Poster Presentation 27th Lorne Cancer Conference 2015

Patient-Derived Xenografts Reveal Intraductal Carcinoma of the Prostate is a Prominent Pathology in BRCA2 Mutation Carriers with Prostate Cancer and Correlates with Poor Prognosis (#251)

Renea Taylor 1 2 , Damien Bolton 2 , David Cloustan 3 , Ania Sliwinskic 4 5 6 , Heather Thorne 4 5 , Sally Hunter 5 , Jason Li 5 , Gillian Mitchell 5 7 , Declan Murphy 6 , Mark Frydenberg 2 8 , David Pook 2 8 , John Pedersen 3 , Roxanne Toivanen 2 , Hong Wang 2 , Melissa Papargiris 2 , Gail Risbridger 2
  1. Dept of Physiology, Monash University, Clayton, Victoria, Australia
  2. Prostate Cancer Research Program, Monash Biomedicine Discovery Institute, Dept Anatomy & Developmental Biology, Monash University, Clayton, Victoria, Australia
  3. Tissupath, Mt Waverley, Victoria, Australia
  4. kConFab, Research Department, The Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
  5. Familial Cancer Centre, The Peter MacCallum Centre, East Melbourne, Victoria, Australia
  6. Dept of Urology, Sir Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia
  7. Dept of Oncology, Sir Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia
  8. Dept of Urology, Monash Medical Centre, Monash University, Clayton, Victoria, Australia
Background: Intraductal carcinoma of the prostate (IDC-P) is a distinct clinicpathologic entity associated with aggressive prostate cancer (PCa). PCa patients carrying a BRCA2 germline mutation also 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 (BRCAX). Methods: 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 IDC-P from original and matched PDX specimens to determine genetic integrity. Clinical data for BRCA2 or BRCAX patients were analysed to determine the incidence of IDC-P and association with overall survival using Kaplan-Meier analysis. Results & Limitations: PDX from BRCA2 tumours showed increased incidence of IDC-P compared to sporadic PCa (p = 0.015). WG-CNA analysis of IDCP from matched (original and PDX) BRCA2 tumours had similar genetic profiles. IDC-P was more common in BRCA2 carriers (42%; n = 33) or BRCAX patients (25.8%; n = 62) compared to sporadic PCa cases (9%; n = 32). Survival outcomes demonstrated BRCA2 carriers and BRCAX patients with IDC-P had significantly worse prognosis than BRCA2 carriers and BRCAX patients without IDC-P (HR: 16.9, p = 0.0064 and HR: 3.57, p = 0.0086). Conclusions: PDX’s revealed IDC-P in patients with a germline BRCA2 mutation or BRCAX classification, identifying aggressive tumours with poor survival even when the stage and grade of cancer at diagnosis was similar. Further study to confirm its prognostic significance in sporadic PCa is warranted. Patient Summary: This study showed IDC-P is common in patients with familial PCa and is associated with poor outcomes. This finding impacts on genetic counselling and indicates earlier and multi-modality treatment may be required.