Impact of TP53 mutations on outcome in EGFR-mutated patients treated with first-line tyrosine kinase inhibitors

Matteo Canale, Elisabetta Petracci, Angelo Delmonte, Elisa Chiadini, Claudio Dazzi, Maximilian Papi, Laura Capelli, Claudia Casanova, Nicoletta De Luigi, Marita Mariotti, Alessandro Gamboni, Rita Chiari, Chiara Bennati, Daniele Calistri, Vienna Ludovini, Lucio Crinò, Dino Amadori, Paola Ulivi

Research output: Contribution to journalArticle

Abstract

Purpose: To analyze the impact of TP53 mutations on response to first-line tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Experimental Design: 136 EGFR-mutated NSCLC patients receiving first-line TKIs were analyzed. TP53 mutations were evaluated in 123 patients in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: TP53 mutations were observed in 37 (30.1%), 10 (27.0%), 6 (16.2%), 9 (24.3%), and 12 (32.4%) patients in exons 5, 6, 7, and 8, respectively. DCR was 70% in TP53- mutated patients compared with 88% in TP53-wild type (wt) patients [relative risk, RR, of disease progression: 3.17 (95% CI, 1.21-8.48), P = 0.019]. In particular, a 42% DCR was observed in patients with TP53 exon 8 mutation versus 87% in exon 8 wt patients [RR of disease progression 9.6 (2.71-36.63), P < 0.001]. Shorter median PFS and OS were observed in patients with TP53 exon 8 mutations compared with others (4.2 vs. 12.5, P = 0.058, and 16.2 vs. 32.3, P = 0.114, respectively); these differences became significant in the subgroup with EGFR exon 19 deletion (4.2 vs. 16.8, P < 0.001, and 7.6 vs. not reached, P = 0.006, respectively), HR 6.99 (95% CI, 2.34-20.87, P < 0.001) and HR 4.75 (95% CI, 1.38-16.29, P = 0.013), respectively. Conclusions: TP53 mutations, especially exon 8 mutations, reduce responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, mainly those carrying exon 19 deletions.

Original languageEnglish
Pages (from-to)2195-2202
Number of pages8
JournalClinical Cancer Research
Volume23
Issue number9
DOIs
Publication statusPublished - May 1 2017

Fingerprint

Protein-Tyrosine Kinases
Mutation
Exons
Non-Small Cell Lung Carcinoma
Disease-Free Survival
Disease Progression
Survival
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Impact of TP53 mutations on outcome in EGFR-mutated patients treated with first-line tyrosine kinase inhibitors. / Canale, Matteo; Petracci, Elisabetta; Delmonte, Angelo; Chiadini, Elisa; Dazzi, Claudio; Papi, Maximilian; Capelli, Laura; Casanova, Claudia; De Luigi, Nicoletta; Mariotti, Marita; Gamboni, Alessandro; Chiari, Rita; Bennati, Chiara; Calistri, Daniele; Ludovini, Vienna; Crinò, Lucio; Amadori, Dino; Ulivi, Paola.

In: Clinical Cancer Research, Vol. 23, No. 9, 01.05.2017, p. 2195-2202.

Research output: Contribution to journalArticle

Canale, M, Petracci, E, Delmonte, A, Chiadini, E, Dazzi, C, Papi, M, Capelli, L, Casanova, C, De Luigi, N, Mariotti, M, Gamboni, A, Chiari, R, Bennati, C, Calistri, D, Ludovini, V, Crinò, L, Amadori, D & Ulivi, P 2017, 'Impact of TP53 mutations on outcome in EGFR-mutated patients treated with first-line tyrosine kinase inhibitors', Clinical Cancer Research, vol. 23, no. 9, pp. 2195-2202. https://doi.org/10.1158/1078-0432.CCR-16-0966
Canale, Matteo ; Petracci, Elisabetta ; Delmonte, Angelo ; Chiadini, Elisa ; Dazzi, Claudio ; Papi, Maximilian ; Capelli, Laura ; Casanova, Claudia ; De Luigi, Nicoletta ; Mariotti, Marita ; Gamboni, Alessandro ; Chiari, Rita ; Bennati, Chiara ; Calistri, Daniele ; Ludovini, Vienna ; Crinò, Lucio ; Amadori, Dino ; Ulivi, Paola. / Impact of TP53 mutations on outcome in EGFR-mutated patients treated with first-line tyrosine kinase inhibitors. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 9. pp. 2195-2202.
@article{18de8b51eca5467eb20072cfd6779a4e,
title = "Impact of TP53 mutations on outcome in EGFR-mutated patients treated with first-line tyrosine kinase inhibitors",
abstract = "Purpose: To analyze the impact of TP53 mutations on response to first-line tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Experimental Design: 136 EGFR-mutated NSCLC patients receiving first-line TKIs were analyzed. TP53 mutations were evaluated in 123 patients in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: TP53 mutations were observed in 37 (30.1{\%}), 10 (27.0{\%}), 6 (16.2{\%}), 9 (24.3{\%}), and 12 (32.4{\%}) patients in exons 5, 6, 7, and 8, respectively. DCR was 70{\%} in TP53- mutated patients compared with 88{\%} in TP53-wild type (wt) patients [relative risk, RR, of disease progression: 3.17 (95{\%} CI, 1.21-8.48), P = 0.019]. In particular, a 42{\%} DCR was observed in patients with TP53 exon 8 mutation versus 87{\%} in exon 8 wt patients [RR of disease progression 9.6 (2.71-36.63), P < 0.001]. Shorter median PFS and OS were observed in patients with TP53 exon 8 mutations compared with others (4.2 vs. 12.5, P = 0.058, and 16.2 vs. 32.3, P = 0.114, respectively); these differences became significant in the subgroup with EGFR exon 19 deletion (4.2 vs. 16.8, P < 0.001, and 7.6 vs. not reached, P = 0.006, respectively), HR 6.99 (95{\%} CI, 2.34-20.87, P < 0.001) and HR 4.75 (95{\%} CI, 1.38-16.29, P = 0.013), respectively. Conclusions: TP53 mutations, especially exon 8 mutations, reduce responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, mainly those carrying exon 19 deletions.",
author = "Matteo Canale and Elisabetta Petracci and Angelo Delmonte and Elisa Chiadini and Claudio Dazzi and Maximilian Papi and Laura Capelli and Claudia Casanova and {De Luigi}, Nicoletta and Marita Mariotti and Alessandro Gamboni and Rita Chiari and Chiara Bennati and Daniele Calistri and Vienna Ludovini and Lucio Crin{\`o} and Dino Amadori and Paola Ulivi",
year = "2017",
month = "5",
day = "1",
doi = "10.1158/1078-0432.CCR-16-0966",
language = "English",
volume = "23",
pages = "2195--2202",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - Impact of TP53 mutations on outcome in EGFR-mutated patients treated with first-line tyrosine kinase inhibitors

AU - Canale, Matteo

AU - Petracci, Elisabetta

AU - Delmonte, Angelo

AU - Chiadini, Elisa

AU - Dazzi, Claudio

AU - Papi, Maximilian

AU - Capelli, Laura

AU - Casanova, Claudia

AU - De Luigi, Nicoletta

AU - Mariotti, Marita

AU - Gamboni, Alessandro

AU - Chiari, Rita

AU - Bennati, Chiara

AU - Calistri, Daniele

AU - Ludovini, Vienna

AU - Crinò, Lucio

AU - Amadori, Dino

AU - Ulivi, Paola

PY - 2017/5/1

Y1 - 2017/5/1

N2 - Purpose: To analyze the impact of TP53 mutations on response to first-line tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Experimental Design: 136 EGFR-mutated NSCLC patients receiving first-line TKIs were analyzed. TP53 mutations were evaluated in 123 patients in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: TP53 mutations were observed in 37 (30.1%), 10 (27.0%), 6 (16.2%), 9 (24.3%), and 12 (32.4%) patients in exons 5, 6, 7, and 8, respectively. DCR was 70% in TP53- mutated patients compared with 88% in TP53-wild type (wt) patients [relative risk, RR, of disease progression: 3.17 (95% CI, 1.21-8.48), P = 0.019]. In particular, a 42% DCR was observed in patients with TP53 exon 8 mutation versus 87% in exon 8 wt patients [RR of disease progression 9.6 (2.71-36.63), P < 0.001]. Shorter median PFS and OS were observed in patients with TP53 exon 8 mutations compared with others (4.2 vs. 12.5, P = 0.058, and 16.2 vs. 32.3, P = 0.114, respectively); these differences became significant in the subgroup with EGFR exon 19 deletion (4.2 vs. 16.8, P < 0.001, and 7.6 vs. not reached, P = 0.006, respectively), HR 6.99 (95% CI, 2.34-20.87, P < 0.001) and HR 4.75 (95% CI, 1.38-16.29, P = 0.013), respectively. Conclusions: TP53 mutations, especially exon 8 mutations, reduce responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, mainly those carrying exon 19 deletions.

AB - Purpose: To analyze the impact of TP53 mutations on response to first-line tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Experimental Design: 136 EGFR-mutated NSCLC patients receiving first-line TKIs were analyzed. TP53 mutations were evaluated in 123 patients in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: TP53 mutations were observed in 37 (30.1%), 10 (27.0%), 6 (16.2%), 9 (24.3%), and 12 (32.4%) patients in exons 5, 6, 7, and 8, respectively. DCR was 70% in TP53- mutated patients compared with 88% in TP53-wild type (wt) patients [relative risk, RR, of disease progression: 3.17 (95% CI, 1.21-8.48), P = 0.019]. In particular, a 42% DCR was observed in patients with TP53 exon 8 mutation versus 87% in exon 8 wt patients [RR of disease progression 9.6 (2.71-36.63), P < 0.001]. Shorter median PFS and OS were observed in patients with TP53 exon 8 mutations compared with others (4.2 vs. 12.5, P = 0.058, and 16.2 vs. 32.3, P = 0.114, respectively); these differences became significant in the subgroup with EGFR exon 19 deletion (4.2 vs. 16.8, P < 0.001, and 7.6 vs. not reached, P = 0.006, respectively), HR 6.99 (95% CI, 2.34-20.87, P < 0.001) and HR 4.75 (95% CI, 1.38-16.29, P = 0.013), respectively. Conclusions: TP53 mutations, especially exon 8 mutations, reduce responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, mainly those carrying exon 19 deletions.

UR - http://www.scopus.com/inward/record.url?scp=85018411913&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85018411913&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-16-0966

DO - 10.1158/1078-0432.CCR-16-0966

M3 - Article

AN - SCOPUS:85018411913

VL - 23

SP - 2195

EP - 2202

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 9

ER -