Impact of somatic mutations on patterns of metastasis in colorectal cancer

Somatic mutation status in metastatic colorectal cancer (mCRC) is becoming increasingly clinically relevant as it may be correlated not only with response to biologic therapies, but also with site-specific pattern of metastatic spread and outcome. In this review, we describe our current understanding of associations between mutational activation of the KRAS, BRAF, PIK3CA, and NRAS oncogenes and clinical outcomes and metastatic patterns of mCRC. The presence of a KRAS mutation is associated with a distinct pattern of metastatic spread with decreased liver metastases and increased lung, brain, and bone metastases. In patients who undergo resection of colorectal liver metastases (CLM) with curative intent, KRAS mutation is associated increased risk of recurrence, worse survival, and increased recurrence outside of the liver, particularly in the lung, but also in the brain and bone. BRAF mutation, a poor prognostic factor in mCRC, is associated with decreased liver-limited metastasis and increased peritoneal and distant lymph node metastases. PIK3CA mutation does not clearly affect outcomes in the metastatic setting, but is associated with concurrent KRAS mutations, and has been associated with an increased incidence of lung and brain metastases, metastatic sites preferentially involved in KRAS mutant mCRC. NRAS mutation may confer worse survival and early studies suggest NRAS mutation may promote tumorigenesis in the setting of colorectal inflammation. As metastasectomy with curative intent is increasingly considered in patients with mCRC, understanding patterns of metastasis associated with tumor mutations may help focus medical treatment, surgical management, and surveillance in patients with mCRC.