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Colorectal cancer is the second most common cause of cancer death in developed countries. Adjuvant chemotherapy is standard for stage III colorectal cancer but its use in stage II is controversial. Several clinicopathological factors have been described to define a high-risk group among stage II colon cancers, which can aid the selection of patients who may benefit from chemotherapy. Local tumor invasion (T4), high histological grade, obstruction and perforation at diagnosis, and number of lymph nodes removed are the most widely accepted factors. Several molecular factors have been also investigated as prognostic candidate biomarkers. DNA ploidy, KRAS and TP53 mutations, thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, loss of heterozygosity on chromosome 18q and microsatellite instability have been widely investigated. The aim of this review is to analyze the current evidence and clinical applications of the classical molecular biomarkers as well as new ones such as BRAF, circulating tumor cells, genome expression signatures and DNA methylation.