EGFR TKIs and patients with sensitizing EGFR mutations as the first line therapy. However, the degree and duration of response to osimertinib are heterogeneous. We hypothesized that the concurrent genomic landscape of these tumors could play a role in clinical outcomes and/or mechanisms of resistance.We conducted a retrospective multicenter study of lung cancer patients who had developed resistance to osimertinib. Genomic profiling was done for all the patients by using targeted next-generation sequencing encompassing 59-1021 cancer-related genes.Known EGFR-dependent resistant mutations and activation of alternative pathways were identified in 44 % of all the patients with great heterogeneity. Gain-of-function mutations of CTNNB1 were highly enriched in our cohort. Some other putative resistance mechanisms to osimertinib, such as the recurrent EGFR V834 L mutation, were also identified. Moreover, pathogenic mutations of TP53 were negatively related to the efficacy of osimertinib. To sum up, heterogeneity of resistance to osimertinib was not only manifested by inter-individual differences, but also embodied in its intra-individual diversity.

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