title: Predictive and Prognostic Value of Ribonucleotide Reductase Regulatory Subunit M1 and Excision Repair Cross-Complementation Group 1 in Advanced Urothelial Carcinoma (UC) Treated with First-Line Gemcitabine Plus Platinum Combination Chemotherapy.
abstract: Preclinical and clinical studies have suggested that expression of ribonucleotide reductase regulatory subunit M1 (RRM1) and excision repair cross-complementation group 1 (ERCC1) is associated with resistance to gemcitabine and cisplatin, respectively. We evaluated the significance of RRM1 and ERCC1 expression to predict tumor response to gemcitabine plus platinum chemotherapy (GP) and survival in advanced UC. We retrospectively collected tumor samples and reviewed clinical data of 53 patients with unresectable or metastatic UC, who were treated with first-line GP. RRM1 and ERCC1 expression were measured by immunohistochemistry. Among 53 patients, 12 (22.6%) and 26 (49.1%) patients had tumors that demonstrated a high expression for RRM1 and ERCC1, respectively. Twenty-nine (70.7%) of 41 patients with low RRM1 expression achieved a clinical response (complete + partial responses), but only 3 (25.0%) of 12 patients with high RRM1 expression achieved a clinical response after GP (P=0.007). Nineteen (70.4%) of 27 patients with low ERCC1 expression achieved a clinical response, while 13 (50.0%) of 26 patients with high ERCC1 expression achieved a clinical response (P=0.130). High RRM1 expression was associated with shorter progression free survival and overall survival (PFS P=0.006, OS P=0.006). Multivariate analysis confirmed that patients with high RRM1 expression had a significantly greater risk of progression and death than those with low RRM1 expression. ERCC1 status was not a significant predictor for PFS and OS. RRM1 expression was predictive and prognostic of clinical outcome in advanced UC treated with gemcitabine plus platinum combination chemotherapy.
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.
authors.forename: Miso
authors.initials: M
authors.lastname: Kim
authors.affiliation: Department of Urology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Ja Hyeon
authors.initials: JH
authors.lastname: Ku
authors.affiliation: Department of Urology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Cheol
authors.initials: C
authors.lastname: Kwak
authors.affiliation: Department of Urology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Hyeon Hoe
authors.initials: HH
authors.lastname: Kim
authors.affiliation: Department of Urology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Eunsik
authors.initials: E
authors.lastname: Lee
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Bhumsuk
authors.initials: B
authors.lastname: Keam
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Tae Min
authors.initials: TM
authors.lastname: Kim
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea; Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Dae Seog
authors.initials: DS
authors.lastname: Heo
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Se-Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Pathology, Seoul National University Hospital, Seoul, Korea.
authors.forename: Kyung Chul
authors.initials: KC
authors.lastname: Moon
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D002945:Cisplatin / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004720:Endonucleases / Q000096:biosynthesis*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D012262:Ribonucleoside Diphosphate Reductase; D015996:Survival Rate; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis*; D014571:Urologic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality; D000093542:Gemcitabine
chemical_list: D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D003841:Deoxycytidine; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; C071447:ERCC1 protein, human; D004720:Endonucleases; D002945:Cisplatin; D000093542:Gemcitabine