Prognostic and Predictive Value of KRAS Mutations in Advanced Non-Small Cell Lung Cancer

Jin Seok Ahn,Deok Won Hwang,Keunchil Park,Jong-Mu Sun,Myung-Ju Ahn,Olga Y Gorlova

doi:10.1371/journal.pone.0064816

Jin Seok Ahn, Deok Won Hwang + Show 4 more

Open Access

https://doi.org/10.1371/journal.pone.0064816

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Journal: PLoS ONE	Publication Date: May 28, 2013
Citations: 75	License type: CC BY 4.0

Affiliation: Samsung Medical Center, Sungkyunkwan University

Abstract

Clinical implications of KRAS mutations in advanced non-small cell lung cancer remain unclear. We retrospectively evaluated the prognostic and predictive value of KRAS mutations in patients with advanced NSCLC. Among 484 patients with available results for both KRAS and EGFR mutations, 39 (8%) had KRAS and 182 (38%) EGFR mutations, with two cases having both mutations. The median overall survivals for patients with KRAS mutations, EGFR mutations, or both wild types were 7.7, 38.0, and 15.0 months, respectively (P<0.001). The KRAS mutation was an independent poor prognostic factor in the multivariate analysis (hazard ratio = 2.6, 95% CI: 1.8–3.7). Response rates and progression-free survival (PFS) for the pemetrexed-based regimen in the KRAS mutation group were 14% and 2.1 months, inferior to those (28% and 3.9 months) in the KRAS wild type group. KRAS mutation tended to be associated with inferior treatment outcomes after gemcitabine-based chemotherapy, while there was no difference regarding taxane-based regimen. Although the clinical outcomes to EGFR tyrosine kinase inhibitors (TKIs) seemed to be better in patients with KRAS wild type than those with KRAS mutations, there was no statistical difference in response rates and PFS according to KRAS mutation status when EGFR mutation status was considered. Two patients with both KRAS and EGFR mutations showed partial response to EGFR TKIs. Although G12D mutation appeared more frequently in never smokers, there was no difference in clinical outcomes according to KRAS genotypes. These results suggested KRAS mutations have an independent prognostic value but a limited predictive role for EGFR TKIs or cytotoxic chemotherapy in advanced NSCLC.

Highlights

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality despite intensive anticancer treatment and improvement of clinical modalities seen in the recent decades
Only epidermal growth factor receptor (EGFR) mutations were tested in 112 patients, neither KRAS nor EGFR mutation test could not be done in 32 patients due to small amount of tumor DNA, and 11 cases who were not tested for both exon 19 and 21 EGFR mutations were classified as unknown mutation status
The present study shows that KRAS mutations are an independent predictor of poor prognosis in patients with advanced NSCLC

Summary

Introduction

Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality despite intensive anticancer treatment and improvement of clinical modalities seen in the recent decades. Some studies previously identified the KRAS mutation as a poor prognostic factor in NSCLC [12,13,14], others have failed to reproduce those results [6,8,15,16,17]. KRAS mutation has been proposed as a mechanism of primary resistance to EGFR TKI [18], and many studies demonstrated poor clinical outcomes to EGFR TKIs in patients with NSCLC harboring KRAS mutation [7,9,19,20]. The analysis of the predictive role of KRAS mutation for EGFR TKI therapy can be confounded by EGFR mutation status [21]. The predictive value of KRAS mutation for EGFR TKI therapy should be analyzed with EGFR mutation status being considered

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