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- W2891377483 abstract "e20506 Background: While conventional organization of EGFR mutations in NSCLC includes classic lesions sensitive to tyrosine kinase inhibitors (TKI) and variants localized to TKD in exons 18-21, NGS raises the prospect of identifying clinically relevant variants in extra-TKD regulatory regions. Methods: Patients (pts) with lung cancer who received tumor profiling with NGS from 2013-2015 via Caris were identified. EGFR mutations were arranged based upon their known distribution relative to the TKD. In silico analysis was performed with PolyPhen-2 (Harvard) to predict nsSNPs’ pathogenicity. Results: 259 pts (248 NSCLC, 11 SC) had median age 65 years (26-85); 50% female; 64% white, 34% black; 73% with ≥20 pack-years (py), 12% non-smokers; 53% of samples were metastases. 65% NSCLC were adenocarcinoma (A), 21% squamous (S), 8% large-cell; 87% stage IV, 12% III. 44 EGFR variants were seen in 40 pts (15%; 39 NSCLC, 1 SC). While 32 pts had TKD lesions demonstrable through standard testing, 8 had extra-TKD mutations (8/44), of which 5 were extracellular domain (ECD), 1 juxtamembrane (JM) and 2 carboxy terminal (CT). Aside from pathogenic ECD mutation G598V, 5/7 extra-TKD nsSNPs were predicted-damaging (pnsSNP) with in silico (Table 1). 7/7 extra-TKD nsSNP+ pts smoked (6/7 ≥20 py) and all 6 NSCLC pts were stage IV; 50% A, 17% S; 83% male. The pt with JM R675Q had erlotinib, 150 mg daily, added following progression of stage IV NSCLC on carboplatin and paclitaxel and had a partial response for 4 months. No other pt received EGFR-directed therapy. Conclusions: 2% NSCLC cases in our cohort had EGFR pnsSNPs located outside of the TKD, representing >18% of all EGFR mutations. Extra-TKD variants should be characterized collaboratively to determine TKI sensitivity and additional therapeutic targets. [Table: see text]" @default.
- W2891377483 created "2018-09-27" @default.
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- W2891377483 date "2017-05-20" @default.
- W2891377483 modified "2023-09-27" @default.
- W2891377483 title "Expanding the search for significant EGFR mutations in NSCLC outside of the tyrosine kinase domain (TKD) with next-generation sequencing (NGS)." @default.
- W2891377483 doi "https://doi.org/10.1200/jco.2017.35.15_suppl.e20506" @default.
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