title: A novel miRNA-based predictive model for biochemical failure following post-prostatectomy salvage radiation therapy.
abstract: OBJECTIVE
  To develop a microRNA (miRNA)-based predictive model for prostate cancer patients of 1) time to biochemical recurrence after radical prostatectomy and 2) biochemical recurrence after salvage radiation therapy following documented biochemical disease progression post-radical prostatectomy.
  
  
  METHODS
  Forty three patients who had undergone salvage radiation therapy following biochemical failure after radical prostatectomy with greater than 4 years of follow-up data were identified. Formalin-fixed, paraffin-embedded tissue blocks were collected for all patients and total RNA was isolated from 1mm cores enriched for tumor (>70%). Eight hundred miRNAs were analyzed simultaneously using the nCounter human miRNA v2 assay (NanoString Technologies; Seattle, WA). Univariate and multivariate Cox proportion hazards regression models as well as receiver operating characteristics were used to identify statistically significant miRNAs that were predictive of biochemical recurrence.
  
  
  RESULTS
  Eighty eight miRNAs were identified to be significantly (p<0.05) associated with biochemical failure post-prostatectomy by multivariate analysis and clustered into two groups that correlated with early (≤ 36 months) versus late recurrence (>36 months). Nine miRNAs were identified to be significantly (p<0.05) associated by multivariate analysis with biochemical failure after salvage radiation therapy. A new predictive model for biochemical recurrence after salvage radiation therapy was developed; this model consisted of miR-4516 and miR-601 together with, Gleason score, and lymph node status. The area under the ROC curve (AUC) was improved to 0.83 compared to that of 0.66 for Gleason score and lymph node status alone.
  
  
  CONCLUSIONS
  miRNA signatures can distinguish patients who fail soon after radical prostatectomy versus late failures, giving insight into which patients may need adjuvant therapy. Notably, two novel miRNAs (miR-4516 and miR-601) were identified that significantly improve prediction of biochemical failure post-salvage radiation therapy compared to clinico-histopathological factors, supporting the use of miRNAs within clinically used predictive models. Both findings warrant further validation studies.
authors.affiliation: Department of Radiation Oncology, Arthur G. James Hospital/ Ohio State Comprehensive Cancer Center, Columbus, Ohio, United States of America.
authors.forename: Erica Hlavin
authors.initials: EH
authors.lastname: Bell
authors.affiliation: Department of Radiation Oncology, Arthur G. James Hospital/ Ohio State Comprehensive Cancer Center, Columbus, Ohio, United States of America; Department of Radiation Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Kirste
authors.affiliation: Department of Radiation Oncology, Arthur G. James Hospital/ Ohio State Comprehensive Cancer Center, Columbus, Ohio, United States of America.
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Fleming
authors.affiliation: Department of Radiation Oncology, Arthur G. James Hospital/ Ohio State Comprehensive Cancer Center, Columbus, Ohio, United States of America; Department of Radiation Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Stegmaier
authors.affiliation: Department of Pathology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Drendel
authors.affiliation: Center for Biostatistics, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Mo
authors.affiliation: Department of Radiation Oncology, Arthur G. James Hospital/ Ohio State Comprehensive Cancer Center, Columbus, Ohio, United States of America.
authors.forename: Stella
authors.initials: S
authors.lastname: Ling
authors.affiliation: Department of Radiation Oncology, Arthur G. James Hospital/ Ohio State Comprehensive Cancer Center, Columbus, Ohio, United States of America.
authors.forename: Denise
authors.initials: D
authors.lastname: Fabian
authors.affiliation: Department of Radiation Oncology, Arthur G. James Hospital/ Ohio State Comprehensive Cancer Center, Columbus, Ohio, United States of America.
authors.forename: Isabel
authors.initials: I
authors.lastname: Manring
authors.affiliation: Department of Urology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Cordula A
authors.initials: CA
authors.lastname: Jilg
authors.affiliation: Department of Urology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schultze-Seemann
authors.affiliation: Department of Radiation Oncology, Arthur G. James Hospital/ Ohio State Comprehensive Cancer Center, Columbus, Ohio, United States of America.
authors.forename: Maureen
authors.initials: M
authors.lastname: McNulty
authors.affiliation: The Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, Ohio, United States of America.
authors.forename: Debra L
authors.initials: DL
authors.lastname: Zynger
authors.affiliation: Department of Radiation Oncology, Arthur G. James Hospital/ Ohio State Comprehensive Cancer Center, Columbus, Ohio, United States of America.
authors.forename: Douglas
authors.initials: D
authors.lastname: Martin
authors.affiliation: Department of Radiation Oncology, Arthur G. James Hospital/ Ohio State Comprehensive Cancer Center, Columbus, Ohio, United States of America.
authors.forename: Julia
authors.initials: J
authors.lastname: White
authors.affiliation: Department of Pathology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Werner
authors.affiliation: Department of Radiation Oncology, University Medical Center Freiburg, Freiburg, Germany.
authors.forename: Anca L
authors.initials: AL
authors.lastname: Grosu
authors.affiliation: Department of Radiation Oncology, Arthur G. James Hospital/ Ohio State Comprehensive Cancer Center, Columbus, Ohio, United States of America.
authors.forename: Arnab
authors.initials: A
authors.lastname: Chakravarti
mesh_terms: D000368:Aged; D019540:Area Under Curve; D014408:Biomarkers, Tumor / Q000378:metabolism*; D018450:Disease Progression; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D012372:ROC Curve; D016879:Salvage Therapy; D017211:Treatment Failure
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs