title: Clinical Evaluation of Cisplatin Sensitivity of Germline Polymorphisms in Neoadjuvant Chemotherapy for Urothelial Cancer.
abstract: Level 1 evidence has demonstrated increased overall survival with cisplatin-based neoadjuvant chemotherapy for patients with muscle-invasive urothelial cancer. Usage remains low, however, in part because neoadjuvant chemotherapy will not be effective for every patient. To identify the patients most likely to benefit, we evaluated germline pharmacogenomic markers for association with neoadjuvant chemotherapy sensitivity in 2 large cohorts of patients with urothelial cancer.
  
  
  
  Patients receiving neoadjuvant cisplatin-based chemotherapy for muscle-invasive urothelial cancer were eligible. Nine germline single nucleotide polymorphisms (SNPs) potentially conferring platinum sensitivity were tested for an association with a complete pathologic response to neoadjuvant chemotherapy (pT0) or elimination of muscle-invasive cancer (<pT2).
  
  
  
  The data from 205 patients were analyzed-59 patients were included in the discovery set and 146 in an independent replication cohort-from 3 institutions. The stage pT0 (26%) and < pT2 (50%) rates were consistent across the discovery and replication populations. Using a multivariate recessive genetic model, rs244898 in RARS (odds ratio, 6.8; 95% confidence interval, 1.8-28.9; P = .006) and rs7937567 in GALNTL4 (odds ratio, 4.8; 95% confidence interval, 1.1-22.6; P = .04) were associated with pT0 in the discovery set. Despite these large effects, neither were associated with achievement of pT0 in the replication set. A third SNP, rs10964552, was associated with stage < pT2 in the discovery set but also failed to replicate.
  
  
  
  Germline SNPs previously associated with platinum sensitivity were not associated with the neoadjuvant chemotherapy response in a large replication cohort of patients with urothelial cancer. These results emphasize the need for replication when evaluating pharmacogenomic markers and demonstrate that multi-institutional efforts are feasible and will be necessary to achieve advances in urothelial cancer pharmacogenomics.
authors.affiliation: The University of Chicago, Chicago, IL. Electronic address: podonnel@medicine.bsd.uchicago.edu.
authors.forename: Peter H
authors.initials: PH
authors.lastname: O'Donnell
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Shaheen
authors.initials: S
authors.lastname: Alanee
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Stratton
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Ilana R
authors.initials: IR
authors.lastname: Garcia-Grossman
authors.affiliation: The University of Chicago, Chicago, IL.
authors.forename: Hongyuan
authors.initials: H
authors.lastname: Cao
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Irina
authors.initials: I
authors.lastname: Ostrovnaya
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Plimack
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Christopher
authors.initials: C
authors.lastname: Manschreck
authors.affiliation: The University of Chicago, Chicago, IL.
authors.forename: Cory
authors.initials: C
authors.lastname: Ganshert
authors.affiliation: The University of Chicago, Chicago, IL.
authors.forename: Norm D
authors.initials: ND
authors.lastname: Smith
authors.affiliation: The University of Chicago, Chicago, IL.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Steinberg
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Joseph
authors.initials: J
authors.lastname: Vijai
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.affiliation: The University of Chicago, Chicago, IL.
authors.forename: Walter M
authors.initials: WM
authors.lastname: Stadler
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, NY.
authors.forename: Dean F
authors.initials: DF
authors.lastname: Bajorin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage* / Q000494:pharmacology; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D000071184:Pharmacogenomic Variants; D020641:Polymorphism, Single Nucleotide; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin
keywords: Bladder cancer; Pharmacogenomics; Precision medicine; Treatment response prediction