Gail P Risbridger1, Renea A Taylor2, David Clouston3, Ania Sliwinski4, Heather Thorne5, Sally Hunter6, Jason Li7, Gillian Mitchell5, Declan Murphy8, Mark Frydenberg9, David Pook1, John Pedersen10, Roxanne Toivanen1, Hong Wang1, Melissa Papargiris1, Mitchell G Lawrence1, Damien M Bolton11. 1. Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia. 2. Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia; Department of Physiology, Monash University, Melbourne, Victoria, Australia. 3. Tissupath, Mt. Waverley, Victoria, Australia. 4. 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. 5. 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; Department of Oncology, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia. 6. 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. 7. Department of Oncology, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia; Bioinformatics, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia. 8. Division of Cancer Surgery, Peter MacCallum Cancer Centre, University of Melbourne, East Melbourne, Victoria, Australia; Epworth Research Centre, Epworth Healthcare, Victoria, Australia. 9. 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. 10. Prostate Cancer Research Group, Department of Anatomy and Developmental Biology, Monash University, Melbourne, Victoria, Australia; Tissupath, Mt. Waverley, Victoria, Australia. 11. Department of Urology, University of Melbourne, Austin Hospital, Melbourne Heidelberg, Victoria, Australia. Electronic address: damienmb@unimelb.edu.au.
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.
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 BRCAXpatient. 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 BRCAXpatients were determined using Kaplan-Meier analysis. RESULTS AND LIMITATIONS: PDXs from BRCA2tumours 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) BRCA2tumour was similar. The incidence of IDC-P was significantly increased in BRCA2 carriers (42%, n=33, p=0.004) but not in BRCAXpatients (25.8%, n=62, p=0.102) when both groups were compared with sporadic cases (9%, n=32). BRCA2 carriers and BRCAXpatients with IDC-P had significantly worse overall and PCa-specific survival compared with BRCA2 carriers and BRCAXpatients 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.
Authors: Pedro Isaacsson Velho; John L Silberstein; Mark C Markowski; Jun Luo; Tamara L Lotan; William B Isaacs; Emmanuel S Antonarakis Journal: Prostate Date: 2018-01-25 Impact factor: 4.104
Authors: Rong Na; S Lilly Zheng; Misop Han; Hongjie Yu; Deke Jiang; Sameep Shah; Charles M Ewing; Liti Zhang; Kristian Novakovic; Jacqueline Petkewicz; Kamalakar Gulukota; Donald L Helseth; Margo Quinn; Elizabeth Humphries; Kathleen E Wiley; Sarah D Isaacs; Yishuo Wu; Xu Liu; Ning Zhang; Chi-Hsiung Wang; Janardan Khandekar; Peter J Hulick; Daniel H Shevrin; Kathleen A Cooney; Zhoujun Shen; Alan W Partin; H Ballentine Carter; Michael A Carducci; Mario A Eisenberger; Sam R Denmeade; Michael McGuire; Patrick C Walsh; Brian T Helfand; Charles B Brendler; Qiang Ding; Jianfeng Xu; William B Isaacs Journal: Eur Urol Date: 2016-12-15 Impact factor: 20.096
Authors: Tamara L Lotan; Harsimar B Kaur; Abdullah M Alharbi; Colin C Pritchard; Jonathan I Epstein Journal: Histopathology Date: 2019-04-01 Impact factor: 5.087
Authors: Mitchell G Lawrence; Daisuke Obinata; Shahneen Sandhu; Luke A Selth; Stephen Q Wong; Laura H Porter; Natalie Lister; David Pook; Carmel J Pezaro; David L Goode; Richard J Rebello; Ashlee K Clark; Melissa Papargiris; Jenna Van Gramberg; Adrienne R Hanson; Patricia Banks; Hong Wang; Birunthi Niranjan; Shivakumar Keerthikumar; Shelley Hedwards; Alisee Huglo; Rendong Yang; Christine Henzler; Yingming Li; Fernando Lopez-Campos; Elena Castro; Roxanne Toivanen; Arun Azad; Damien Bolton; Jeremy Goad; Jeremy Grummet; Laurence Harewood; John Kourambas; Nathan Lawrentschuk; Daniel Moon; Declan G Murphy; Shomik Sengupta; Ross Snow; Heather Thorne; Catherine Mitchell; John Pedersen; David Clouston; Sam Norden; Andrew Ryan; Scott M Dehm; Wayne D Tilley; Richard B Pearson; Ross D Hannan; Mark Frydenberg; Luc Furic; Renea A Taylor; Gail P Risbridger Journal: Eur Urol Date: 2018-07-23 Impact factor: 20.096