Pooled analysis of the prognostic and predictive effects of TP53 comutation status combined with KRAS or EGFR mutation in early-stage resected non-small-cell lung cancer in four trials of adjuvant chemotherapy

Frances A. Shepherd, Benjamin Lacas, Gwénäel Le Teuff, Pierre Hainaut, Pasi A. Jänne, Jean Pierre Pignon, Thierry Le Chevalier, Lesley Seymour, Jean Yves Douillard, Stephen Graziano, Elizabeth Brambilla, Robert Pirker, Martin Filipits, Robert Kratzke, Jean Charles Soria, Ming Sound Tsao

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44 Scopus citations

Abstract

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 adeno-carcinoma 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.

Original languageEnglish (US)
Pages (from-to)2018-2027
Number of pages10
JournalJournal of Clinical Oncology
Volume35
Issue number18
DOIs
StatePublished - Jun 20 2017

Bibliographical note

Funding Information:
Supported by the Canadian Cancer Society Research Institute (Canada), la Ligue Nationale Contre le Cancer (France), le Programme National d'Excellence Sp?cialis? Cancer du poumon de l'Institut National du Cancer (France), the National Cancer Institute (United States), and an unrestricted grant from Sanofi.

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