title: Prognostic and Predictive Effect of TP53 Mutations in Patients with Non-Small Cell Lung Cancer from Adjuvant Cisplatin-Based Therapy Randomized Trials: A LACE-Bio Pooled Analysis.
abstract: Tumor protein p53 gene (TP53) mutations are common in stage I through III non-small cell lung cancer, but clinical trials have shown inconsistent results regarding their relationship to the effects of adjuvant therapy. The objective is to clarify their putative prognostic and predictive effects.
  
  
  
  A pooled analysis of TP53 mutations (exons 5-8) was conducted in four randomized trials (the International Adjuvant Lung Cancer Trial, J BRonchus 10, Cancer and Leukemia Group B-9633, and Adjuvant Navelbine International Trialist Association trial) of platinum-based adjuvant chemotherapy (ACT) versus observation (OBS). Hazard ratios (HRs) and 95% confidence intervals (CIs) of mutant versus wild-type (WT) TP53 for overall survival (OS) and disease-free survival (DFS) were estimated using a multivariable Cox model stratified on trial and adjusted on sex, age, and clinicopathological variables. Predictive value was evaluated with an interaction between treatment and TP53.
  
  
  
  A total of 1209 patients (median follow-up 5.5 years) were included. There were 573 deaths (47%) and 653 DFS events (54%). Mutations (434 [36%]) had no prognostic effect (OBS HROS = 0.99, 95% CI: 0.77-1.28, p = 0.95; HRDFS = 0.99, 95% CI: 0.78-1.25, p = 0.92) but were marginally predictive of benefit from ACT for OS (test for interaction: OS, p = 0.06; DFS, p = 0.11). Patients with WT TP53 had a tendency toward better outcomes with ACT than did those in the OBS group (HROS = 0.77, 95% CI: 0.62-0.95, p = 0.02; HRDFS = 0.75, 95% CI: 0.62-0.92, p = 0.005). In the ACT arm, a deleterious effect of mutant versus WT TP53 was observed (HROS = 1.40, 95% CI: 1.10-1.78, p = 0.006; HRDFS = 1.31, 95% CI: 1.04-1.64, p = 0.02).
  
  
  
  TP53 mutation had no prognostic effect but was marginally predictive for survival from ACT. In patients who received ACT, TP53 mutation tended to be associated with shorter survival than wild-type TP53.
authors.affiliation: International Agency for Research on Cancer, Lyon, France; Central Laboratory, Jinan Central Hospital, Jinan, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Biostatistics, Gustave-Roussy, Paris, France; Inserm U1018, CESP, Paris-Sud and Paris-Saclay University, Villejuif, France; Ligue contre le Cancer, Paris, France.
authors.forename: Gwénaël
authors.initials: G
authors.lastname: Le Teuff
authors.affiliation: Department of Biostatistics, Gustave-Roussy, Paris, France; Inserm U1018, CESP, Paris-Sud and Paris-Saclay University, Villejuif, France; Ligue contre le Cancer, Paris, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lacas
authors.affiliation: Department of Pathology, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ming Sound
authors.initials: MS
authors.lastname: Tsao
authors.affiliation: Department of Medicine, State University of New York Upstate Medical University, Syracuse, New York.
authors.forename: Stephen
authors.initials: S
authors.lastname: Graziano
authors.affiliation: Department of Biostatistics, Gustave-Roussy, Paris, France; Inserm U1018, CESP, Paris-Sud and Paris-Saclay University, Villejuif, France; Ligue contre le Cancer, Paris, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Pignon
authors.affiliation: Department of Medical Oncology Institut de Cancérologie de l'Ouest, R Gauducheau, St. Herblain, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Douillard
authors.affiliation: Department of Medical Oncology Institut de Cancérologie de l'Ouest, R Gauducheau, St. Herblain, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Le Chevalier
authors.affiliation: National Cancer Institute of Canada Clinical Trials Group, Queen's University, Kingston, Ontario, Canada.
authors.forename: Lesley
authors.initials: L
authors.lastname: Seymour
authors.affiliation: Institute of Cancer Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Martin
authors.initials: M
authors.lastname: Filipits
authors.affiliation: Department of Medicine I, Medical University of Vienna, Vienna, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Pirker
authors.affiliation: Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.affiliation: Department of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.affiliation: Institut Albert Bonniot, Inserm U1209 CNRS 5309 Université Grenoble Alpes, Grenoble, France; Department of Pathology, Centre Hospitalier Universitaire, Grenoble, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brambilla
authors.affiliation: Department of Medicine, Gustave-Roussy, Paris, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.affiliation: International Agency for Research on Cancer, Lyon, France; Department of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada; Department of Pathology, Centre Hospitalier Universitaire, Grenoble, France; International Prevention Research Institute, Lyon, France. Electronic address: pierre.hainaut@univ-grenoble-alpes.fr.
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000077235:Vinorelbine
chemical_list: D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D014747:Vinblastine; D016190:Carboplatin; D002945:Cisplatin; D000077235:Vinorelbine
keywords: Lung cancer; Predictive; Prognostic; TP53 mutations