Pooled analysis of the prognostic and predictive effects of KRAS mutation status and KRAS mutation subtype in early-stage resected non–small-cell lung cancer in four trials of adjuvant chemotherapy

Frances A. Shepherd, Caroline Domerg, Pierre Hainaut, Pasi A. Jänne, Jean Pierre Pignon, Stephen Graziano, Jean Yves Douillard, Elizabeth Brambilla, Thierry Le Chevalier, Lesley Seymour, Abderrahmane Bourredjem, Gwénaël Le Teuff, Robert Pirker, Martin Filipits, Rafael Rosell, Robert Kratzke, Bizhan Bandarchi, Xiaoli Ma, Marzia Capelletti, Jean Charles SoriaMing Sound Tsao

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172 Scopus citations

Abstract

Purpose: We undertook this analysis of KRAS mutation in four trials of adjuvant chemotherapy (ACT) versus observation (OBS) to clarify the prognostic/predictive roles of KRAS in non–small-cell lung cancer (NSCLC). Methods: KRAS mutation was determined in blinded fashion. Exploratory analyses were performed to characterize relationships between mutation status and subtype and survival outcomes using a multivariable Cox model. Results: Among 1,543 patients (763 OBS, 780 ACT), 300 had KRAS mutations (codon 12, n = 275; codon 13, n = 24; codon 14, n = 1). In OBS patients, there was no prognostic difference for overall survival for codon-12 (mutation v wild type [WT] hazard ratio [HR] = 1.04; 95% CI, 0.77 to 1.40) or codon-13 (HR = 1.01; 95% CI, 0.47 to 2.17) mutations. No significant benefit from ACT was observed for WT-KRAS (ACT v OBS HR = 0.89; 95% CI, 0.76 to 1.04; P = .15) or codon-12 mutations (HR = 0.95; 95% CI, 0.67 to 1.35; P = .77); with codon-13 mutations, ACT was deleterious (HR = 5.78; 95% CI, 2.06 to 16.2; P < .001; interaction P = .002). There was no prognostic effect for specific codon-12 amino acid substitution. The effect of ACT was variable among patients with codon-12 mutations: G12A or G12R (HR = 0.66; P = .48), G12C or G12V (HR = 0.94; P = .77) and G12D or G12S (HR = 1.39; P = .48; comparison of four HRs, including WT, interaction P = .76). OBS patients with KRAS-mutated tumors were more likely to develop second primary cancers (HR = 2.76, 95% CI, 1.34 to 5.70; P = .005) but not ACT patients (HR = 0.66; 95% CI, 0.25 to 1.75; P = .40; interaction, P = .02). Conclusion: KRAS mutation status is not significantly prognostic. The potential interaction in patients with codon-13 mutations requires validation. At this time, KRAS status cannot be recommended to select patients with NSCLC for ACT.

Original languageEnglish (US)
Pages (from-to)2173-2181
Number of pages9
JournalJournal of Clinical Oncology
Volume31
Issue number17
DOIs
StatePublished - Jun 10 2013

Bibliographical note

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

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