Paola Ulivi1, Elisa Chiadini2, Claudio Dazzi3, Alessandra Dubini4, Matteo Costantini4, Laura Medri4, Maurizio Puccetti5, Laura Capelli2, Daniele Calistri2, Alberto Verlicchi3, Alessandro Gamboni6, Maximilian Papi7, Marita Mariotti8, Nicoletta De Luigi8, Emanuela Scarpi9, Sara Bravaccini2, Gian Michele Turolla10, Dino Amadori8, Lucio Crinò11, Angelo Delmonte8. 1. Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. Electronic address: paola.ulivi@irst.emr.it. 2. Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. 3. Medical Oncology Unit, S.Maria delle Croci Hospital, Ravenna, Italy. 4. Pathology Unit, Morgagni-Pierantoni Hospital, Forlì, Italy. 5. Pathology Unit, S. Maria delle Croci Hospital, Ravenna, Italy. 6. Medical Oncology Unit, Degli Infermi Hospital, Faenza, Italy. 7. Department of Oncology, Per gli Infermi Hospital, Rimini, Italy. 8. Medical Oncology Unit, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. 9. Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. 10. Oncology Unit, Lugo Hospital, Lugo di Ravenna, Italy. 11. Division of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia, Italy.
Abstract
BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND:Epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten ratsarcoma 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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: Francesco Facchinetti; Marcello Tiseo; Massimo Di Maio; Paolo Graziano; Emilio Bria; Giulio Rossi; Silvia Novello Journal: Transl Lung Cancer Res Date: 2016-06
Authors: Mónica Garzón; Sergi Villatoro; Cristina Teixidó; Clara Mayo; Alejandro Martínez; Maria de Los Llanos Gil; Santiago Viteri; Daniela Morales-Espinosa; Rafael Rosell Journal: Transl Lung Cancer Res Date: 2016-10
Authors: Giuseppe Lo Russo; Martina Imbimbo; Giulia Corrao; Claudia Proto; Diego Signorelli; Milena Vitali; Monica Ganzinelli; Laura Botta; Nicoletta Zilembo; Filippo de Braud; Marina Chiara Garassino Journal: Oncotarget Date: 2017-04-26