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

Authors

  • Liza C. Villaruz MD,

    Corresponding author
    1. University of Pittsburgh Cancer Institute, School of Medicine/Hematology-Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania
    • Corresponding author: Liza C. Villaruz, MD, University of Pittsburgh Cancer Institute, Division of Hematology/Oncology, UPMC Cancer Pavilion, 5150 Centre Avenue, 5th Floor, Pittsburgh, PA 15232. E-mail: villaruzl@upmc.edu Fax: (412) 648-6579

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  • Mark A. Socinski MD,

    1. University of Pittsburgh Cancer Institute, School of Medicine/Hematology-Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Diana E. Cunningham,

    1. Department of Biostatistics, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Simion I. Chiosea MD,

    1. Department of Pathology, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Timothy F. Burns MD, PhD,

    1. University of Pittsburgh Cancer Institute, School of Medicine/Hematology-Oncology, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Jill M. Siegfried PhD,

    1. Department of Pharmacology, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania
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  • Sanja Dacic MD, PhD

    1. Department of Pathology, University of Pittsburgh Medical Center, University of Pittsburgh, Pittsburgh, Pennsylvania
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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. Cancer 2013;119:2268–2274. © 2013 American Cancer Society.

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