Non-small-cell lung cancer (NSCLC) is a heterogeneous disease due to the presence of different clinically relevant molecular subtypes. Until today, several biological events have been identified in lung adenocarcinoma, including epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations, offering new hopes to patients with metastatic disease. Unfortunately, in approximately 50% of adenocarcinoma and for those harbouring K-RAS mutations, the most frequent mutation in Caucasian lung adenocarcinoma, so far no specific drug demonstrated efficacy. The rat sarcoma (RAS) genes, including H-RAS, K-RAS, and N-RAS, encode a family of proteins regulating cell growth, differentiation, and apoptosis. K-RAS mutations are present in 20–30% of NSCLC and occur most commonly, but not exclusively, in adenocarcinoma histology and life-long smokers. Although in colorectal cancer patients K-RAS mutations represent a validated negative predictive biomarker for treatment with anti-EGFR monoclonal antibodies, their role in selecting specific treatment for NSCLC patients remains undefined. Aim of the present paper is to critically analyze the prognostic and predictive value of K-RAS mutations in NSCLC. 1. Introduction In 2011 non-small-cell lung cancer (NSCLC) remains the principal cause of cancer-related death worldwide, accounting for more than one million deaths per year [1]. Therapeutic progresses have signed out the last decade, but median survival for patients in advanced stage is still disappointing [2]. NSCLC accounts for 80% of lung tumors, including adenocarcinoma in 35–40% of cases, squamous cell carcinoma in 25–30%, and large cell carcinoma in 10–15%. For many years we treated metastatic NSCLC with the same regimens, irrespective of any clinical or biological characteristics. Today, histology seems a relevant parameter for defining the best regimen, with new agents, such as pemetrexed and bevacizumab, effective and safe only in non-squamous populations [3, 4]. During the last few years, improvement in the knowledge of lung cancer biology led to identification of molecular events crucial for tumor cell survival. Cancer cell survival might depend on the expression of a single-mutant oncogene according to a model called “oncogene addiction” [5, 6]. In NSCLC a number of driving mutations have been identified, including Epidermal growth factor receptor (EGFR) mutations, KRAS mutations, HER2 mutations and EML4-ALK translocations. Since their identification in 2004, activating EGFR gene mutations have emerged as the most relevant
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