Prevalence and clinical association of gene mutations through Multiplex Mutation Testing in patients with NSCLC: Results from the ETOP Lungscape Project.

Kerr KM1, Dafni U2, Schulze K3, Thunnissen E4, Bubendorf L5, Hager H6, Finn S7, Biernat W8, Vliegen L9, Losa JH10, Marchetti A11, Cheney R12, Warth A13, Speel EJ14, Blackhall F15, Monkhorst K16, Jantus Lewintre E17, Tischler V18, Clark C19, Bertran-Alamillo J20, Meldgaard P21, Gately K22, Wrona A23, Vandenberghe P9, Felip E24, De Luca G11, Savic S5, Muley T25, Smit EF26, Dingemans AC27, Priest L15, Baas P28, Camps C29, Weder W30, Polydoropoulou V31, Geiger TR32, Kammler R32, Sumiyoshi T3, Molina MA20, Shames DS3, Stahel RA33, Peters S34; ETOP Lungscape Consortium.

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Abstract

BACKGROUND:

Reported prevalence of driver gene mutations in non-small cell lung cancer (NSCLC) is highly variable and clinical correlations are emerging. Using NSCLC biomaterial and clinical data from the ETOP Lungscape iBiobank, we explore the epidemiology of mutations and association to clinicopathological features and patient outcome (relapse-free survival, time-to-relapse, overall survival).

METHODS:

Clinically-annotated, resected stage I-III NSCLC FFPE tissue was assessed for gene mutation using a microfluidics-based multiplex PCR platform. Mutant-allele detection sensitivity is > 1% for most of the ∼150 (13 genes) mutations covered in the multiplex test.

RESULTS:

Multiplex testing has been performed in 2063 (76.2%) of the 2709 Lungscape cases (median follow-up 4.8 years). FFPE samples mostly date from 2005-8, yet recently extracted DNA quality and quantity was generally good. Average DNA yield/case was 2.63µg; 38 cases (1.4%) failed QC and were excluded from study. 95.1% of included cases allowed the complete panel of mutations to be tested. Most common were KRAS, MET, EGFR and PIK3CA mutations with overall prevalence of 23.0%, 6.8%, 5.4% and 4.9% respectively. KRAS and EGFR mutations were significantly more frequent in adenocarcinomas: PIK3CA in squamous cell carcinomas. MET mutation prevalence did not differ between histology groups. EGFR mutations were found predominantly in never smokers; KRAS in current/former smokers. For all the above mutations, there was no difference in outcome between mutated and non-mutated cases.

CONCLUSION:

Archival FFPE NSCLC material is adequate for multiplex mutation analysis. In this large, predominantly European, clinically-annotated stage I-III NSCLC cohort, none of the mutations characterized showed prognostic significance.