Please use this identifier to cite or link to this item: http://hdl.handle.net/11434/259
Title: 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.
Epworth Authors: Murphy, Declan
Frydenberg, Mark
Bolton, Damien
Other Authors: Rishbridger, Gail
Taylor, Renea
Clouston, David
Sliwinski, Ania
Thorne, Heather
Hunter, Sally
Li, Jason
Mitchell, Gillian
Pook, David
Pedersen, John
Toivanen, Roxanne
Wang, Hong
Papargiris, Melissa
Lawrence, Mitchell
Keywords: Prostate Cancer
Cancer of the Prostate
Prostate Neoplasms
Neoplasms, Prostate
Carcinoma, Intraductal
Prostate Cancer Aggressiveness
BRCA2 Germline Mutations
Familial Prostate Cancer
Intraductal Carcinoma
Pathology
Patient-derived Xenografts
Epworth Research Centre, Epworth Healthcare, Victoria, Australia
Issue Date: Aug-2014
Publisher: Elsevier
Citation: European Urology 2014 Aug 21. pii: S0302-2838(14)00749-0
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.
Description: This study identified that intraductal carcinoma of the prostate is more common in patients with familial prostate cancer than with sporadic cases and was associated with poor outcomes. This negative prognostic indicator affects genetic counselling and patient selection for earlier and multimodality prostate cancer treatment.
URI: http://hdl.handle.net/11434/259
DOI: 10.1016/j.eururo.2014.08.007
PubMed URL: http://www.ncbi.nlm.nih.gov/pubmed/25154392
ISSN: 0090-4295
Journal Title: European Urology
Type: Journal Article
Affiliated Organisations: Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
Department of Physiology, Monash University, Melbourne, Victoria, Australia
Tissupath, Mt. Waverley, Victoria, Australia
kConFab, Research Department, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia
Familial Cancer Centre, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia
Division of Cancer Surgery, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia
Department of Oncology, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia
Bioinformatics, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia
Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia
Department of Urology, Monash Medical Centre, Monash University, Melbourne, Victoria, Australia
Department of Urology, University of Melbourne, Austin Hospital, Melbourne Heidelberg, Victoria, Australia
Type of Clinical Study or Trial: Prospective Cohort Study
Appears in Collections:UroRenal, Vascular

Files in This Item:
There are no files associated with this item.


Items in EKB are protected by copyright, with all rights reserved, unless otherwise indicated.