title: Gene mutation analysis in EGFR wild type NSCLC responsive to erlotinib: are there features to guide patient selection?
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.
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy. paola.ulivi@irst.emr.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Ulivi
authors.affiliation: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy. angelo.delmonte@irst.emr.it.
authors.forename: Angelo
authors.initials: A
authors.lastname: Delmonte
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy. elisa.chiadini@irst.emr.it.
authors.forename: Elisa
authors.initials: E
authors.lastname: Chiadini
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy. daniele.calistri@irst.emr.it.
authors.forename: Daniele
authors.initials: D
authors.lastname: Calistri
authors.affiliation: Department of Oncology, Per gli Infermi Hospital, Rimini 47900, Italy. maximilianpapi@libero.it.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Papi
authors.affiliation: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy. marita.mariotti@irst.emr.it.
authors.forename: Marita
authors.initials: M
authors.lastname: Mariotti
authors.affiliation: Department of Medical Oncology, Santa Maria delle Croci Hospital, Ravenna 48121, Italy. alberto28981@gmail.com.
authors.forename: Alberto
authors.initials: A
authors.lastname: Verlicchi
authors.affiliation: Unit of Biostatistics and Clinical Trials, IRST IRCCS, Meldola 47014, Italy. angela.ragazzini@irst.emr.it.
authors.forename: Angela
authors.initials: A
authors.lastname: Ragazzini
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy. laura.capelli@irst.emr.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Capelli
authors.affiliation: Oncology Unit, Degli Infermi Hospital, Faenza 48018, Italy. a.gamboni@ausl.ra.it.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gamboni
authors.affiliation: Pathology Unit, Santa Maria delle Croci Hospital, Ravenna 48121, Italy. m.puccetti@ausl.ra.it.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Puccetti
authors.affiliation: Pathology Unit, Morgagni-Pierantoni Hospital, Forlì 47121, Italy. a.dubini@ausl.fo.it.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Dubini
authors.affiliation: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy. marco.burgio@irst.emr.it.
authors.forename: Marco Angelo
authors.initials: MA
authors.lastname: Burgio
authors.affiliation: Department of Medical Oncology, Santa Maria delle Croci Hospital, Ravenna 48121, Italy. c.casanova@ausl.ra.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Casanova
authors.affiliation: Division of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia 06156, Italy. lucio.crino@ospedale.perugia.it.
authors.forename: Lucio
authors.initials: L
authors.lastname: Crinò
authors.affiliation: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola 47014, Italy. dino.amadori@irst.emr.it.
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
authors.affiliation: Department of Medical Oncology, Santa Maria delle Croci Hospital, Ravenna 48121, Italy. c.dazzi@ausl.ra.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Dazzi
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005091:Exons; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D051881:Receptor, Notch1; D016159:Tumor Suppressor Protein p53; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D018631:ras Proteins