학술논문
Targeting rare and non-canonical driver variants in NSCLC – An uncharted clinical field.
Document Type
Article
Author
Volckmar, Anna-Lena; Christopoulos, Petros; Kirchner, Martina; Allgäuer, Michael; Neumann, Olaf; Budczies, Jan; Rempel, Eugen; Horak, Peter; Glade, Julia; Goldschmid, Hannah; Seker-Cin, Huriye; Brandt, Regine; Kriegsmann, Mark; Leichsenring, Jonas; Winter, Hauke; Faehling, Martin; Fischer, Jürgen R.; Heußel, Claus Peter; Herth, Felix; Brummer, Tilman
Source
Subject
*NON-small-cell lung carcinoma
*GENE fusion
*PROTEIN-tyrosine kinases
*EPIDERMAL growth factor receptors
*NUCLEOTIDE sequencing
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Language
ISSN
0169-5002
Abstract
• Analysis of biological and clinical implications of rare or non-canonical variants in potentially druggable drivers (e.g. EGFR) is challenging and requires extensive resources. • Sequencing data of > 4000 NSCLC were comprehensively analyzed for non-canonical variants. • 5.5 % non-canonical mutations are potentially druggable. • Comprehensive up-to-date resource for molecular tumorboards and clinical decision making. Implementation of tyrosine kinase inhibitors (TKI) and other targeted therapies was a main advance in thoracic oncology with survival gains ranging from several months to years for non-small-cell lung cancer (NSCLC) patients. High-throughput comprehensive molecular profiling is of key importance to identify patients that can potentially benefit from these novel treatments. Next-generation sequencing (NGS) was performed on 4500 consecutive formalin-fixed, paraffin-embedded specimens of advanced NSCLC (n = 4172 patients) after automated extraction of DNA and RNA for parallel detection of mutations and gene fusions, respectively. Besides the 24.9 % (n = 1040) of cases eligible for approved targeted therapies based on the presence of canonical alterations in EGFR exons 18–21, BRAF , ROS1 , ALK , NTRK , and RET , an additional n = 1260 patients (30.2 %) displayed rare or non-canonical mutations in EGFR (n = 748), BRAF (n = 135), ERBB2 (n = 30), KIT (n = 32), PIK3CA (n = 221), and CTNNB1 (n = 94), for which targeted therapies could also be potentially effective. A systematic literature search in conjunction with in silico evaluation identified n = 232 (5.5 %) patients, for which a trial of targeted treatment would be warranted according to available evidence (NCT level 1, i.e. published data showing efficacy in the same tumor entity). In conclusion, a sizeable fraction of NSCLC patients harbors rare or non-canonical alterations that may be associated with clinical benefit from currently available targeted drugs. Systematic identification and individualized management of these cases can expand applicability of precision oncology in NSCLC and extend clinical gain from established molecular targets. These results can also inform clinical trials. [ABSTRACT FROM AUTHOR]