The prognostic value of KRAS and BRAF in stage I-III colorectal cancer. A systematic review.

BACKGROUND: Colorectal cancer (CRC) is one of the leading cause of cancer deaths worldwide. The aetiology of CRC is complex and involves interaction on environmental and genetic factors. The two most important pathways are the EGFR (Epidermal Grow Factor Receptor) signaling pathway, with the involvement of KRAS and BRAF, and the DNA mismatch repair (MMR). Generally, KRAS and BRAF mutations are mutually exclusive. They are both able to cause RAS/RAF/MAPK signaling pathway upregulation and are necessary for CRC development. BRAF mutations confers a poor prognosis in Western CRC patients, particularly in metastatic CRC (mCRC) and its mutations occur in approximately 4-20% CRC, with the vast majority being the V600E hotspot mutation. KRAS mutations are observed in 30- 40% CRC patients and act as predictive markers of resistance to epidermal growth factor receptor (EGFR)-targeted antibodies in metastatic CRC. Initial patient management is defined by TNM stage at diagnosis but in patient with stage II and III CRC, TNM staging alone does not predict outcome in CRC patients who may be eligible for adjuvant chemotherapy. Furthermore, for stage II and III, non-metastatic CRC patients, the prognostic role of BRAF and KRAS mutations is still controversial, particularly comparing microsatellite-unstable (MSI) and - stable tumors (MSS). The aim of this study was to clarify the impact of KRAS/BRAF mutations on prognosis in patients with stage I-III CRC. MATERIALS AND METHODS: A systematic review of literature was undertaken to evaluate the prognostic value of KRAS and BRAF mutations in stage I-III colorectal cancer. Four major databases (PUBMED, EMBASE, WEB OF SCIENCE and COCHRANE LIBRARY) were searched. RESULTS: Ninety-two studies were identified. After screening of titles, abstract and inclusion criteria sixteen articles were included. Of the selected articles, five were prospective, ten were retrospectives studies, and one was a combined retrospective/ prospective study. CONCLUSION: In our opinion, a combination of molecular markers, tumor location with the other clinical-pathological variables and microsatellite status is essential to have a correct prognosis. Nevertheless, this combination could be useful as a predictive factor in stage I-III CRC. KEY WORDS: BRAF, Colorectal Cancer, KRAS, Stage I-III CRC, Translational research.