KRAS, NRAS, BRAF, HER2 and microsatellite instability in metastatic colorectal cancer – practical implications for the clinician

Abstract

 Colorectal cancer is a model of genetic biomarker development in oncology. At present, RAS and BRAF gene mutation tests are standard in clinical practice for patients suffering from metastatic colorectal cancer (mCRC). KRAS and NRAS mutations occur in approximately 40% of patients, 6% of the mCRC patients respectively, unevenly distributed across geographical regions. Both genetic alterations in the tumor act as predictors for anti-EGFR treatment, while only NRAS mutations may play a role in prognosis. The survival of patients with NRAS mutation seems significantly shorter compared to those with wild type (WT) tumors. BRAF V600E mutations are rare (8-10% of the patients), occur mostly in female patients older than 70 with tumors located in the right colon, poorly differentiated and mucinous. Such tumors typically metastasize in the peritoneum and are more prevalent in patients with microsatellite instability (MSI-H). BRAF is instrumental in establishing prognosis: Survival is shorter by 10-16 months in BRAF-mutant patients, and BRAF may be a negative prognosis factor for patients who undergo hepatic or pulmonary metastasectomy. Moreover, this mutation is used as a negative prognosis factor for anti-EGFR therapies. The aim of this review was to raise the awareness of clinicians by providing them with less known insights into the particular features of mCRC mutations, which may contribute to a more individualized patient-oriented approach in daily clinical practice.