title: Defects in DNA Repair Genes Predict Response to Neoadjuvant Cisplatin-based Chemotherapy in Muscle-invasive Bladder Cancer.
abstract: BACKGROUND
  Cisplatin-based neoadjuvant chemotherapy (NAC) before cystectomy is the standard of care for muscle-invasive bladder cancer (MIBC), with 25-50% of patients expected to achieve a pathologic response. Validated biomarkers predictive of response are currently lacking.
  
  
  OBJECTIVE
  To discover and validate biomarkers predictive of response to NAC for MIBC.
  
  
  METHODS
  Pretreatment MIBC samples prospectively collected from patients treated in two separate clinical trials of cisplatin-based NAC provided the discovery and validation sets. DNA from pretreatment tumor tissue was sequenced for all coding exons of 287 cancer-related genes and was analyzed for base substitutions, indels, copy number alterations, and selected rearrangements in a Clinical Laboratory Improvements Amendments-certified laboratory.
  
  
  METHODS
  The mean number of variants and variant status for each gene were correlated with response. Variant data from the discovery cohort were used to create a classification tree to discriminate responders from nonresponders. The resulting decision rule was then tested in the independent validation set.
  
  
  CONCLUSIONS
  Patients with a pathologic complete response had more alterations than those with residual tumor in both the discovery (p=0.024) and validation (p=0.018) sets. In the discovery set, alteration in one or more of the three DNA repair genes ATM, RB1, and FANCC predicted pathologic response (p<0.001; 87% sensitivity, 100% specificity) and better overall survival (p=0.007). This test remained predictive for pathologic response in the validation set (p=0.033), with a trend towards better overall survival (p=0.055). These results require further validation in additional sample sets.
  
  
  CONCLUSIONS
  Genomic alterations in the DNA repair-associated genes ATM, RB1, and FANCC predict response and clinical benefit after cisplatin-based chemotherapy for MIBC. The results suggest that defective DNA repair renders tumors sensitive to cisplatin.
  
  
  RESULTS
  Chemotherapy given before bladder removal (cystectomy) improves the chance of cure for some but not all patients with muscle-invasive bladder cancer. We found a set of genetic mutations that when present in tumor tissue predict benefit from neoadjuvant chemotherapy, suggesting that testing before chemotherapy may help in selecting patients for whom this approach is recommended.
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA. Electronic address: elizabeth.plimack@fccc.edu.
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Plimack
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Roland L
authors.initials: RL
authors.lastname: Dunbrack
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Brennan
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Andrake
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Ilya G
authors.initials: IG
authors.lastname: Serebriiskii
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Slifker
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Alpaugh
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Essel
authors.initials: E
authors.lastname: Dulaimi
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.
authors.forename: Norma
authors.initials: N
authors.lastname: Palma
authors.affiliation: Thomas Jefferson University Hospital, Philadelphia, PA, USA.
authors.forename: Jean
authors.initials: J
authors.lastname: Hoffman-Censits
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Marijo
authors.initials: M
authors.lastname: Bilusic
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Yu-Ning
authors.initials: YN
authors.lastname: Wong
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kutikov
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Rosalia
authors.initials: R
authors.lastname: Viterbo
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Greenberg
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: David Y T
authors.initials: DY
authors.lastname: Chen
authors.affiliation: Thomas Jefferson University Hospital, Philadelphia, PA, USA.
authors.forename: Costas D
authors.initials: CD
authors.lastname: Lallas
authors.affiliation: Thomas Jefferson University Hospital, Philadelphia, PA, USA.
authors.forename: Edouard J
authors.initials: EJ
authors.lastname: Trabulsi
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Yelensky
authors.affiliation: MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: McConkey
authors.affiliation: Foundation Medicine Inc., Cambridge, MA, USA.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Miller
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Erica A
authors.initials: EA
authors.lastname: Golemis
authors.affiliation: Fox Chase Cancer Center, Philadelphia, PA, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Ross
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002945:Cisplatin / Q000627:therapeutic use*; D004260:DNA Repair; D005260:Female; D005819:Genetic Markers; D006801:Humans; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009361:Neoplasm Invasiveness; D011379:Prognosis; D011446:Prospective Studies; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D005819:Genetic Markers; D002945:Cisplatin
keywords: ATM; Biomarkers; Bladder cancer; Cisplatin resistance; Cisplatin sensitivity; DNA repair; FANCC; Neoadjuvant chemotherapy; RB1; Urothelial carcinoma