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.

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.