RAS Mutations Affect Pattern of Metastatic Spread and Increase Propensity for Brain Metastasis in Colorectal Cancer

BACKGROUNDRAS and PIK3CA mutations in metastatic colorectal cancer (mCRC) have been associated with worse survival. We sought to evaluate the impact of RAS and PIK3CA mutations on cumulative incidence of metastasis to potentially curable sites of liver and lung and other sites such as bone and brain. METHODSWe performed a computerized search of the electronic medical record of our institution for mCRC cases genotyped for RAS or PIK3CA mutations from 2008 to 2012. Cases were reviewed for patient characteristics, survival, and site-specific metastasis. RESULTSAmong the 918 patients identified, 477 cases were RAS wild type, and 441 cases had a RAS mutation (394 at KRAS exon 2, 29 at KRAS exon 3 or 4, and 18 in NRAS). RAS mutation was significantly associated with shorter median overall survival (OS) and on multivariate analysis independently predicted worse OS (HR, 1.6; P<.01). RAS mutant mCRC exhibited a significantly higher cumulative incidence of lung, bone, and brain metastasis and on multivariate analysis was an independent predictor of involvement of these sites (HR, 1.5, 1.6, and 3.7, respectively). PIK3CA mutations occurred in 10% of the 786 cases genotyped, did not predict for worse survival, and did not exhibit a site-specific pattern of metastatic spread. CONCLUSIONSThe metastatic potential of CRC varies with the presence of RAS mutation. RAS mutation is associated with worse OS and increased incidence of lung, bone, and brain metastasis. An understanding of this site-specific pattern of spread may help to inform physicians' assessment of symptoms in patients with mCRC. Cancer 2015;121:1195-1203. (c) 2014 American Cancer Society. In an analysis of a large series of genetically annotated, metastatic colorectal cancer cases, we find that patients whose tumors harbor a RAS mutation experience shorter overall survival and a significantly higher cumulative incidence of brain, bone, and lung metastases, while the presence of a PIK3CA mutation does not predict for worse outcomes or a site-specific pattern of metastatic spread. These data suggest a role for RAS activation in tumor metastatic progression and may help inform physicians' assessment of symptoms in patients with metastatic colorectal cancer.