J Clin Oncol 2017 Jun 28;35(18):2018-2027. Epub 2017 Apr 28.
Frances A. Shepherd and Ming-Sound Tsao, Princess Margaret Cancer Centre; University of Toronto, Toronto; Lesley Seymour, Queen's University, Kingston, Ontario, Canada; Benjamin Lacas, Gwénaël Le Teuff, Jean-Pierre Pignon, Thierry Le Chevalier, and Jean-Charles Soria, Institut Gustave-Roussy; Benjamin Lacas, Gwénaël Le Teuff, Jean-Pierre Pignon, Thierry Le Chevalier, and Jean-Charles Soria, University Paris XI, Paris; Pierre Hainaut, International Agency for Research on Cancer, Lyon; Jean-Yves Douillard, R Gauducheau, St Herblain; Elizabeth Brambilla, Inserm U823, Institut Albert Bonniot, Département de Pathologie CHU, Albert Michallon University Joseph Fourrier, Grenoble, France; Pasi A. Jänne, Dana-Farber Cancer Institute, Boston, MA; Stephen Graziano, State University of New York Upstate Medical University, Syracuse, NY; Robert Kratzke, University of Minnesota Medical School, Minneapolis, MN; and Robert Pirker and Martin Filipits, Medical University of Vienna, Vienna, Austria.
Purpose Our previous work evaluated individual prognostic and predictive roles of TP53, KRAS, and EGFR in non-small-cell lung cancer (NSCLC). In this analysis, we explore the prognostic and predictive roles of TP53/KRAS and TP53/EGFR comutations in randomized trials of adjuvant chemotherapy versus observation. Patients and Methods Mutation analyses (wild-type [WT] and mutant) for TP53, KRAS, and EGFR were determined in blinded fashion in multiple laboratories. Primary and secondary end points of pooled analysis were overall survival and disease-free survival. We evaluated the role of TP53/KRAS comutation in all patients and in the adenocarcinoma subgroup as well as the TP53/EGFR comutation in adenocarcinoma only through a multivariable Cox proportional hazards model stratified by trial. Results Of 3,533 patients with NSCLC, 1,181 (557 deaths) and 404 (170 deaths) were used for TP53/KRAS and TP53/EGFR analyses. For TP53/KRAS mutation status, no prognostic effect was observed ( P = .61), whereas a borderline predictive effect ( P = .04) was observed with a deleterious effect of chemotherapy with TP53/KRAS comutations versus WT/WT (hazard ratio, 2.49 [95% CI, 1.10 to 5.64]; P = .03). TP53/EGFR comutation in adenocarcinoma was neither prognostic ( P = .83), nor significantly predictive ( P = .86). Similar results were observed for both groups for disease-free survival. Conclusion We could identify no prognostic effect of the KRAS or EGFR driver and TP53 tumor suppressor comutation. Our observation of a potential negative predictive effect of TP53/KRAS comutation requires validation.