Colorectal Carcinoma (CRC) [C18.-, C19, C20, C21.-]
Dipl.-Ing. (FH) Tanja Hinrichsen,
Prof. Dr. med. Barbara Dockhorn-Dworniczak
Colorectal carcinomas (CRC) are responsible for approximately 14% of all tumors in adults. Approximately 27,000 men and 30,000 women develop colon cancer annually in Germany. Disease prognosis is dependent on localization (colon versus rectum) and disease stage at diagnosis. While the 5-year survival rate for stage I and II is 85-90%, for people with stage III colorectal cancer the 5-year survival rate is about 60% and for stage IV disease it is 5%. Significant progress has been made in recent years with the introduction of new chemotherapeutics. The development and use of antibodies and so called small molecules that block the effect of tumor-specific growth factors (e.g. epidermal growth factor (EGF, cetuximab, panitumumab) or angiogeneic cytokines (vascular endothelial growth factor, VEGF, bevacizumab) can, used in combination with chemotherapy further improve treatment and achieve an increase in overall survival.
Anti-epidermal growth factor receptor (EGFR) therapy is effective only for patients without known mutations in KRAS or NRAS. Mutations in these genes lead to a ligand-independent, constitutive activation of the MAPK signaling pathway and loss of antiproliferative effect of EGFR antibodies. Due to the fact that approximately 50% of CRC patients have mutations in KRAS and 5% have mutations in NRAS, and that these are considered negative predictive markers for the response to treatment with EGFR antibodies, it is absolutely necessary to perform a mutation analysis of these genes before starting anti-EGFR therapy.
A further 8-10% of CRC patients show mutations in BRAF, associated with an aggressive CRC phenotype, chemotherapy resistance, microsatellite instability and a decreased overall survival rate. These patients also show no improvement with regard to overall and progression-free survival with anti-EGFR therapy. At the moment chemotherapy with or without bevacizumab seems to be the best treatment option, however preclinical data shows promising activity for a combination of anti-EGFR therapy, BRAF inhibitor and, if applicable, a MEK inhibitor.
Approximately 10-20% non-selected CRC patients have mutations in PIK3CA, which can also occur together with mutations in KRAS and BRAF and thus KRAS and BRAF status should also be determined. Patients with mutations in PIK3CA, especially in exon 20, appear to be resistant to anti-EGFR therapy which may be an explanation for treatment failure in cancer patients with RAS wild type.