KRAS, BRAF and gastric cancer

Gastric cancer (GC) remains a major worldwide health problem and survival rates continue to be poor in patients with advanced stage disease despite multimodal treatment combining different chemo(radio) therapy regimens with surgery or best supportive care. Thus, there is an urgent clinical need to identify new potential drug targets in order to improve survival for GC patients. KRAS encodes a small guanosine triphosphatase and point mutations in codons 12 and 13 of KRAS have been detected in many human cancers. BRAF is a member of the RAF family of protein kinases and has a hotspot for mutations in codon 600 (so called V600E mutation). KRAS and BRAF proteins are both components of the MAPK/ERK pathway. When mutated, KRAS becomes constitutively active resulting in enhanced BRAF activity. KRAS and BRAF mutations in colorectal cancers (CRC) are known predictors of poor response to epidermal growth factor receptor (EGFR) targeting agents. This PubMed and Web of Science based review aimed to analyze and summarize the current literature on mutations in KRAS and BRAF in GC and their relationship to clinicopathological and molecular variables including KRAS amplification. In total, 69 studies were included in this review. The median incidence of a KRAS mutation was 6.5% ranging from 0-29%. The median incidence of KRAS mutations was similar in studies from the East and the West (East: 6%, ranging from 0-20%; West 7.5%, ranging from 0-29%). KRAS amplifications were reported at an incidence of 1-9%. The median BRAF mutation incidence in GC was 0%, ranging from 0% to 12%. Due to the low incidence and often small study size, many of the published studies had insufficient statistical power to detect a potential relationship between KRAS mutation status and clinicopathological variables including patient survival. In summary, the current literature on KRAS and BRAF in GC is still limited and very heterogeneous making any comparisons between different studies difficult. BRAF V600E mutations are very rare in GC. Interestingly, the incidence of KRAS mutations in GC is much lower than that in CRC and there appears to be no difference by ethnicity of the patients. KRAS mutations and KRAS amplifications seem to be mutually exclusive suggesting the need to screen GC patients for both genetic aberrations. So far, all clinical studies in unselected patients with metastatic GC have failed to show a significant benefit for EGFR targeting therapy. However, there has been a recent report indicating that the subgroup of signet ring cell GC, which is known to be resistant to standard cytotoxic chemotherapy, has a higher incidence of KRAS mutations (15%). Thus, EGFR targeted therapy in this particular histological subtype of GC could potentially be a promising treatment option in the future.