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Int. J. Mol. Sci. 2015, 16(1), 747-757; doi:10.3390/ijms16010747

Gene Mutation Analysis in EGFR Wild Type NSCLC Responsive to Erlotinib: Are There Features to Guide Patient Selection?

1
Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
2
Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy
3
Department of Oncology, Per gli Infermi Hospital, Rimini 47900, Italy
4
Department of Medical Oncology, Santa Maria delle Croci Hospital, Ravenna 48121, Italy
5
Unit of Biostatistics and Clinical Trials, IRST IRCCS, Meldola 47014, Italy
6
Oncology Unit, Degli Infermi Hospital, Faenza 48018, Italy
7
Pathology Unit, Santa Maria delle Croci Hospital, Ravenna 48121, Italy
8
Pathology Unit, Morgagni-Pierantoni Hospital, Forlì 47121, Italy
9
Division of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia 06156, Italy
*
Author to whom correspondence should be addressed.
Academic Editor: William Chi-shing Cho
Received: 17 October 2014 / Accepted: 23 December 2014 / Published: 31 December 2014
View Full-Text   |   Download PDF [677 KB, uploaded 31 December 2014]

Abstract

Tyrosine kinase inhibitors (TKIs) are very efficacious in non-small-cell lung cancer (NSCLC) patients harboring activating Epidermal Growth Factor Receptor (EGFR) mutations. However, about 10% of EGFR wild type (wt) patients respond to TKI, with unknown molecular mechanisms of sensitivity. We considered a case series of 34 EGFR wt NSCLC patients responsive to erlotinib after at least one line of therapy. Responsive patients were matched with an equal number of non-responsive EGFR wt patients. A panel of 26 genes, for a total of 214 somatic mutations, was analyzed by MassARRAY® System (Sequenom, San Diego, CA, USA). A 15% KRAS mutation was observed in both groups, with a prevalence of G12C in non-responders (80% vs. 40% in responders). NOTCH1, p53 and EGFR-resistance-related mutations were found more frequently in non-responders, whereas EGFR-sensitizing mutations and alterations in genes involved in proliferation pathways were more frequent in responders. In conclusion, our findings indicate that p53, NOTCH1 and exon 20 EGFR mutations seem to be related to TKI resistance. KRAS mutations do not appear to influence the TKI response, although G12C mutation is more frequent in non-responders. Finally, the use of highly sensitive methodologies could lead to the identification of under-represented EGFR mutations potentially associated with TKI sensitivity. View Full-Text
Keywords: NSCLC; erlotinib; EGFR wt; p53; KRAS NSCLC; erlotinib; EGFR wt; p53; KRAS
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Ulivi, P.; Delmonte, A.; Chiadini, E.; Calistri, D.; Papi, M.; Mariotti, M.; Verlicchi, A.; Ragazzini, A.; Capelli, L.; Gamboni, A.; Puccetti, M.; Dubini, A.; Burgio, M.A.; Casanova, C.; Crinò, L.; Amadori, D.; Dazzi, C. Gene Mutation Analysis in EGFR Wild Type NSCLC Responsive to Erlotinib: Are There Features to Guide Patient Selection? Int. J. Mol. Sci. 2015, 16, 747-757.

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