title: PI3K pathway mutations are associated with longer time to local progression after radioembolization of colorectal liver metastases.
abstract: OBJECTIVE
  To establish the relationship between common mutations in the MAPK and PI3K signaling pathways and local progression after radioembolization.
  
  
  METHODS
  Retrospective review of a HIPAA-compliant institutional review-board approved database identified 40 patients with chemo-refractory colorectal liver metastases treated with radioembolization who underwent tumor genotyping for hotspot mutations in 6 key genes in the MAPK/PI3K pathways (KRAS, NRAS, BRAF, MEK1, PIK3CA, and AKT1). Mutation status as well as clinical, tumor, and treatment variables were recorded. These factors were evaluated in relation to time to local progression (TTLP), which was calculated from time of radioembolization to first radiographic evidence of local progression. Predictors of outcome were identified using a proportional hazards model for both univariate and multivariate analysis with death as a competing risk.
  
  
  RESULTS
  Sixteen patients (40%) had no mutations in either pathway, eighteen patients (45%) had mutations in the MAPK pathway, ten patients (25%) had mutations in the PI3K pathway and four patients (10%) had mutations in both pathways. The cumulative incidence of progression at 6 and 12 months was 33% and 55% for the PI3K mutated group compared with 76% and 92% in the PI3K wild type group. Mutation in the PI3K pathway was a significant predictor of longer TTLP in both univariate (p=0.031, sHR 0.31, 95% CI: 0.11-0.90) and multivariate (p=0.015, sHR=0.27, 95% CI: 0.096-0.77) analysis. MAPK pathway alterations were not associated with TTLP.
  
  
  CONCLUSIONS
  PI3K pathway mutation predicts longer time to local progression after radioembolization of colorectal liver metastases.
authors.affiliation: Interventional Radiology Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Etay
authors.initials: E
authors.lastname: Ziv
authors.affiliation: Department of Radiology, Mount Sinai Hospital, New York, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Bergen
authors.affiliation: Interventional Radiology Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Hooman
authors.initials: H
authors.lastname: Yarmohammadi
authors.affiliation: Interventional Radiology Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: F Ed
authors.initials: FE
authors.lastname: Boas
authors.affiliation: Interventional Radiology Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: E Nadia
authors.initials: EN
authors.lastname: Petre
authors.affiliation: Interventional Radiology Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Constantinos T
authors.initials: CT
authors.lastname: Sofocleous
authors.affiliation: Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Rona
authors.initials: R
authors.lastname: Yaeger
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, USA.|Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan-Kettering Cancer Center, New York, USA.|Genitourinary Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.affiliation: Interventional Radiology Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Solomon
authors.affiliation: Interventional Radiology Service, Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Erinjeri
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D018450:Disease Progression; D004621:Embolization, Therapeutic / Q000379:methods; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000556:secondary / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D017063:Outcome Assessment, Health Care / Q000379:methods / Q000706:statistics & numerical data; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011379:Prognosis; D016016:Proportional Hazards Models; D011878:Radiotherapy / Q000379:methods; D012189:Retrospective Studies; D015398:Signal Transduction / Q000235:genetics*; D013997:Time Factors
chemical_list: D019869:Phosphatidylinositol 3-Kinases
keywords: MAPK; PI3K; biomarkers; colorectal; radioembolization