title: Ribonucleotide reductase subunit M1 expression in resectable, muscle-invasive urothelial cancer correlates with survival in younger patients.
abstract: OBJECTIVE
  To assess whether high ribonucleotide reductase subunit M1 (RRM1) expression in patients with resected, muscle-invasive (T2-4NxM0) urothelial carcinoma (UC) correlated with longer overall survival (OS). RRM1 is the primary cellular target of gemcitabine and previous studies in resected early-stage lung cancer have shown a survival benefit for patients with high expression.
  
  
  METHODS
  In all, 84 radical cystectomy specimens with muscle-invasive UC were identified from existing tissue microarrays. The patients' medical records were retrospectively reviewed to confirm pathology and stage. Specimens were analysed for RRM1 expression using automated quantitative analysis. The median value of RRM1 was established a priori as the threshold for high and low expression.
  
  
  RESULTS
  The median age of the patients was 69 years. Stages were nearly equally distributed: 30%, 38%, and 32% for stage II, III, and IV, respectively. Most were high grade (99%) with no nodal involvement (69%). The median (range) OS was 2.0 (0-13.1) years. Tumoral RRM1 levels did not correlate with OS for the entire cohort, but when adjusted for age, high tumoral RRM1 expression in younger patients (aged <70 years) correlated with increased survival. Younger patients with high RRM1 expression had a median OS of 10.6 years compared with 1.6 years in older patients (P= 0.001). There was no difference in OS among low RRM1 expressors: 2.3 vs 1.6 years in younger and older patients, respectively (P= 0.22).
  
  
  CONCLUSIONS
  Our results suggest that high RRM1 expression may be prognostic for improved survival in patients with muscle-invasive UC aged <70 years.
authors.affiliation: Division of Oncology and Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. laurenhs@stanford.edu
authors.forename: Lauren C
authors.initials: LC
authors.lastname: Harshman
authors.forename: Gerold
authors.initials: G
authors.lastname: Bepler
authors.forename: Zhong
authors.initials: Z
authors.lastname: Zheng
authors.forename: John P
authors.initials: JP
authors.lastname: Higgins
authors.forename: Genevera I
authors.initials: GI
authors.lastname: Allen
authors.forename: Sandy
authors.initials: S
authors.lastname: Srinivas
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D002295:Carcinoma, Transitional Cell / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology / Q000628:therapy; D015331:Cohort Studies; D015653:Cystectomy; D005260:Female; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D011379:Prognosis; D012189:Retrospective Studies; D012262:Ribonucleoside Diphosphate Reductase; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D001749:Urinary Bladder Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology / Q000628:therapy
chemical_list: D025521:Tumor Suppressor Proteins; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase