Elsevier

European Urology

Volume 67, Issue 3, March 2015, Pages 496-503
European Urology

Platinum Priority – Prostate Cancer
Editorial by Rodolfo Montironi, Liang Cheng, Antonio Lopez-Beltran, Marina Scarpelli and Francesco Montorsi on pp. 504–507 of this issue
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

https://doi.org/10.1016/j.eururo.2014.08.007Get rights and content

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.

Introduction

Breast cancer 1, early onset (BRCA1) and breast cancer 2, early onset (BRCA2) are tumour suppressor genes associated with increased risk of developing breast cancer, ovarian cancer, and prostate cancer (PCa) [1], [2]. BRCA2 mutation carriers and men from high-risk breast cancer families with no identified BRCA mutation (BRCAX) have an increased risk of PCa and a higher rate of PCa-specific mortality with high Gleason score (GS) disease being more prevalent in BRCA2-associated PCa [3], [4], [5], [6], [7], [8], [9], [10].

The mechanisms by which BRCA2 mutations contribute to highly aggressive PCa are not completely understood. Serum prostate-specific antigen (PSA) levels, GS, and clinical staging are combined to predict PCa outcomes using D’Amico risk grading [11], [12]. These discriminators are less predictive of outcome in BRCA2 carriers with PCa, and they fail to predict the poorer outcomes in BRCA2 carriers compared with noncarriers, even when matched for GS [6], [13].

Intraductal carcinoma of the prostate (IDC-P) is a distinct clinicopathology associated with aggressive PCa and predicts poor treatment response [14], [15]. It is unknown whether IDC-P has a functional role in disease progression or is simply a marker of aggressiveness. This study investigated the significance of IDC-P in men with PCa from breast cancer–prone families with either a BRCA2 mutation or no BRCA1/BRCA2 mutation (BRCAX).

Section snippets

Patients and methods

PCa cases were identified from 1600 families recruited into the Kathleen Cunningham Consortium for Research into Familial Breast Cancer (kConFab), the Australian and New Zealand consortium for families at high risk of breast cancer [16]. Inclusion in kConFab requires a strong multicase family history of breast and/or ovarian cancer or a germline mutation in a breast cancer predisposition gene such as BRCA1 or BRCA2 (full recruitment criteria are available at www.kconfab.org).

Male kConFab

Results

PDXs were established from three BRCA2 patients and one BRCAX patient. Unexpectedly, pathologic examination of the PDXs from the BRCA patients revealed prominent areas of IDC-P, in addition to typical adenocarcinoma. IDC-P foci in the PDX tumours showed a solid or solid/cribriform architecture, marked cytologic atypia, areas of central necrosis, ERG- and AMACR-positive tumour cells, and peripheral p63-positive basal cells, all consistent with hallmarks of IDC-P (Fig. 1A and 1B).

IDC-P was

Discussion

IDC-P has been reported as an important predictor of invasive disease and a prognostic variable in men with PCa [15], [20], [22], [25], [26], [27], [28], [29]. It is unknown whether IDC-P has an additional role in tumour progression, but studies of high-risk populations suggest that IDC-P has potential as a useful clinical marker [30]. This study reports for the first time the high prevalence of IDC-P in BRCA2 and BRCAX patients with PCa and its association with poor overall survival.

Prostate

Conclusions

Given the association between IDC-P and poor outcome in BRCA2 carriers and BRCAX patients, greater recognition and reporting of IDC-P in prostate specimens is required to improve treatment strategies and clinical outcomes. The development of a default recognition–exclusion template for pathologists to report IDC-P may be justified. This template might identify patients who may benefit from immediate multimodality treatment with curative intent rather than active surveillance. If active

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  • Cited by (0)

    These authors contributed equally to this work.

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