Concomitant driver mutations in advanced EGFR-mutated non-small-cell lung cancer and their impact on erlotinib treatment

TY - JOUR

T1 - Concomitant driver mutations in advanced EGFR-mutated non-small-cell lung cancer and their impact on erlotinib treatment

AU - Jakobsen, Jan Nyrop

AU - Santoni-Rugiu, Eric

AU - Grauslund, Morten

AU - Melchior, Linea

AU - Sørensen, Jens Benn

PY - 2018

Y1 - 2018

N2 - Background: Patients with EGFR-mutated non-small-cell lung cancer benefit from EGFR tyrosine kinase inhibitors (TKIs) like erlotinib. However, the efficacy may be impaired by driver mutations in other genes.Methods: Five hundred and fourteen consecutive patients with NSCLC of all stages were tested for EGFR-mutations by cobas® EGFR Mutation Test. Fluorescent in situ hybridization (FISH) for MET-amplification, immunohistochemistry (IHC) for MET- and ALK-expression, and Next Generation Sequencing (NGS) for concomitant driver mutations were performed on EGFR-mutated tumor samples from erlotinib-treated patients.Results: Thirty-six patients (7%) had EGFR-mutations, including 2 with intrinsic resistance mutation p.T790M together with the p.L858R sensitizing mutation and 1 harboring the p.G719C/S768I double-mutation. Twenty-three patients had either locally advanced or advanced disease and received first-line erlotinib-treatment. Concomitant driver mutations were found in 15/21 (71%) of NGS-analyzed TKI-treated NSCLCs, involving in 67% of cases TP53, in 13% CTNNB1, and in 7% KRAS, MET, SMAD4, PIK3CA, FGFR1, FGFR3, NRAS, DDR2, and ERBB4. No ALK-expression was found, whereas MET-overexpression and MET-amplification were observed in 5 and 4 patients, respectively. Objective responses occurred in 17/23 patients (74%), 4 did not respond (17%), and 2 harboring a SMAD4-mutation (p.R135*(stop)) and a FGFR3-mutation (p.D785fs*31), respectively, displayed mixed response with simultaneously progressing and responding tumors (8.7%). Thus, EGFR-mutated tumors harboring co-mutations were not less likely to respond.Conclusion: Co-mutations in other cancer-driver genes (oncogenes or tumor suppressor genes) were frequent in EGFR-mutated NSCLCs and few cases harbored concomitant activating and resistance EGFR-mutations before TKI-treatment. Most co-mutations did not impact the response to first-line erlotinib-treatment, but may represent potential additional therapeutic targets.

AB - Background: Patients with EGFR-mutated non-small-cell lung cancer benefit from EGFR tyrosine kinase inhibitors (TKIs) like erlotinib. However, the efficacy may be impaired by driver mutations in other genes.Methods: Five hundred and fourteen consecutive patients with NSCLC of all stages were tested for EGFR-mutations by cobas® EGFR Mutation Test. Fluorescent in situ hybridization (FISH) for MET-amplification, immunohistochemistry (IHC) for MET- and ALK-expression, and Next Generation Sequencing (NGS) for concomitant driver mutations were performed on EGFR-mutated tumor samples from erlotinib-treated patients.Results: Thirty-six patients (7%) had EGFR-mutations, including 2 with intrinsic resistance mutation p.T790M together with the p.L858R sensitizing mutation and 1 harboring the p.G719C/S768I double-mutation. Twenty-three patients had either locally advanced or advanced disease and received first-line erlotinib-treatment. Concomitant driver mutations were found in 15/21 (71%) of NGS-analyzed TKI-treated NSCLCs, involving in 67% of cases TP53, in 13% CTNNB1, and in 7% KRAS, MET, SMAD4, PIK3CA, FGFR1, FGFR3, NRAS, DDR2, and ERBB4. No ALK-expression was found, whereas MET-overexpression and MET-amplification were observed in 5 and 4 patients, respectively. Objective responses occurred in 17/23 patients (74%), 4 did not respond (17%), and 2 harboring a SMAD4-mutation (p.R135*(stop)) and a FGFR3-mutation (p.D785fs*31), respectively, displayed mixed response with simultaneously progressing and responding tumors (8.7%). Thus, EGFR-mutated tumors harboring co-mutations were not less likely to respond.Conclusion: Co-mutations in other cancer-driver genes (oncogenes or tumor suppressor genes) were frequent in EGFR-mutated NSCLCs and few cases harbored concomitant activating and resistance EGFR-mutations before TKI-treatment. Most co-mutations did not impact the response to first-line erlotinib-treatment, but may represent potential additional therapeutic targets.

U2 - 10.18632/oncotarget.25490

DO - 10.18632/oncotarget.25490

M3 - Journal article

C2 - 29899852

SN - 1949-2553

VL - 9

SP - 26195

EP - 26208

JO - Oncotarget

JF - Oncotarget

IS - 40

ER -