title: Nonsquamous, Non-Small-Cell Lung Cancer Patients Who Carry a Double Mutation of EGFR, EML4-ALK or KRAS: Frequency, Clinical-Pathological Characteristics, and Response to Therapy.
abstract: Epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, and echinoderm microtubule-associated protein-like 4 (EML4) anaplastic lymphoma kinase (ALK) translocation are generally considered to be mutually exclusive. However, concomitant mutations are found in a small number of patients and the effect of these on response to targeted therapy is still unknown.
  
  
  
  We considered 380 non-small-cell lung cancer (NSCLC) patients who underwent nonsequential testing for EGFR and EML4-ALK translocation. KRAS mutation analysis was also performed on 282 patients.
  
  
  
  We found 1.6%, 1.1%, and 2.5% of patients who showed a double mutation comprising EGFR and EML4-ALK, EGFR and KRAS, and EML4-ALK and KRAS, respectively. Twenty-eight patients with EGFR mutation underwent first-line therapy with a tyrosine kinase receptor; a clinical benefit was observed in 81.8% of patients with EGFR mutations only and in 67% of those who also showed an EML4-ALK translocation. Twelve patients with an EML4-ALK translocation received crizotinib and 7 of these had disease progression within 3 months (2 had a concomitant KRAS mutation and 1 had a concomitant EGFR mutation). Two patients showed stable disease, 1 of whom also had a KRAS mutation. Two patients obtained a partial response and 1 had a complete response; all harbored an EML4-ALK translocation only. The median overall survival of patients who carried an EML4-ALK translocation alone or concomitant with a KRAS mutation was 57.1 (range, 10.7-not reached) and 10.7 (range, 4.6-not reached) months, respectively.
  
  
  
  Concomitant EGFR, EML4-ALK, or KRAS mutations can occur in NSCLC. Concomitant KRAS mutation and EML4-ALK translocation represents the most common double alteration and confers a poor prognosis.
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. Electronic address: paola.ulivi@irst.emr.it.
authors.forename: Paola
authors.initials: P
authors.lastname: Ulivi
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Chiadini
authors.affiliation: Medical Oncology Unit, S.Maria delle Croci Hospital, Ravenna, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Dazzi
authors.affiliation: Pathology Unit, Morgagni-Pierantoni Hospital, Forlì, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Dubini
authors.affiliation: Pathology Unit, Morgagni-Pierantoni Hospital, Forlì, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Costantini
authors.affiliation: Pathology Unit, Morgagni-Pierantoni Hospital, Forlì, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Medri
authors.affiliation: Pathology Unit, S. Maria delle Croci Hospital, Ravenna, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Puccetti
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Capelli
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Calistri
authors.affiliation: Medical Oncology Unit, S.Maria delle Croci Hospital, Ravenna, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Verlicchi
authors.affiliation: Medical Oncology Unit, Degli Infermi Hospital, Faenza, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Gamboni
authors.affiliation: Department of Oncology, Per gli Infermi Hospital, Rimini, Italy.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Papi
authors.affiliation: Medical Oncology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Marita
authors.initials: M
authors.lastname: Mariotti
authors.affiliation: Medical Oncology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: De Luigi
authors.affiliation: Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Scarpi
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Bravaccini
authors.affiliation: Oncology Unit, Lugo Hospital, Lugo di Ravenna, Italy.
authors.forename: Gian Michele
authors.initials: GM
authors.lastname: Turolla
authors.affiliation: Medical Oncology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Dino
authors.initials: D
authors.lastname: Amadori
authors.affiliation: Division of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia, Italy.
authors.forename: Lucio
authors.initials: L
authors.lastname: Crinò
authors.affiliation: Medical Oncology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Delmonte
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D000077547:Crizotinib; D018450:Disease Progression; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D011379:Prognosis; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D012189:Retrospective Studies; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C522504:EML4-ALK fusion protein, human; C117307:KRAS protein, human; D015514:Oncogene Proteins, Fusion; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Crizotinib; Double mutations; NSCLC; Prognosis; Tyrosine kinase inhibitors