Xiaoli Ma1, Gwénaël Le Teuff2, Benjamin Lacas2, Ming Sound Tsao3, Stephen Graziano4, Jean-Pierre Pignon2, Jean-Yves Douillard5, Thierry Le Chevalier5, Lesley Seymour6, Martin Filipits7, Robert Pirker8, Pasi A Jänne9, Frances A Shepherd10, Elisabeth Brambilla11, Jean-Charles Soria12, Pierre Hainaut13. 1. International Agency for Research on Cancer, Lyon, France; Central Laboratory, Jinan Central Hospital, Jinan, China. 2. Department of Biostatistics, Gustave-Roussy, Paris, France; Inserm U1018, CESP, Paris-Sud and Paris-Saclay University, Villejuif, France; Ligue contre le Cancer, Paris, France. 3. Department of Pathology, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada. 4. Department of Medicine, State University of New York Upstate Medical University, Syracuse, New York. 5. Department of Medical Oncology Institut de Cancérologie de l'Ouest, R Gauducheau, St. Herblain, France. 6. National Cancer Institute of Canada Clinical Trials Group, Queen's University, Kingston, Ontario, Canada. 7. Institute of Cancer Research, Medical University of Vienna, Vienna, Austria. 8. Department of Medicine I, Medical University of Vienna, Vienna, Austria. 9. Lowe Center for Thoracic Oncology and the Belfer Institute for Applied Cancer Science, Dana Farber Cancer Institute, Boston, Massachusetts. 10. Department of Medical Oncology and Hematology, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, Canada. 11. Institut Albert Bonniot, Inserm U1209 CNRS 5309 Université Grenoble Alpes, Grenoble, France; Department of Pathology, Centre Hospitalier Universitaire, Grenoble, France. 12. Department of Medicine, Gustave-Roussy, Paris, France. 13. 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.
Abstract
INTRODUCTION: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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.
RCT Entities:
INTRODUCTION: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: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: M-S Tsao; G Le Teuff; F A Shepherd; C Landais; P Hainaut; M Filipits; R Pirker; T Le Chevalier; S Graziano; R Kratze; J-C Soria; J-P Pignon; L Seymour; E Brambilla Journal: Ann Oncol Date: 2017-04-01 Impact factor: 32.976
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Authors: Kajsa Ericson Lindquist; Anna Karlsson; Per Levéen; Hans Brunnström; Christel Reuterswärd; Karolina Holm; Mats Jönsson; Karin Annersten; Frida Rosengren; Karin Jirström; Jaroslaw Kosieradzki; Lars Ek; Åke Borg; Maria Planck; Göran Jönsson; Johan Staaf Journal: Oncotarget Date: 2017-05-23
Authors: Siddhartha Devarakonda; Federico Rotolo; Ming-Sound Tsao; Irena Lanc; Elisabeth Brambilla; Ashiq Masood; Ken A Olaussen; Robert Fulton; Shingo Sakashita; Anne McLeer-Florin; Keyue Ding; Gwénaël Le Teuff; Frances A Shepherd; Jean-Pierre Pignon; Stephen L Graziano; Robert Kratzke; Jean-Charles Soria; Lesley Seymour; Ramaswamy Govindan; Stefan Michiels Journal: J Clin Oncol Date: 2018-08-14 Impact factor: 50.717