基于 RB1、PTEN 和 TP53 的转移性激素敏感性前列腺癌患者预后基因表达特征的建立和独立验证。

Development and Independent Validation of a Prognostic Gene Expression Signature Based on RB1, PTEN, and TP53 in Metastatic Hormone-sensitive Prostate Cancer Patients.

机构信息

Translational Genomics and Targeted Therapeutics in Solid Tumors Lab, Fundació de Recerca Clínic Barcelona - Institut d'Investigacions Biomèdiques August Pi i Sunyer (FRCB-IDIBAPS), Barcelona, Spain.

出版信息

Eur Urol Oncol. 2024 Aug;7(4):954-964. doi: 10.1016/j.euo.2023.12.012. Epub 2024 Mar 1.

DOI:10.1016/j.euo.2023.12.012

PMID:38429210

Abstract

BACKGROUND

Androgen deprivation therapy (ADT) with docetaxel (D) and/or antiandrogen receptor therapies (ARTs) are the standard therapies in metastatic hormone-sensitive prostate cancer (mHSPC). Alterations in the tumor suppressor genes (TSGs) RB1, PTEN, and TP53 are associated with an aggressive evolution and treatment resistance in castration-resistant prostate cancer (CRPC).

OBJECTIVE

To study the clinical implications of TSG mRNA expression in mHSPC patients.

DESIGN, SETTING, AND PARTICIPANTS: This is a multicenter retrospective biomarker study in mHSPC patients. TSG status was defined when two or more out of the three TSGs presented low RNA expression by nCounter in formalin-fixed paraffin-embedded samples and TSG for the remaining cases. The microarray data from the CHAARTED trial were analyzed as an independent validation cohort.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS

Molecular data were correlated with CRPC-free survival (CRPC-FS) and overall survival (OS) by the Kaplan-Meier method and multivariate Cox analysis.

RESULTS AND LIMITATIONS

A total of 226 patients were included, of whom 218 were eligible: 93 were treated with ADT and 125 with ADT + D; 75.7% presented de novo stage IV and 67.9% high-volume disease. TSG (19.2%) was independently correlated with shorter CRPC-FS (hazard ratio [HR] 1.8, p = 0.002) and OS (HR 2, p = 0.002). In the CHAARTED trial, TSG was independently correlated with lower CRPC-FS (HR 2.2, p = 0.02); no differences in clinical outcomes according to treatment were observed in TSG patients, while a significant benefit was observed for ADT + D in the TSG group for CRPC-FS (HR 0.4, p < 0.001) and OS (HR 0.4, p = 0.001). However, no interaction was observed between TSG signature and treatment in either series. Study limitations are the retrospective design, small sample size, and lack of inclusion of patients treated with ADT + ART.

CONCLUSIONS

TSG expression correlates with adverse outcomes in patients with mHSPC. The investigation of new therapeutic strategies in these patients is warranted.

PATIENT SUMMARY

The low RNA expression of tumor suppressor genes in the tumors is correlated with adverse outcomes in patients with metastatic hormone-sensitive prostate cancer.

摘要

背景

多西他赛（Docetaxel，D）联合去势治疗或抗雄激素受体治疗（Antiandrogen receptor therapies，ARTs）是转移性去势敏感性前列腺癌（metastatic hormone-sensitive prostate cancer，mHSPC）的标准治疗方法。肿瘤抑制基因（tumor suppressor genes，TSGs）RB1、PTEN 和 TP53 的改变与去势抵抗性前列腺癌（castration-resistant prostate cancer，CRPC）的侵袭性演变和治疗耐药有关。

目的

研究 TSG mRNA 表达在 mHSPC 患者中的临床意义。

设计、地点和参与者：这是一项 mHSPC 患者多中心回顾性生物标志物研究。当三个 TSG 中有两个或更多的 TSG 通过 nCounter 在福尔马林固定石蜡包埋样本中呈现低 RNA 表达时，确定 TSG 状态，其余病例的 TSG 则确定为阳性。CHAARTED 试验的微阵列数据被分析为独立验证队列。

观察指标和统计分析

通过 Kaplan-Meier 法和多变量 Cox 分析，将分子数据与 CRPC 无进展生存期（CRPC-free survival，CRPC-FS）和总生存期（overall survival，OS）相关联。

结果和局限性

共纳入 226 例患者，其中 218 例符合条件：93 例接受去势治疗，125 例接受去势+多西他赛治疗；75.7%为初诊 IV 期，67.9%为大体积疾病。TSG（19.2%）与较短的 CRPC-FS（风险比[hazard ratio，HR]1.8，p=0.002）和 OS（HR 2，p=0.002）独立相关。在 CHAARTED 试验中，TSG 与较低的 CRPC-FS 独立相关（HR 2.2，p=0.02）；在 TSG 患者中，根据治疗方案观察到的临床结局无差异，但在 TSG 组中，去势+多西他赛治疗在 CRPC-FS（HR 0.4，p<0.001）和 OS（HR 0.4，p=0.001）方面具有显著获益。然而，在两个系列中，均未观察到 TSG 特征与治疗之间的相互作用。研究的局限性在于回顾性设计、样本量小以及缺乏接受去势+ART 治疗的患者。