Treatment strategies for KRAS mutated non-small cell lung cancer

Abstract

RAS mutations, one of the most frequent oncogenes in non-small cell lung cancer (NSCLC), occur in 15-30 % of cases. KRAS, mutations are more frequent in adenocarcinoma, patients of Caucasian decent, and smokers and are detected mainly in codons 12 and 13 of exon 2 of the KRAS gene. The prognostic role of KRAS is still debated. Based on two large meta-analyses, KRAS mutation appears to be a weak negative prognostic factor in NSCLC; however, this was not confirmed in a recent pooled analysis from four clinical trials of adjuvant chemotherapy for early stage lung cancer (LACE-BIO study). Furthermore, different types of mutations potentially may have different prognostic effects, but this observation requires further investigation and validation. There is no strong evidence of a predictive role for KRAS mutation status that would determine patient selection for chemotherapy or molecularly targeted treatments. Two meta-analyses suggest that KRAS mutation may be a negative predictive biomarker for response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC, but a definitive association between KRAS status and survival benefit has not been established. Recently the LACE-BIO group showed that chemotherapy could be deleterious in patients with codon 13 mutations, and that patients with tumors harbouring combined KRAS and p53 mutations also have a worse outcome when treated with adjuvant chemotherapy compared with patients with double wild type tumors. These finding require further validation. Thus, at this time, KRAS mutation cannot be used to select NSCLC patients for therapy.To date, there is no effective targeted therapy available for KRAS mutant NSCLC and targeting KRAS remains experimental. The combination of chemotherapy and MEK inhibitors has shown interesting preliminary results in KRAS mutant NSCLC and is being evaluated in phase III trials. Other drugs also are under study, but results remain premature. The inhibition of KRAS activity likely will require combined, and maybe customized, therapy targeting several activated downstream effectors.