Does KRAS mutational status predict chemoresistance in advanced non-small cell lung cancer (NSCLC)?
Introduction
Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related death worldwide with more than one million deaths every year. However, over the last ten years new therapeutic options have enriched the lung anti-cancer armamentarium, and today in the metastatic setting multiple lines of therapy have become available [1], [2], [3]. Large scale studies showed that nearly all lung cancer cells exhibit inactivation of growth inhibitor pathways (TP53, RB1, p16, STK11 and CDKN2A tumor suppressors) [4] or mutations of growth regulatory genes (KRAS, EGFR, BRAF, MEK-1, HER2, MET, EML-4-ALK, KIF5B-RET, and NKX2.1). Beyond EGFR mutations and ALK rearrangements [5], [6], other “actionable” molecular mutations may be explored and used to select targeted therapies such as amplification of HER2, FGFR1 and c-MET, rearrangements of RET or ROS1, activating mutations of HER2, FGFR2, and PI3K [7], [8], [9], [10], [11], [12], [13]. Among the most common molecular alterations observed in NSCLC lie the mutations of KRAS. These mutations occur in 15–30% of NSCLC and are more frequent in adenocarcinoma (20–50%) [14]. KRAS mutations are usually mutually exclusive with EGFR mutation and ALK rearrangements [15], [16]. The prognostic value of KRAS mutations has been investigated in both the adjuvant and the metastatic setting, but its value remains controversial [17], [18]. Alongside, the predictive value of KRAS mutations to define chemosensitivity to specific chemotherapeutic agents is an area of intense debate [19].
We performed a monocentric retrospective study regarding the chemosensitivity of KRAS mutant (MUT) vs. KRAS/EGFR wild-type (WT) advanced NSCLC. We secondarily analyzed the relationship between specific KRAS mutations and patient's outcomes. The treatment response was assessed evaluating kinetics of tumor growth as well as with RECIST criteria 1.1 [22], [23].
Section snippets
Study population
Consecutive patients with advanced NSCLC treated at Gustave Roussy between June 2009 and June 2012 were retrospectively reviewed. All patients with a determination of KRAS and EGFR status and treated with a platinum-based chemotherapy (CT) in the 1st line setting were included in this analysis. Patients with unknown mutational traits or with actionable alterations, when known, were excluded (i.e. PI3K, HER2, BRAF, FGFR4, ERBB4, PTEN, NRAS, and STK11 mutations; HER2, FGFR1, and MET
Patient characteristics
Among a total of 340 patients with NSCLC included from June 1, 2009 to June 30, 2012, 108 assessable patients were eligible for this analysis, 39 in MUT group (mutated KRAS and wild-type EGFR) and 69 WT group (wild-type KRAS and wild-type EGFR) (Fig. 1). Patient baseline demographics and disease characteristics are summarized in Table 1. The groups were balanced by sex, age, smoking status, PS and TNM. There was a trend for more adenocarcinomas in the MUT group (P = 0.10). Cardiovascular
Discussion
The prognostic and predictive role of KRAS tumor mutations has been debated for years. Some studies showed a poorer outcome for patients with KRAS mutant tumor, but other failed to confirm it [14], [24], [25], [26], [27]. The resistance to treatment with EGFR tyrosin-kinase inhibitors (TKIs) of tumor harboring KRAS mutations is also partially controversial, considering potential escape pathways downstream [28], [29] and different response according to type of KRAS mutations (codon 12 vs. 13)
Conflict of interest statement
None declared.
Acknowledgements
During this project, Marianna Macerelli was supported by a grant from the Italian Association of Thoracic Oncology (AIOT). This work was supported by the European Community's Seventh Framework Programme (FP7/2007–2013) under Grant agreement number HEALTH-F2-2010-258677 – CURELUNG project.
References (37)
- et al.
Targeted agents in the third-/fourth-line treatment of patients with advanced (stage III/IV) non-small cell lung cancer (NSCLC)
Cancer Treat Rev
(2013) - et al.
Epidermal growth factor receptor inhibition in lung cancer: status 2012
J Thorac Oncol
(2013) - et al.
Oncogenic pathways, molecularly targeted therapies, and highlighted clinical trials in non-small-cell lung cancer (NSCLC)
Clin Lung Cancer
(2012) - et al.
Targeting ROS1 with anaplastic lymphoma kinase inhibitors: a promising therapeutic strategy for a newly defined molecular subset of non-small-cell lung cancer
J Thorac Oncol
(2012) Molecular biology of lung cancer: clinical implications
Clin Chest Med
(2011)- et al.
Tumour growth rates and RECIST criteria in early drug development
Eur J Cancer
(2011) - et al.
KRAS mutations as prognostic and predictive markers in non-small cell lung cancer
J Thorac Oncol
(2013) - et al.
Impact of systematic EGFR and KRAS mutation evaluatio on progression-free survival and overall survival inpatients with advanced non-small-cell lung cancer treated by erlotinib in a French prospective cohort (ERMETIC project—part 2)
J Thorac Oncol
(2012) - et al.
Impact of specific mutant KRAS on clinical outcome of EGFR-TKI-treated advanced non-small cell lung cancer patients with an EGFR wild type genotype
Lung Cancer
(2012) - et al.
Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebo-controlled, phase 2 study
Lancet Oncol
(2013)
Mutated K-ras gene analysis in a randomized trial of preoperative chemotherapy plus surgery versus surgery in stage IIIA non-small cell lung cancer
Lung Cancer
Third-line chemotherapy in advanced non-small cell lung cancer: identifying the candidates for routine
J Thorac Oncol
Retrospective analysis of third-line and fourth-line chemotherapy for advanced non-small-cell lung cancer
Clin Lung Cancer
Identification of somatic mutations in non-small cell lung carcinomas using whole-exome sequencing
Carcinogenesis
Genotyping and genomic profiling of non-small-cell lung cancer: implications for current and future therapies
J Clin Oncol
Signaling networks associated with AKT activation in non-small cell lung cancer (NSCLC): new insights on the role of phosphatydil-inositol-3 kinase
PLoS ONE
MDM2 overexpression deregulates the transcriptional control of RB/E2F leading to DNA methyltransferase 3A overexpression in lung cancer
Clin Cancer Res
Clinicopathologic significance of β-catenin and matrix metalloproteinase-2 expression in non-small cell lung cancer
Med Oncol
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