title: Tissue microRNAs as predictors of outcome in patients with metastatic colorectal cancer treated with first line Capecitabine and Oxaliplatin with or without Bevacizumab.
abstract: OBJECTIVE
  We tested the hypothesis that expression of microRNAs (miRNAs) in cancer tissue can predict effectiveness of bevacizumab added to capecitabine and oxaliplatin (CAPEOX) in patients with metastatic colorectal cancer (mCRC).
  
  
  METHODS
  Patients with mCRC treated with first line CAPEOX and bevacizumab (CAPEOXBEV): screening (n = 212) and validation (n = 121) cohorts, or CAPEOX alone: control cohort (n = 127), were identified retrospectively and archival primary tumor samples were collected. Expression of 754 miRNAs was analyzed in the screening cohort using polymerase chain reaction (PCR) arrays and expression levels were related to time to disease progression (TTP) and overall survival (OS). Significant miRNAs from the screening study were analyzed in all three cohorts using custom PCR arrays. In situ hybridization (ISH) was done for selected miRNAs.
  
  
  RESULTS
  In the screening study, 26 miRNAs were significantly correlated with outcome in multivariate analyses. Twenty-two miRNAs were selected for further study. Higher miR-664-3p expression and lower miR-455-5p expression were predictive of improved outcome in the CAPEOXBEV cohorts and showed a significant interaction with bevacizumab effectiveness. The effects were strongest for OS. Both miRNAs showed high expression in stromal cells. Higher expression of miR-196b-5p and miR-592 predicted improved outcome regardless of bevacizumab treatment, with similar effect estimates in all three cohorts.
  
  
  CONCLUSIONS
  We have identified potentially predictive miRNAs for bevacizumab effectiveness and additional miRNAs that could be related to chemotherapy effectiveness or prognosis in patients with mCRC. Our findings need further validation in large cohorts, preferably from completed randomized trials.
authors.affiliation: Department of Oncology, Herlev University Hospital, Herlev, Denmark.
authors.forename: Mogens K
authors.initials: MK
authors.lastname: Boisen
authors.affiliation: Statistics, Bioinformatics and Registry, Danish Cancer Society Research Center, Copenhagen, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Dehlendorff
authors.affiliation: Department of Pathology, Herlev University Hospital, Herlev, Denmark.
authors.forename: Dorte
authors.initials: D
authors.lastname: Linnemann
authors.affiliation: Bioneer, Hørsholm, Denmark.
authors.forename: Boye S
authors.initials: BS
authors.lastname: Nielsen
authors.affiliation: Department of Oncology, Roskilde Hospital, Roskilde, Denmark.
authors.forename: Jim S
authors.initials: JS
authors.lastname: Larsen
authors.affiliation: Department of Oncology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Kell
authors.initials: K
authors.lastname: Osterlind
authors.affiliation: Department of Oncology and Palliation, Hillerød Hospital, Hillerød, Denmark.
authors.forename: Svend E
authors.initials: SE
authors.lastname: Nielsen
authors.affiliation: Department of Oncology, Odense University Hospital, Odense, Denmark.
authors.forename: Line S
authors.initials: LS
authors.lastname: Tarpgaard
authors.affiliation: Department of Oncology, Odense University Hospital, Odense, Denmark.
authors.forename: Camilla
authors.initials: C
authors.lastname: Qvortrup
authors.affiliation: Department of Oncology, Odense University Hospital, Odense, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Pfeiffer
authors.affiliation: Department of Oncology, Næstved Hospital, Næstved, Denmark.
authors.forename: Niels H
authors.initials: NH
authors.lastname: Holländer
authors.affiliation: Department of Oncology, Herning Hospital, Herning, Denmark.
authors.forename: Nina
authors.initials: N
authors.lastname: Keldsen
authors.affiliation: Department of Oncology, Vejle Hospital, Vejle, Denmark.
authors.forename: Torben F
authors.initials: TF
authors.lastname: Hansen
authors.affiliation: Department of Medicine, Queen Ingrid Hospital, Nuuk, Greenland; Department of Oncology, Sydvestjysk Hospital, Esbjerg, Denmark.
authors.forename: Brita B
authors.initials: BB
authors.lastname: Jensen
authors.affiliation: Department of Pathology, Herlev University Hospital, Herlev, Denmark.
authors.forename: Estrid V S
authors.initials: EV
authors.lastname: Høgdall
authors.affiliation: Department of Oncology, Herlev University Hospital, Herlev, Denmark.
authors.forename: Benny V
authors.initials: BV
authors.lastname: Jensen
authors.affiliation: Department of Oncology, Herlev University Hospital, Herlev, Denmark; Department of Medicine, Herlev University Hospital, Herlev, Denmark.
authors.forename: Julia S
authors.initials: JS
authors.lastname: Johansen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D000068258:Bevacizumab; D000069287:Capecitabine; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis*; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage*; D000077150:Oxaliplatin; D011379:Prognosis; D046888:Tissue Array Analysis; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D035683:MicroRNAs; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000068258:Bevacizumab; D000069287:Capecitabine; D005472:Fluorouracil