与转移性去势抵抗性前列腺癌患者对阿比特龙联合泼尼松或恩扎卢胺治疗反应相关的基于血液的基因表达特征。

Blood-based gene expression signature associated with metastatic castrate-resistant prostate cancer patient response to abiraterone plus prednisone or enzalutamide.

机构信息

Division of Hematology/Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Department of Radiation Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

出版信息

Prostate Cancer Prostatic Dis. 2021 Jun;24(2):448-456. doi: 10.1038/s41391-020-00295-z. Epub 2020 Oct 2.

DOI:10.1038/s41391-020-00295-z

PMID:33009489

Abstract

BACKGROUND

Precision medicine approaches for managing patients with metastatic castrate-resistant prostate cancer (mCRPC) are lacking. Non-invasive approaches for molecular monitoring of disease are urgently needed, especially for patients suffering from bone metastases for whom tissue biopsy is challenging. Here we utilized baseline blood samples to identify mCRPC patients most likely to benefit from abiraterone plus prednisone (AAP) or enzalutamide.

METHODS

Baseline blood samples were collected for circulating tumor cell (CTC) enumeration and qPCR-based gene expression analysis from 51 men with mCRPC beginning treatment with abiraterone or enzalutamide.

RESULTS

Of 51 patients (median age 68 years [51-82]), 22 received AAP (abiraterone 1000 mg/day plus prednisone 10 mg/day) and 29 received enzalutamide (160 mg/day). The cohort was randomly divided into training (n = 37) and test (n = 14) sets. Baseline clinical variables (Gleason score, PSA, testosterone, and hemoglobin), CTC count, and qPCR-based gene expression data for 141 genes/isoforms in CTC-enriched blood were analyzed with respect to overall survival (OS). Genes with expression most associated with OS included MSLN, ARG2, FGF8, KLK3, ESRP2, NPR3, CCND1, and WNT5A. Using a Cox-elastic net model for our test set, the 8-gene expression signature had a c-index of 0.87 (95% CI [0.80, 0.94]) and was more strongly associated with OS than clinical variables or CTC count alone, or a combination of the three variables. For patients with a low-risk vs. high-risk gene expression signature, median OS was not reached vs. 18 months, respectively (HR 5.32 [1.91-14.80], p = 0.001). For the subset of 41 patients for whom progression-free survival (PFS) data was available, the median PFS for patients with a low-risk vs high-risk gene expression signature was 20 vs. 5 months, respectively (HR 2.95 [1.46-5.98], p = 0.003).

CONCLUSIONS

If validated in a larger prospective study, this test may predict patients most likely to benefit from second-generation antiandrogen therapy.

摘要

背景

目前缺乏针对转移性去势抵抗性前列腺癌（mCRPC）患者的精准医学方法。迫切需要用于疾病分子监测的非侵入性方法，特别是对于那些因骨转移而进行组织活检具有挑战性的患者。在这里，我们利用基线血液样本来识别最有可能从阿比特龙加泼尼松（AAP）或恩扎鲁胺中获益的 mCRPC 患者。

方法

对 51 名开始接受阿比特龙或恩扎鲁胺治疗的 mCRPC 男性患者的基线血液样本进行循环肿瘤细胞（CTC）计数和基于 qPCR 的基因表达分析。

结果

51 名患者（中位年龄 68 岁[51-82]）中，22 名接受 AAP（阿比特龙 1000mg/天加泼尼松 10mg/天）治疗，29 名接受恩扎鲁胺（160mg/天）治疗。该队列被随机分为训练（n=37）和测试（n=14）组。基于总生存期（OS），分析了基线临床变量（Gleason 评分、PSA、睾酮和血红蛋白）、CTC 计数以及 CTC 富集血液中 141 个基因/同种型的基于 qPCR 的基因表达数据。与 OS 最相关的基因包括 MSLN、ARG2、FGF8、KLK3、ESRP2、NPR3、CCND1 和 WNT5A。在我们的测试集中，使用 Cox 弹性网络模型，8 个基因表达特征的 c 指数为 0.87（95%CI[0.80, 0.94]），与 OS 的相关性强于临床变量或 CTC 计数，或三个变量的组合。对于低风险与高风险基因表达特征的患者，中位 OS 分别为未达到与 18 个月（HR 5.32[1.91-14.80]，p=0.001）。对于 41 名有进展无进展生存（PFS）数据的患者亚组，低风险与高风险基因表达特征患者的中位 PFS 分别为 20 个月与 5 个月（HR 2.95[1.46-5.98]，p=0.003）。