KRAS Mutation Is a Significant Prognostic Factor in Early-stage Lung Adenocarcinoma

Abstract

The potential clinical impact of KRAS and epidermal growth factor receptor (EGFR) mutations has been investigated in lung adenocarcinomas; however, their prognostic value remains controversial. In our study, we sought to investigate the prognostic significance of driver mutations using a large cohort of early-stage lung adenocarcinomas. We reviewed patients with pathologic early-stage, lymph node-negative, solitary lung adenocarcinoma who had undergone surgical resection (1995 to 2005; stage I/II=463/19). Tumors were classified according to the IASLC/ATS/ERS classification and genotyped by Sequenom MassARRAY system and polymerase chain reaction-based assays. In stage I disease, the Kaplan-Meier method and cumulative incidence of recurrence analyses were used to estimate the probability of overall survival (OS) and recurrence, respectively. Of all, 129 (27%) patients had mutations in KRAS, 86 (18%) in EGFR, 8 (2%) in BRAF, 8 (2%) in PIK3CA, 4 (1%) in NRAS, and 1 (0.2%) in AKT1. EGFR L858R mutation correlated with lepidic predominant histology (P=0.006), whereas exon 19 deletion correlated with acinar predominant histology (P<0.001). EGFR mutations were not detected in invasive mucinous adenocarcinomas (P=0.033). The 5-year OS of patients with KRAS-mutant tumors was significantly worse (n=124; 5-year OS, 63%) than those with KRAS wild-type (n=339; 77%; P<0.001). In solid predominant tumors, KRAS mutations correlated with worse OS (P=0.008) and increased risk of recurrence (P=0.005). On multivariate analysis, KRAS mutation was an independent prognosticator of OS in all patients (hazard ratio, 1.87; P<0.001) and recurrence in solid predominant tumors (hazard ratio, 4.73; P=0.012). In patients with resected stage I lung adenocarcinomas, KRAS mutation was an independent prognostic factor for OS and recurrence, especially in solid predominant tumors.

Figure 1. KRAS mutation associations with overall survival (OS)

(A) 5-year OS of patients with KRAS-mutant tumors was significantly worse (n = 124; 5-year OS, 63%) than those with KRAS wild-type tumors (n = 339; 77%; P < 0.001). (B) In architecturally intermediate-grade tumors (acinar predominant and papillary predominant subtypes), 5-year OS of patients with KRAS-mutant tumors was significantly worse (n = 86; 5-year OS, 66%) than those with KRAS wild-type tumors (n = 248; 77%; P = 0.005). (C) 5-year OS of patient with KRAS codon 12 mutated tumors were significantly better (n = 107; 5-year OS, 67%) than those with other KRAS-mutant tumors (n = 17; 29%; P = 0.002)

Figure 2. KRAS mutation associations with overall survival (OS) and cumulative incidence of recurrence (CIR) in solid predominant tumors

(A) In solid predominant tumors, 5-year OS of patients with KRAS-mutant tumors was significantly worse (n = 16; 5-year OS, 43%) than those with KRAS wild-type (n = 42; 77%; P = 0.008). (B) In solid predominant tumors, 5-year CIR of patients with KRAS-mutant tumors was significantly higher (5-year OS, 50%) than those with KRAS wild-type tumors (18%; P = 0.005).

Figure 3. EGFR mutation associations with overall survival (OS)

(A) Patients with EGFR-mutant tumors trended with better OS (n = 85; 5-year OS, 86%) than those with EGFR wild-type tumors (n = 378; 70%; P = 0.055). (B) Type of EGFR mutation (exon 21 L858R mutation vs. exon 19 deletion) was not associated with OS (P = 0.64).

Figure 4. BRAF mutation associations with overall survival (OS)

Patients with BRAF-mutant tumors were likely to have worse prognosis (5-year OS, 50%) than those with BRAF wild-type tumors (73%); although, this difference was based on a small number of BRAF-mutant tumors (n = 6) and was not statistically significant (P = 0.19).