患者衍生异种移植物揭示，前列腺内导管癌是携带 BRCA2 突变的前列腺癌患者的突出病理学特征，与不良预后相关。

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.

机构信息

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.

出版信息

Eur Urol. 2015 Mar;67(3):496-503. doi: 10.1016/j.eururo.2014.08.007. Epub 2014 Aug 22.

DOI:10.1016/j.eururo.2014.08.007

PMID:25154392

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.

摘要

背景

前列腺导管内癌（IDC-P）是一种与侵袭性前列腺癌（PCa）相关的独特临床病理实体。携带乳腺癌 2 号基因，早发（BRCA2）种系突变的 PCa 患者表现出侵袭性更强、预后更差的肿瘤。

目的

研究在具有强烈 PCa 家族史的男性中，携带 BRCA2 种系突变（BRCA2M）或不携带突变（BRCAX）的情况下，IDC-P 的存在及其意义。

设计、地点和参与者：从 3 名种系 BRCA2 突变携带者和 1 名 BRCAX 患者中生成患者衍生的异种移植物（PDX）。检查组织学证据以确定 IDC-P 的存在。对来自原发性和匹配 PDX 标本的 IDC-P 进行全基因组拷贝数分析（WG-CNA）。

观察指标和统计分析

使用 Kaplan-Meier 分析确定 BRCA2 和 BRCAX 患者中 IDC-P 的发生率及其与总生存率的关系。

结果和局限性

与散发性 PCa 相比，BRCA2 肿瘤的 PDX 显示出更高的 IDC-P 发生率（p=0.015）。WG-CNA 证实，匹配（原发性和 PDX）BRCA2 肿瘤的 IDC-P 的遗传特征相似。当将 BRCA2 携带者（42%，n=33，p=0.004）与 BRCAX 患者（25.8%，n=62，p=0.102）与散发性病例（9%，n=32）进行比较时，IDC-P 的发生率显着增加。与无 IDC-P 的 BRCA2 携带者和 BRCAX 患者相比，有 IDC-P 的 BRCA2 携带者和 BRCAX 患者的总生存率和 PCa 特异性生存率均显着降低（风险比 [HR]：16.9，p=0.0064 和 HR：3.57，p=0.0086）。