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

Fingerprint

Epidermal Growth Factor Receptor
Non-Small Cell Lung Carcinoma
Mutation
Therapeutics
MAP4
anaplastic lymphoma kinase
Receptor Protein-Tyrosine Kinases
Oncogenes
Sarcoma
Disease Progression
Survival

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

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

In: Clinical Lung Cancer, 04.09.2015.

Research output: Contribution to journalArticle

Ulivi, Paola ; Chiadini, Elisa ; Dazzi, Claudio ; Dubini, Alessandra ; Costantini, Matteo ; Medri, Laura ; Puccetti, Maurizio ; Capelli, Laura ; Calistri, Daniele ; Verlicchi, Alberto ; Gamboni, Alessandro ; Papi, Maximilian ; Mariotti, Marita ; De Luigi, Nicoletta ; Scarpi, Emanuela ; Bravaccini, Sara ; Turolla, Gian Michele ; Amadori, Dino ; Crinò, Lucio ; Delmonte, Angelo. / 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. In: Clinical Lung Cancer. 2015.
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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 = "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.",
keywords = "Crizotinib, Double mutations, NSCLC, Prognosis, Tyrosine kinase inhibitors",
author = "Paola Ulivi and Elisa Chiadini and Claudio Dazzi and Alessandra Dubini and Matteo Costantini and Laura Medri and Maurizio Puccetti and Laura Capelli and Daniele Calistri and Alberto Verlicchi and Alessandro Gamboni and Maximilian Papi and Marita Mariotti and {De Luigi}, Nicoletta and Emanuela Scarpi and Sara Bravaccini and Turolla, {Gian Michele} and Dino Amadori and Lucio Crin{\`o} and Angelo Delmonte",
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T1 - Nonsquamous, Non-Small-Cell Lung Cancer Patients Who Carry a Double Mutation of EGFR, EML4-ALK or KRAS

T2 - Frequency, Clinical-Pathological Characteristics, and Response to Therapy

AU - Ulivi, Paola

AU - Chiadini, Elisa

AU - Dazzi, Claudio

AU - Dubini, Alessandra

AU - Costantini, Matteo

AU - Medri, Laura

AU - Puccetti, Maurizio

AU - Capelli, Laura

AU - Calistri, Daniele

AU - Verlicchi, Alberto

AU - Gamboni, Alessandro

AU - Papi, Maximilian

AU - Mariotti, Marita

AU - De Luigi, Nicoletta

AU - Scarpi, Emanuela

AU - Bravaccini, Sara

AU - Turolla, Gian Michele

AU - Amadori, Dino

AU - Crinò, Lucio

AU - Delmonte, Angelo

PY - 2015/9/4

Y1 - 2015/9/4

N2 - 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.

AB - 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.

KW - Crizotinib

KW - Double mutations

KW - NSCLC

KW - Prognosis

KW - Tyrosine kinase inhibitors

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