The Presence of Concomitant Mutations Affects the Activity of EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) Patients

Anna Maria Rachiglio, Francesca Fenizia, Maria Carmela Piccirillo, Domenico Galetta, Lucio Crinò, Bruno Vincenzi, Emiddio Barletta, Carmine Pinto, Francesco Ferraù, Matilde Lambiase, Agnese Montanino, Cristin Roma, Vienna Ludovini, Elisabetta Sara Montagna, Antonella De Luca, Gaetano Rocco, Gerardo Botti, Francesco Perrone, Alessandro Morabito, Nicola Normanno

Research output: Contribution to journalArticle

Abstract

Recent findings suggest that a fraction of EGFR-mutant non-small-cell lung cancers (NSCLC) carry additional driver mutations that could potentially affect the activity of EGFR tyrosine kinase inhibitors (TKIs). We investigated the role of concomitant KRAS, NRAS, BRAF, PIK3CA, MET and ERBB2 mutations (other mutations) on the outcome of 133 EGFR mutant patients, who received first-line therapy with EGFR TKIs between June 2008 and December 2014. Analysis of genomic DNA by Next Generation Sequencing (NGS) revealed the presence of hotspot mutations in genes other than the EGFR, including KRAS, NRAS, BRAF, ERBB2, PIK3CA, or MET, in 29/133 cases (21.8%). A p.T790M mutation was found in 9/133 tumour samples (6.8%). The progression free survival (PFS) of patients without other mutations was 11.3 months vs. 7 months in patients with other mutations (log-rank test univariate: p = 0.047). In a multivariate Cox regression model including the presence of other mutations, age, performance status, smoking status, and the presence of p.T790M mutations, the presence of other mutations was the only factor significantly associated with PFS (Hazard Ratio 1.63, 95% CI 1.04⁻2.58; p = 0.035). In contrast, no correlation was found between TP53 mutations and patients' outcome. These data suggest that a subgroup of EGFR mutant tumours have concomitant driver mutations that might affect the activity of first-line EGFR TKIs.

Original languageEnglish
JournalCancers
Volume11
Issue number3
DOIs
Publication statusPublished - Mar 10 2019

Fingerprint

Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Mutation
Disease-Free Survival
erbB-1 Genes
Proportional Hazards Models
Neoplasms
Smoking

Cite this

The Presence of Concomitant Mutations Affects the Activity of EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) Patients. / Rachiglio, Anna Maria; Fenizia, Francesca; Piccirillo, Maria Carmela; Galetta, Domenico; Crinò, Lucio; Vincenzi, Bruno; Barletta, Emiddio; Pinto, Carmine; Ferraù, Francesco; Lambiase, Matilde; Montanino, Agnese; Roma, Cristin; Ludovini, Vienna; Montagna, Elisabetta Sara; De Luca, Antonella; Rocco, Gaetano; Botti, Gerardo; Perrone, Francesco; Morabito, Alessandro; Normanno, Nicola.

In: Cancers, Vol. 11, No. 3, 10.03.2019.

Research output: Contribution to journalArticle

@article{06fc22428bb8456cb91b464a126a3193,
title = "The Presence of Concomitant Mutations Affects the Activity of EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) Patients",
abstract = "Recent findings suggest that a fraction of EGFR-mutant non-small-cell lung cancers (NSCLC) carry additional driver mutations that could potentially affect the activity of EGFR tyrosine kinase inhibitors (TKIs). We investigated the role of concomitant KRAS, NRAS, BRAF, PIK3CA, MET and ERBB2 mutations (other mutations) on the outcome of 133 EGFR mutant patients, who received first-line therapy with EGFR TKIs between June 2008 and December 2014. Analysis of genomic DNA by Next Generation Sequencing (NGS) revealed the presence of hotspot mutations in genes other than the EGFR, including KRAS, NRAS, BRAF, ERBB2, PIK3CA, or MET, in 29/133 cases (21.8{\%}). A p.T790M mutation was found in 9/133 tumour samples (6.8{\%}). The progression free survival (PFS) of patients without other mutations was 11.3 months vs. 7 months in patients with other mutations (log-rank test univariate: p = 0.047). In a multivariate Cox regression model including the presence of other mutations, age, performance status, smoking status, and the presence of p.T790M mutations, the presence of other mutations was the only factor significantly associated with PFS (Hazard Ratio 1.63, 95{\%} CI 1.04⁻2.58; p = 0.035). In contrast, no correlation was found between TP53 mutations and patients' outcome. These data suggest that a subgroup of EGFR mutant tumours have concomitant driver mutations that might affect the activity of first-line EGFR TKIs.",
author = "Rachiglio, {Anna Maria} and Francesca Fenizia and Piccirillo, {Maria Carmela} and Domenico Galetta and Lucio Crin{\`o} and Bruno Vincenzi and Emiddio Barletta and Carmine Pinto and Francesco Ferra{\`u} and Matilde Lambiase and Agnese Montanino and Cristin Roma and Vienna Ludovini and Montagna, {Elisabetta Sara} and {De Luca}, Antonella and Gaetano Rocco and Gerardo Botti and Francesco Perrone and Alessandro Morabito and Nicola Normanno",
year = "2019",
month = "3",
day = "10",
doi = "10.3390/cancers11030341",
language = "English",
volume = "11",
journal = "Cancers",
issn = "2072-6694",
publisher = "MDPI AG",
number = "3",

}

TY - JOUR

T1 - The Presence of Concomitant Mutations Affects the Activity of EGFR Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) Patients

AU - Rachiglio, Anna Maria

AU - Fenizia, Francesca

AU - Piccirillo, Maria Carmela

AU - Galetta, Domenico

AU - Crinò, Lucio

AU - Vincenzi, Bruno

AU - Barletta, Emiddio

AU - Pinto, Carmine

AU - Ferraù, Francesco

AU - Lambiase, Matilde

AU - Montanino, Agnese

AU - Roma, Cristin

AU - Ludovini, Vienna

AU - Montagna, Elisabetta Sara

AU - De Luca, Antonella

AU - Rocco, Gaetano

AU - Botti, Gerardo

AU - Perrone, Francesco

AU - Morabito, Alessandro

AU - Normanno, Nicola

PY - 2019/3/10

Y1 - 2019/3/10

N2 - Recent findings suggest that a fraction of EGFR-mutant non-small-cell lung cancers (NSCLC) carry additional driver mutations that could potentially affect the activity of EGFR tyrosine kinase inhibitors (TKIs). We investigated the role of concomitant KRAS, NRAS, BRAF, PIK3CA, MET and ERBB2 mutations (other mutations) on the outcome of 133 EGFR mutant patients, who received first-line therapy with EGFR TKIs between June 2008 and December 2014. Analysis of genomic DNA by Next Generation Sequencing (NGS) revealed the presence of hotspot mutations in genes other than the EGFR, including KRAS, NRAS, BRAF, ERBB2, PIK3CA, or MET, in 29/133 cases (21.8%). A p.T790M mutation was found in 9/133 tumour samples (6.8%). The progression free survival (PFS) of patients without other mutations was 11.3 months vs. 7 months in patients with other mutations (log-rank test univariate: p = 0.047). In a multivariate Cox regression model including the presence of other mutations, age, performance status, smoking status, and the presence of p.T790M mutations, the presence of other mutations was the only factor significantly associated with PFS (Hazard Ratio 1.63, 95% CI 1.04⁻2.58; p = 0.035). In contrast, no correlation was found between TP53 mutations and patients' outcome. These data suggest that a subgroup of EGFR mutant tumours have concomitant driver mutations that might affect the activity of first-line EGFR TKIs.

AB - Recent findings suggest that a fraction of EGFR-mutant non-small-cell lung cancers (NSCLC) carry additional driver mutations that could potentially affect the activity of EGFR tyrosine kinase inhibitors (TKIs). We investigated the role of concomitant KRAS, NRAS, BRAF, PIK3CA, MET and ERBB2 mutations (other mutations) on the outcome of 133 EGFR mutant patients, who received first-line therapy with EGFR TKIs between June 2008 and December 2014. Analysis of genomic DNA by Next Generation Sequencing (NGS) revealed the presence of hotspot mutations in genes other than the EGFR, including KRAS, NRAS, BRAF, ERBB2, PIK3CA, or MET, in 29/133 cases (21.8%). A p.T790M mutation was found in 9/133 tumour samples (6.8%). The progression free survival (PFS) of patients without other mutations was 11.3 months vs. 7 months in patients with other mutations (log-rank test univariate: p = 0.047). In a multivariate Cox regression model including the presence of other mutations, age, performance status, smoking status, and the presence of p.T790M mutations, the presence of other mutations was the only factor significantly associated with PFS (Hazard Ratio 1.63, 95% CI 1.04⁻2.58; p = 0.035). In contrast, no correlation was found between TP53 mutations and patients' outcome. These data suggest that a subgroup of EGFR mutant tumours have concomitant driver mutations that might affect the activity of first-line EGFR TKIs.

U2 - 10.3390/cancers11030341

DO - 10.3390/cancers11030341

M3 - Article

C2 - 30857358

VL - 11

JO - Cancers

JF - Cancers

SN - 2072-6694

IS - 3

ER -