Oral Presentation The Annual Scientific Meeting of the Endocrine Society of Australia and the Society for Reproductive Biology 2014

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 (#92)

Renea Taylor 1 , David Clouston 2 , Ania Sliwinski 3 , Heather Thorne 3 , Sally Hunter 3 , Jason Li 3 , k ConFab 3 , Gillian Mitchell 3 , Declan Murphy 3 , Mark Frydenberg 1 , David Pook 1 , John Pedersen 2 , Roxanne Toivanen 1 , Hong Wang 1 , Melissa Papargiris 1 , Damien Bolton 4 , Gail Risbridger 1
  1. Monash University, Clayton, VIC, Australia
  2. TissuPath, Mt Waverly
  3. Peter MacCallum Cancer Center, Melbourne
  4. Department of Urology, Austin Hospital, Melbourne

Intraductal carcinoma of the prostate (IDC-P) is a distinct clinic-pathologic entity associated with aggressive prostate cancer. Prostate cancer patients carrying a BRCA2 germline mutation also exhibit highly aggressive tumours with poor prognosis. In this study, we investigated the presence and implications of IDC-P in men with a strong family history of prostate cancer, including those with a pathogenic BRCA2 mutation. Patient-derived xenografts (PDXs) were generated from three germline BRCA2 mutation-carriers. Specimens were examined for histologic evidence of IDC-P. Whole Genome Copy Number Analysis (WG-CNA) was performed IDC-P from primary and matched PDX specimens to determine genetic integrity. Clinical data for BRCA2 patients were analysed to determine the incidence of IDC-P and association with overall survival using Kaplan-Meier analysis. PDX from BRCA2 tumours showed increased incidence of IDC-P compared to sporadic prostate cancer (p = 0.015). WG-CNA analysis of IDC-P from matched (primary and PDX) BRCA2 tumours had highly similar genetic profiles. IDC-P was more common in BRCA2 carriers (42%; n = 33) compared to sporadic prostate cancer cases (9%; n = 32). Survival outcomes demonstrated BRCA2 carriers patients with IDC-P had significantly worse prognosis than BRCA2 carriers without IDC-P (HR: 16.9, p = 0.0064). These novel data using PDXs revealed IDC-P in patients with familial prostate cancer possess an aggressive tumour phenotype. This phenotype (ICDP) correlated with poor survival, even when the stage and grade of cancer at diagnosis was similar. This study highlights the utility of laboratory-based models (PDX) to identify novel tumour biology with clinical implications.