Nondisruptive p53 mutations are associated with shorter survival in patients with advanced non-small cell lung cancer.
OBJECTIVE
TP53 mutations in early-stage non-small cell lung cancer (NSCLC) may be associated with worse survival but their prognostic role in advanced NSCLC is controversial. In addition, it remains unclear whether mutated patients represent a clinically homogeneous group.


METHODS
We retrospectively examined TP53 mutations and outcome in a training cohort of 318 patients with stage IIIB-IV NSCLC: 125 epidermal growth factor receptor (EGFR) wild-type (wt) and 193 EGFR mutated (mut). An independent validation cohort of 64 EGFR-mut patients was subsequently analyzed. Mutations were classified as "disruptive" and "nondisruptive" according to their predicted degree of disturbance of the p53 protein structure and function.


RESULTS
In the training cohort, TP53 mutations were found in 43 of the 125 EGFR-wt patients (34.4%). Of these, 28 had nondisruptive TP53 mutations and a median overall survival (OS) of 8.5 months, compared with 15.6 months for the remaining 97 patients (P=0.003). In the EGFR-mut group, TP53 mutations were found in 50 of the 193 patients (25.9%). The OS for the 26 patients with TP53 nondisruptive mutations was 17.8 months versus 28.4 months for the remaining 167 patients (P=0.04). In the validation cohort, the 11 patients with nondisruptive TP53 mutations had a median OS of 18.1 months compared with 37.8 months for the 53 remaining patients (P=0.006). In multivariate analyses, nondisruptive TP53 mutations had an independent, significant association with a shorter OS.


CONCLUSIONS
Nondisruptive mutations in the TP53 gene are an independent prognostic factor of shorter survival in advanced NSCLC.
Breakthrough Cancer Research Unit, Pangaea Biotech S.L; rrosell@iconcologia.net mamolina@pangaeabiotech.com.
Miguel A
MA
Molina-Vila
Breakthrough Cancer Research Unit, Pangaea Biotech S.L;
Jordi
J
Bertran-Alamillo
Instituto Oncológico Dr Rosell (IOR), Quirón Dexeus University Hospital;
Amaya
A
Gascó
Breakthrough Cancer Research Unit, Pangaea Biotech S.L;
Clara
C
Mayo-de-las-Casas
Departamento de Cirugía, Ciencias Médicas y Sociales, Universidad de Alcalá, Alcalá de Henares;
María
M
Sánchez-Ronco
Instituto Oncológico Dr Rosell (IOR), Quirón Dexeus University Hospital;
Laia
L
Pujantell-Pastor
Second Medical Oncology Unit, Istituto Oncologico Veneto I.R.C.C.S, Padova, Italy;
Laura
L
Bonanno
Second Medical Oncology Unit, Istituto Oncologico Veneto I.R.C.C.S, Padova, Italy;
Adolfo G
AG
Favaretto
Clinical and Traslational Oncology Group, Institute of Oncology, Fundación Santa Fe de Bogotá; Foundation for Clinical and Applied Cancer Research (FICMAC), Bogotá, Colombia; and.
Andrés F
AF
Cardona
Hôpital du Cluzeau, Limoges, France.
Alain
A
Vergnenègre
Hospital de la Santa Creu i Sant Pau;
Margarita
M
Majem
Hospital General de Alicante, Alicante, Spain;
Bartomeu
B
Massuti
Hospital Germans Trias i Pujol, Badalona;
Teresa
T
Morán
Hospital Germans Trias i Pujol, Badalona;
Enric
E
Carcereny
Instituto Oncológico Dr Rosell (IOR), Quirón Dexeus University Hospital;
Santiago
S
Viteri
Hospital Germans Trias i Pujol, Badalona; Molecular Oncology Research Foundation (MORe), Barcelona; rrosell@iconcologia.net mamolina@pangaeabiotech.com.
Rafael
R
Rosell
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C512478:EGFR protein, human; D066246:ErbB Receptors