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

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.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Overall survival (A, B, C) and disease-free survival (D, E, F) for patients with KRAS wild-type tumors compared with patients with KRAS mutated tumors. (A) All patients; (B) patients in observation arm; (C) all patients with adenocarcinoma; (D) all patients; (E) patients in observation arm; (F) all patients with adenocarcinoma. HR, hazard ratio.

Fig 2.

Overall survival benefit from adjuvant chemotherapy (ACT) compared with observation (OBS) in (A) patients with KRAS wild-type tumors and (C) patients with KRAS-mutated tumors, for patients with (B) adenocarcinoma and KRAS wild-type tumors and (D) adenocarcinoma with KRAS-mutated tumors, and for patients with (E) KRAS codon 12 mutations and (F) codon 13 mutations. (A) KRAS wild type; (B) adenocarcinoma KRAS wild type; (C) KRAS mutated; (D) adenocarcinoma KRAS mutated; (E) KRAS codon 12 mutated; (F) KRAS codon 13 mutated. HR, hazard ratio.

Fig 3.

The risk of developing a second primary malignancy in observation patients with KRAS-mutated tumors. HR, hazard ratio.