University of California San Diego, San Diego, California.
Dana-Farber Cancer Institute, Boston, Massachusetts.
Clin Cancer Res. 2021 Jul 1;27(13):3610-3619. doi: 10.1158/1078-0432.CCR-20-4616. Epub 2021 Apr 13.
Enzalutamide is a second-generation androgen receptor (AR) inhibitor that has improved overall survival (OS) in metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients develop resistance. We designed a phase II multicenter study of enzalutamide in metastatic CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving resistance.
Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy and then initiated enzalutamide 160 mg daily. A repeat metastasis biopsy was obtained at radiographic progression from the same site when possible. Blood for circulating tumor cell (CTC) analysis was collected at baseline and progression. The primary objective was to analyze mechanisms of resistance in serial biopsies. Whole-exome sequencing was performed on tissue biopsies. CTC samples underwent RNA sequencing.
A total of 65 patients initiated treatment, of whom 22 (33.8%) had received prior abiraterone. Baseline biopsies were enriched for alterations in (mutations, amplifications) and tumor suppression genes (, and ), which were observed in 73.1% and 92.3% of baseline biopsies, respectively. Progression biopsies revealed increased amplifications (64.7% at progression vs. 53.9% at baseline) and alterations (64.7% at progression vs. 38.5% at baseline). Genomic analysis of baseline and progression CTC samples demonstrated increased AR splice variants, AR-regulated genes, and neuroendocrine markers at progression.
Our results demonstrate that a large proportion of enzalutamide-treated patients have baseline and progression alterations in the AR pathway and tumor suppressor genes. We demonstrate an increased number of alterations post-enzalutamide, highlighting the importance of serial tumor sampling in CRPC.
恩扎卢胺是第二代雄激素受体（AR）抑制剂，可提高转移性去势抵抗性前列腺癌（CRPC）患者的总生存期（OS）。然而，几乎所有患者最终都会产生耐药性。我们设计了一项多中心 II 期恩扎卢胺治疗转移性 CRPC 的研究，纳入了组织和血液生物标志物，以剖析耐药性产生的机制。
符合条件的转移性 CRPC 患者在基线时进行转移灶活检，然后开始每天服用恩扎卢胺 160mg。当可能时，在同一部位出现放射学进展时，获取重复的转移灶活检。在基线和进展时采集循环肿瘤细胞（CTC）分析用血液。主要目的是分析连续活检中的耐药机制。对组织活检进行全外显子组测序。对 CTC 样本进行 RNA 测序。
共有 65 例患者开始接受治疗，其中 22 例（33.8%）曾接受过阿比特龙治疗。基线活检中富集了（突变、扩增）和肿瘤抑制基因（、和）的改变，分别有 73.1%和 92.3%的基线活检存在这些改变。进展活检显示 扩增（进展时为 64.7%，基线时为 53.9%）和 改变（进展时为 64.7%，基线时为 38.5%）增加。基线和进展时 CTC 样本的基因组分析表明，进展时 AR 剪接变体、AR 调控基因和神经内分泌标志物增加。
我们的研究结果表明，相当大比例的恩扎卢胺治疗患者在 AR 通路和肿瘤抑制基因中存在基线和进展时的改变。我们发现在恩扎卢胺治疗后出现了更多的 改变，强调了在 CRPC 中进行连续肿瘤采样的重要性。
