Role of NRAS mutations as prognostic and predictive markers in metastatic colorectal cancer

NRAS mutations occur in 3-5% of colorectal cancer. Differently from KRAS and BRAF mutations, the role of NRAS mutations as prognostic and predictive markers in metastatic colorectal cancer (mCRC) has been investigated to a lesser extent. A retrospective series suggested the role of NRAS mutations as predictors of resistance to anti-EGFR monoclonal antibodies (MoAbs) in chemo-refractory patients with mCRC. In our study, KRAS codons 12, 13, 61 and BRAF codon 600 mutational status were evaluated in mCRCs referred to our Institution from 2009 to 2012. NRAS codons 12, 13 and 61 mutational status was analyzed in KRAS/BRAF wt patients. We collected pathological and clinical features in the overall population and outcome data in a subset of NRAS mutated chemo-refractory patients treated with anti-EGFR MoAbs in advanced lines. NRAS was mutated in 47/786 (6%) mCRCs. NRAS and KRAS mutated tumors did not show significant differences in terms of clinical and pathological characteristics, except for a lower prevalence of mucinous histology (p-‰=-‰0.012) and lung metastases (p-‰=-‰0.012) among NRAS mutated tumors. In the uni- and multivariate model, NRAS mutations were associated with shorter overall survival (OS) compared to all wt patients (median OS 25.6 vs 42.7 months; univ: HR-‰=-‰1.91, 95% CI 1.39-3.86, p-‰=-‰0.0013; multiv: HR-‰=-‰1.75, 95% CI 1.1.3-2.72, p-‰=-‰0.013). None of the chemo-refractory NRAS mutated patients evaluable for response to anti-EGFRs achieved response. In conclusion, NRAS mutations have a relevant incidence in patients with mCRC and showed an association with specific clinical and pathological features. NRAS mutations affect mCRC patients' prognosis and predict lack of response to anti-EGFRs. What's new? The RAS family of genes plays a key role in human cancers. While mutations in KRAS and BRAF have been widely studied. The clinico-pathological features and the prognostic impact of NRAS mutations are less known. Here the authors identify NRAS mutations in 6% of metastatic colorectal cancers. Clinical and pathological characteristics of NRAS-mutant tumors were similar to those with KRAS mutations. Moreover NRAS mutations functioned as reliable predictors of resistance to anti-EGFR monoclonal antibody therapy. This study highlights the importance of including analysis of NRAS mutations into the molecular characterization of metastatic colorectal tumors.