title: Impact ofTP53Mutations on Outcome inEGFR-Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors.
abstract: Purpose:To analyze the impact ofTP53mutations on response to first-line tyrosine kinase inhibitors (TKI) in patients withEGFR-mutated non-small cell lung cancer (NSCLC).Experimental Design:136EGFR-mutated NSCLC patients receiving first-line TKIs were analyzed.TP53mutations 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:TP53mutations 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% inTP53-mutated patients compared with 88% inTP53-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 withTP53exon 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 withTP53exon 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 withEGFRexon 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:TP53mutations, especially exon 8 mutations, reduce responsiveness to TKIs and worsen prognosis inEGFR-mutated NSCLC patients, mainly those carrying exon 19 deletions.Clin Cancer Res; 23(9); 2195-202. ©2016 AACR.
authors: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Matteo
authors: M
authors: Canale
authors: Unit of Biostatistics and Clinical Trials, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Elisabetta
authors: E
authors: Petracci
authors: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Angelo
authors: A
authors: Delmonte
authors: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Elisa
authors: E
authors: Chiadini
authors: Medical Oncology Unit, S.Maria delle Croci Hospital, Ravenna, Italy.
authors: Claudio
authors: C
authors: Dazzi
authors: Infermi Hospital, Rimini, Italy.
authors: Maximilian
authors: M
authors: Papi
authors: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Laura
authors: L
authors: Capelli
authors: Medical Oncology Unit, S.Maria delle Croci Hospital, Ravenna, Italy.
authors: Claudia
authors: C
authors: Casanova
authors: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Nicoletta
authors: N
authors: De Luigi
authors: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Marita
authors: M
authors: Mariotti
authors: Medical Oncology Unit, Degli Infermi Hospital, Faenza, Italy.
authors: Alessandro
authors: A
authors: Gamboni
authors: Division of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia, Italy.
authors: Rita
authors: R
authors: Chiari
authors: Division of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia, Italy.
authors: Chiara
authors: C
authors: Bennati
authors: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Daniele
authors: D
authors: Calistri
authors: Division of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia, Italy.
authors: Vienna
authors: V
authors: Ludovini
authors: Division of Medical Oncology, Santa Maria della Misericordia Hospital, Perugia, Italy.
authors: Lucio
authors: L
authors: Crinò
authors: Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors: Dino
authors: D
authors: Amadori
authors: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy. paola.ulivi@irst.emr.it.
authors: Paola
authors: P
authors: Ulivi
mesh_terms: D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D017384:Sequence Deletion / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D047428:Protein Kinase Inhibitors; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C512478:EGFR protein, human; D066246:ErbB Receptors