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

Paola Ulivi, Elisa Chiadini, Claudio Dazzi, Alessandra Dubini, Matteo Costantini, Laura Medri, Maurizio Puccetti, Laura Capelli, Daniele Calistri, Alberto Verlicchi, Alessandro Gamboni, Maximilian Papi, Marita Mariotti, Nicoletta De Luigi, Emanuela Scarpi, Sara Bravaccini, Gian Michele Turolla, Dino Amadori, Lucio Crinò, Angelo Delmonte

Research output: Contribution to journalArticle

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.

Original languageEnglish
JournalClinical Lung Cancer
DOIs
Publication statusAccepted/In press - Sep 4 2015

Keywords

  • Crizotinib
  • Double mutations
  • NSCLC
  • Prognosis
  • Tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pulmonary and Respiratory Medicine

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    Ulivi, P., Chiadini, E., Dazzi, C., Dubini, A., Costantini, M., Medri, L., Puccetti, M., Capelli, L., Calistri, D., Verlicchi, A., Gamboni, A., Papi, M., Mariotti, M., De Luigi, N., Scarpi, E., Bravaccini, S., Turolla, G. M., Amadori, D., Crinò, L., & Delmonte, A. (Accepted/In press). 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. Clinical Lung Cancer. https://doi.org/10.1016/j.cllc.2015.11.004