Significance of TP53 mutations as predictive markers of adjuvant cisplatin-based chemotherapy in completely resected non-small-cell lung cancer.
Adjuvant cisplatin-based chemotherapy only marginally improves survival in patients with completely resected non-small-cell lung cancer (NSCLC). We have evaluated the predictive value of mutations in TP53, encoding the tumour suppressor p53, in the International Adjuvant Lung Cancer Trial (IALT), a randomized trial of adjuvant cisplatin-based chemotherapy against observation. TP53 (exons 4-8) was sequenced in 524 archived specimens of IALT patients with a median follow-up of 7.5 years. Predictive analyses were based on Cox models adjusted for clinical and pathological variables. P-values ≤ 0.01 were considered as significant. Mutations were detected in 221 patients (42%) and had no predictive value for the effect of chemotherapy (interaction between TP53 and treatment: p = 0.17 for Overall Survival (OS); p = 0.06 for Disease-Free Interval, (DFS)). However, among patients with mutations, outcome appeared worse in treatment compared to observation arms (HR for OS = 1.36 (95% CI [0.97-1.31), p = 0.08; DFS = 1.40 (95% CI [1.01-1.95]), p = 0.04). When grouping mutations into classes according to predicted effects on protein structure, the tendency towards worse outcomes was restricted to "structure" mutations affecting residues of the hydrophobic core that are not located at the p53 protein-DNA interface (HR for death in this class vs wild-type T53 = 1.66; 95% CI [1.10-2.52], p = 0.02). Overall, TP53 mutations are not significant predictors of outcome in this trial of cisplatin-based chemotherapy, although a specific class of structural mutations may be associated with a tendency towards worse outcomes upon treatment.
International Agency for Research on Cancer, Lyon, France.
Xiaoli
X
Ma
Biostatistics and Epidemiology Unit, Institut Gustave Roussy, Villejuif, France.
Vanessa
V
Rousseau
International Agency for Research on Cancer, Lyon, France.
Haiji
H
Sun
Department of Anatomy and Cytology, Centre Hospitalo-Universitaire, Albert Michallon, Grenoble, France.
Sylvie
S
Lantuejoul
Department of Medicine I, Medical University Vienna, Vienna, Austria.
Martin
M
Filipits
Department of Medicine I, Medical University Vienna, Vienna, Austria.
Robert
R
Pirker
Institute of Pathology, Medical University of Graz, Austria.
Helmut
H
Popper
Biostatistics and Epidemiology Unit, Institut Gustave Roussy, Villejuif, France.
Jean
J
Mendiboure
Biostatistics and Epidemiology Unit, Institut Gustave Roussy, Villejuif, France.
Anne-Lise
AL
Vataire
Department of Medicine/Service des Innovations Thérapeutiques Précoces, Institut Gustave Roussy, Villejuif, France.
Thierry
T
Le Chevalier
Department of Medicine/Service des Innovations Thérapeutiques Précoces, Institut Gustave Roussy, Villejuif, France; Institut National de la Santé et de la Recherche Médicale U981, Villejuif, France; Clinical and Translational Research Division, Institut Gustave Roussy, Villejuif, France.
Jean Charles
JC
Soria
Department of Anatomy and Cytology, Centre Hospitalo-Universitaire, Albert Michallon, Grenoble, France.
Elisabeth
E
Brambilla
Biostatistics and Epidemiology Unit, Institut Gustave Roussy, Villejuif, France.
Ariane
A
Dunant
University of Strathclyde School of Global Public Health at iPRI, International Prevention Research Institute, Lyon, France; Institut Albert Bonniot, Institut National de la Santé et de la Recherche Médicale U 823, Grenoble, France. Electronic address: pierre.hainaut@i-pri.org.
Pierre
P
Hainaut
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000175:diagnosis / Q000235:genetics*; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000627:therapeutic use*; D018572:Disease-Free Survival; D006801:Humans; D008175:Lung Neoplasms / Q000175:diagnosis / Q000235:genetics*; D008875:Middle Aged; D008958:Models, Molecular; D009154:Mutation; D011379:Prognosis; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D000970:Antineoplastic Agents; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin
Chemotherapy; Cisplatin; Mutations; NSCLC; Randomized trial; TP53