title: Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer.
abstract: OBJECTIVE
  To analyze the baseline clinicopathologic characteristics of prostate tumors with germline BRCA1 and BRCA2 (BRCA1/2) mutations and the prognostic value of those mutations on prostate cancer (PCa) outcomes.
  
  
  METHODS
  This study analyzed the tumor features and outcomes of 2,019 patients with PCa (18 BRCA1 carriers, 61 BRCA2 carriers, and 1,940 noncarriers). The Kaplan-Meier method and Cox regression analysis were used to evaluate the associations between BRCA1/2 status and other PCa prognostic factors with overall survival (OS), cause-specific OS (CSS), CSS in localized PCa (CSS_M0), metastasis-free survival (MFS), and CSS from metastasis (CSS_M1).
  
  
  RESULTS
  PCa with germline BRCA1/2 mutations were more frequently associated with Gleason ≥ 8 (P = .00003), T3/T4 stage (P = .003), nodal involvement (P = .00005), and metastases at diagnosis (P = .005) than PCa in noncarriers. CSS was significantly longer in noncarriers than in carriers (15.7 v 8.6 years, multivariable analyses [MVA] P = .015; hazard ratio [HR] = 1.8). For localized PCa, 5-year CSS and MFS were significantly higher in noncarriers (96% v 82%; MVA P = .01; HR = 2.6%; and 93% v 77%; MVA P = .009; HR = 2.7, respectively). Subgroup analyses confirmed the poor outcomes in BRCA2 patients, whereas the role of BRCA1 was not well defined due to the limited size and follow-up in this subgroup.
  
  
  CONCLUSIONS
  Our results confirm that BRCA1/2 mutations confer a more aggressive PCa phenotype with a higher probability of nodal involvement and distant metastasis. BRCA mutations are associated with poor survival outcomes and this should be considered for tailoring clinical management of these patients.
authors.affiliation: Spanish National Cancer Research Centre 3, Melchor Fernández Almagro, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Castro
authors.forename: Chee
authors.initials: C
authors.lastname: Goh
authors.forename: David
authors.initials: D
authors.lastname: Olmos
authors.forename: Ed
authors.initials: E
authors.lastname: Saunders
authors.forename: Daniel
authors.initials: D
authors.lastname: Leongamornlert
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Tymrakiewicz
authors.forename: Nadiya
authors.initials: N
authors.lastname: Mahmud
authors.forename: Tokhir
authors.initials: T
authors.lastname: Dadaev
authors.forename: Koveela
authors.initials: K
authors.lastname: Govindasami
authors.forename: Michelle
authors.initials: M
authors.lastname: Guy
authors.forename: Emma
authors.initials: E
authors.lastname: Sawyer
authors.forename: Rosemary
authors.initials: R
authors.lastname: Wilkinson
authors.forename: Audrey
authors.initials: A
authors.lastname: Ardern-Jones
authors.forename: Steve
authors.initials: S
authors.lastname: Ellis
authors.forename: Debra
authors.initials: D
authors.lastname: Frost
authors.forename: Susan
authors.initials: S
authors.lastname: Peock
authors.forename: D Gareth
authors.initials: DG
authors.lastname: Evans
authors.forename: Marc
authors.initials: M
authors.lastname: Tischkowitz
authors.forename: Trevor
authors.initials: T
authors.lastname: Cole
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Davidson
authors.forename: Diana
authors.initials: D
authors.lastname: Eccles
authors.forename: Carole
authors.initials: C
authors.lastname: Brewer
authors.forename: Fiona
authors.initials: F
authors.lastname: Douglas
authors.forename: Mary E
authors.initials: ME
authors.lastname: Porteous
authors.forename: Alan
authors.initials: A
authors.lastname: Donaldson
authors.forename: Huw
authors.initials: H
authors.lastname: Dorkins
authors.forename: Louise
authors.initials: L
authors.lastname: Izatt
authors.forename: Jackie
authors.initials: J
authors.lastname: Cook
authors.forename: Shirley
authors.initials: S
authors.lastname: Hodgson
authors.forename: M John
authors.initials: MJ
authors.lastname: Kennedy
authors.forename: Lucy E
authors.initials: LE
authors.lastname: Side
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Eason
authors.forename: Alex
authors.initials: A
authors.lastname: Murray
authors.forename: Antonis C
authors.initials: AC
authors.lastname: Antoniou
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Easton
authors.forename: Zsofia
authors.initials: Z
authors.lastname: Kote-Jarai
authors.forename: Rosalind
authors.initials: R
authors.lastname: Eeles
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001918:Brachytherapy; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D053208:Kaplan-Meier Estimate; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D049451:Nomograms; D010166:Palliative Care / Q000379:methods; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy; D018714:Radiotherapy, Adjuvant; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors
chemical_list: D018931:Antineoplastic Agents, Hormonal; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human