title: RAS mutations affect pattern of metastatic spread and increase propensity for brain metastasis in colorectal cancer.
abstract: BACKGROUND
  RAS 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  Among 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Rona
authors.initials: R
authors.lastname: Yaeger
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Cowell
authors.forename: Joanne F
authors.initials: JF
authors.lastname: Chou
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Gewirtz
authors.forename: Laetitia
authors.initials: L
authors.lastname: Borsu
authors.forename: Efsevia
authors.initials: E
authors.lastname: Vakiani
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.forename: Neal
authors.initials: N
authors.lastname: Rosen
authors.forename: Marinela
authors.initials: M
authors.lastname: Capanu
authors.forename: Marc
authors.initials: M
authors.lastname: Ladanyi
authors.forename: Nancy
authors.initials: N
authors.lastname: Kemeny
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001859:Bone Neoplasms / Q000235:genetics / Q000556:secondary; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology / Q000556:secondary*; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D016019:Survival Analysis; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins
keywords: PIK3CA; RAS; colorectal cancer; neoplasm metastasis; prognosis