title: DNA Damage Response and Repair Gene Alterations Are Associated with Improved Survival in Patients with Platinum-Treated Advanced Urothelial Carcinoma.
abstract: Purpose:Platinum-based chemotherapy remains the standard treatment for advanced urothelial carcinoma by inducing DNA damage. We hypothesize that somatic alterations in DNA damage response and repair (DDR) genes are associated with improved sensitivity to platinum-based chemotherapy.Experimental Design:Patients with diagnosis of locally advanced and metastatic urothelial carcinoma treated with platinum-based chemotherapy who had exon sequencing with the Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) assay were identified. Patients were dichotomized based on the presence/absence of alterations in a panel of 34 DDR genes. DDR alteration status was correlated with clinical outcomes and disease features.Results:One hundred patients were identified, of which 47 harbored alterations in DDR genes. Patients with DDR alterations had improved progression-free survival (9.3 vs. 6.0 months, log-rankP= 0.007) and overall survival (23.7 vs. 13.0 months, log-rankP= 0.006). DDR alterations were also associated with higher number mutations and copy-number alterations. A trend toward positive correlation between DDR status and nodal metastases and inverse correlation with visceral metastases were observed. Different DDR pathways also suggested variable impact on clinical outcomes.Conclusions:Somatic DDR alteration is associated with improved clinical outcomes in platinum-treated patients with advanced urothelial carcinoma. Once validated, it can improve patient selection for clinical practice and future study enrollment.Clin Cancer Res; 23(14); 3610-8. ©2017 AACR.
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Min Yuen
authors.initials: MY
authors.lastname: Teo
authors.affiliation: Department of Medical Oncology, Cork University Hospital, Cork, Ireland.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Bambury
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Zabor
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Emmet
authors.initials: E
authors.lastname: Jordan
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Hikmat
authors.initials: H
authors.lastname: Al-Ahmadie
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Mariel E
authors.initials: ME
authors.lastname: Boyd
authors.affiliation: Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Nancy
authors.initials: N
authors.lastname: Bouvier
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Mullane
authors.affiliation: Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Eugene K
authors.initials: EK
authors.lastname: Cha
authors.affiliation: Medical Oncology Service, National Cancer Institute, Bethesda, Maryland.
authors.forename: Nitin
authors.initials: N
authors.lastname: Roper
authors.affiliation: Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Irina
authors.initials: I
authors.lastname: Ostrovnaya
authors.affiliation: Developmental Therapeutics, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: David M
authors.initials: DM
authors.lastname: Hyman
authors.affiliation: Urology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Bernard H
authors.initials: BH
authors.lastname: Bochner
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arcila
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: David B
authors.initials: DB
authors.lastname: Solit
authors.affiliation: Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Berger
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Dean F
authors.initials: DF
authors.lastname: Bajorin
authors.affiliation: Bladder Cancer Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Bellmunt
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Gopakumar
authors.initials: G
authors.lastname: Iyer
authors.affiliation: Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York. rosenbj1@mskcc.org.
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: Rosenberg
mesh_terms: D000368:Aged; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics*; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D010984:Platinum / Q000008:administration & dosage* / Q000009:adverse effects; D019459:Urothelium / Q000187:drug effects / Q000473:pathology
chemical_list: D010984:Platinum