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. 2013 Jun 15;119(12):2268-74.
doi: 10.1002/cncr.28039. Epub 2013 Mar 22.

The prognostic and predictive value of KRAS oncogene substitutions in lung adenocarcinoma

Liza C Villaruz  1 , Mark A Socinski, Diana E Cunningham, Simion I Chiosea, Timothy F Burns, Jill M Siegfried, Sanja Dacic
Affiliations

The prognostic and predictive value of KRAS oncogene substitutions in lung adenocarcinoma

Liza C Villaruz et al. Cancer. .

Abstract

Background: The prognostic and therapeutic implications of the spectrum of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) oncogene substitutions in lung cancer remain poorly understood. The objective of this study was to determine whether KRAS oncogene substitutions differed with regard to prognosis or predictive value in lung adenocarcinoma.

Methods: KRAS oncogene substitutions and mutant allele-specific imbalance (MASI) were determined in patients with lung adenocarcinoma, and the associations with overall survival (OS), recurrence-free survival (RFS), and chemotherapy interactions were assessed.

Results: KRAS mutational analysis was performed on 988 lung adenocarcinomas, and 318 KRAS mutations were identified. In this predominantly early stage cohort (78.6% of patients had stage I-III disease), OS and RFS did not differ according to the type of KRAS substitution (OS, P = .612; RFS, P = .089). There was a trend toward better OS in the subset of patients with KRAS codon 13 mutations (P = .052), but that trend was not significant in multivariate analysis (P = .076). RFS did not differ according to codon type in univariate analysis (P = .322). There was a marked difference in RFS based on the presence of MASI in univariate analysis (P = .004) and multivariate analysis (P = .009). A test for interaction was performed to determine whether the effect of chemotherapy on OS and RFS differed based on KRAS substitution type, codon type, or the presence of MASI. That test indicated that there were no differences in the effects of chemotherapy for any of variables examined.

Conclusions: KRAS codon 13 mutations and MASI were identified as candidate biomarkers for prognosis, and it may be useful to incorporate them into prospective studies evaluating novel therapies in KRAS-mutant lung adenocarcinoma.

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Conflict of interest statement

Conflict of Interest: For the remaining authors none were declared.

Figures

Figure 1
Figure 1
Kaplan-Meier survival curves for patients with KRAS mutations: (A) overall survival by KRAS amino acid substitution, (B) recurrence free survival by KRAS amino acid substitution, (C) overall survival by KRAS codon type and (D) recurrence free survival by KRAS codon type.
Figure 1
Figure 1
Kaplan-Meier survival curves for patients with KRAS mutations: (A) overall survival by KRAS amino acid substitution, (B) recurrence free survival by KRAS amino acid substitution, (C) overall survival by KRAS codon type and (D) recurrence free survival by KRAS codon type.
Figure 1
Figure 1
Kaplan-Meier survival curves for patients with KRAS mutations: (A) overall survival by KRAS amino acid substitution, (B) recurrence free survival by KRAS amino acid substitution, (C) overall survival by KRAS codon type and (D) recurrence free survival by KRAS codon type.
Figure 1
Figure 1
Kaplan-Meier survival curves for patients with KRAS mutations: (A) overall survival by KRAS amino acid substitution, (B) recurrence free survival by KRAS amino acid substitution, (C) overall survival by KRAS codon type and (D) recurrence free survival by KRAS codon type.
Figure 2
Figure 2
Assessment of recurrence free survival and mutant allele-specific imbalance (MASI) (A) defined on sequencing electropherograms as either a KRAS mutant peak equal to the wild-type peak (M=W) or a KRAS mutant peak greater than the wild-type peak (M>W). (B) Kaplan-Meier survival curve for recurrence free survival and KRAS MASI and (C) a multivariate analysis of recurrence free survival and MASI adjusting for stage.
Figure 2
Figure 2
Assessment of recurrence free survival and mutant allele-specific imbalance (MASI) (A) defined on sequencing electropherograms as either a KRAS mutant peak equal to the wild-type peak (M=W) or a KRAS mutant peak greater than the wild-type peak (M>W). (B) Kaplan-Meier survival curve for recurrence free survival and KRAS MASI and (C) a multivariate analysis of recurrence free survival and MASI adjusting for stage.
Figure 2
Figure 2
Assessment of recurrence free survival and mutant allele-specific imbalance (MASI) (A) defined on sequencing electropherograms as either a KRAS mutant peak equal to the wild-type peak (M=W) or a KRAS mutant peak greater than the wild-type peak (M>W). (B) Kaplan-Meier survival curve for recurrence free survival and KRAS MASI and (C) a multivariate analysis of recurrence free survival and MASI adjusting for stage.
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