Patient-derived Xenografts Reveal that Intraductal Carcinoma of the Prostate Is a Prominent Pathology in BRCA2 Mutation Carriers with Prostate Cancer and Correlates with Poor Prognosis

Gail P Risbridger, Renea A Taylor, David Clouston, Ania Sliwinski, Heather J Thorne, Sally M Hunter, Jason Li, Gillian W E Mitchell, Declan G M Murphy, Mark Frydenberg, David William Pook, John S Pedersen, Roxanne Toivanen, Hong Wang, Melissa Papargiris, Mitchell G Lawrence, Damien M Bolton

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Abstract

Background: Intraductal carcinoma of the prostate (IDC-P) is a distinct clinicopathologic entity associated with aggressive prostate cancer (PCa). PCa patients carrying a breast cancer 2, early onset (BRCA2) germline mutation exhibit highly aggressive tumours with poor prognosis. Objective: To investigate the presence and implications of IDC-P in men with a strong family history of PCa who either carry a BRCA2 pathogenic mutation or do not carry the mutation (BRCAX). Design, setting, and participants: Patient-derived xenografts (PDXs) were generated from three germline BRCA2 mutation carriers and one BRCAX patient. Specimens were examined for histologic evidence of IDC-P. Whole-genome copy number analysis (WG-CNA) was performed on IDC-P from a primary and a matched PDX specimen. Outcome measurements and statistical analysis: The incidence of IDC-P and association with overall survival for BRCA2 and BRCAX patients were determined using Kaplan-Meier analysis. Results and limitations: PDXs from BRCA2 tumours showed increased incidence of IDC-P compared with sporadic PCa (p = 0.015). WG-CNA confirmed that the genetic profile of IDC-P from a matched (primary and PDX) BRCA2 tumour was similar. The incidence of IDC-P was significantly increased in BRCA2 carriers (42%, n = 33, p = 0.004) but not in BRCAX patients (25.8%, n = 62, p = 0.102) when both groups were compared with sporadic cases (9%, n = 32). BRCA2 carriers and BRCAX patients with IDC-P had significantly worse overall and PCa-specific survival compared with BRCA2 carriers and BRCAX patients without IDC-P (hazard ratio [HR]: 16.9, p = 0.0064 and HR: 3.57, p = 0.0086, respectively). Conclusions: PDXs revealed IDC-P in patients with germline BRCA2 mutations or BRCAX classification, identifying aggressive tumours with poor survival even when the stage and grade of cancer at diagnosis were similar. Further studies of the prognostic significance of IDC-P in sporadic PCa are warranted. Patient summary: Intraductal carcinoma of the prostate is common in patients with familial prostate cancer and is associated with poor outcomes. This finding affects genetic counselling and identifies patients in whom earlier multimodality treatment may be required. © 2014 European Association of Urology.

Original languageEnglish
Pages (from-to)496 - 503
Number of pages8
JournalEuropean Urology
Volume67
Issue number3
DOIs
Publication statusPublished - 1 Mar 2015

Keywords

  • BRCA2 germline mutations
  • Familial prostate cancer
  • Intraductal carcinoma
  • Pathology
  • Patient-derived xenografts

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