候选雄激素信号特征可预测转移性去势抵抗性前列腺癌男性患者对醋酸阿比特龙的反应。
A candidate androgen signalling signature predictive of response to abiraterone acetate in men with metastatic castration-resistant prostate cancer.
机构信息
Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Centre, Houston, TX, USA.
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
出版信息
Eur J Cancer. 2020 Mar;127:67-75. doi: 10.1016/j.ejca.2019.12.027. Epub 2020 Jan 24.
BACKGROUND
The unmet need for predictive biomarkers emerged from the unpredictable pattern of response to androgen signalling inhibition in metastatic castration-resistant prostate cancer (mCRPC). Here, we report on the testing of a previously identified candidate androgen signalling signature associated with response to androgen signalling inhibition.
PATIENTS AND METHODS
We report on the outcome of the first module of a phase II trial on abiraterone acetate (AA) followed by combination with dasatinib or sunitinib. Bone marrow biopsies (BMBs) with matched bone marrow aspirate and blood samples were collected at baseline and upon progression. End-points included assessment of a prespecified molecular signature consisting of nuclear androgen receptor (AR) overexpression, cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17) expression, and AR-C-/N terminal expression ratio of ≥0.8 by immunohistochemistry (IHC) in patients with benefit versus primary resistance to AA (i.e. progression within 4 months). Tumour markers also included v-ets avian erythroblastosis virus E26 oncogene homologue (ERG), androgen receptor splice variant (ARV7) by IHC and steroids by liquid chromatography-tandem mass spectrometry.
RESULTS
Of 170 patients accrued from 03/2011 to 02/2015, 44 (26%) were primary resistant to AA. Forty-eight patients had tumour infiltrated BMB at baseline. Pretreatment androgen signalling signature was linked to benefit from AA (p < 0.001). Presence of ERG was associated with benefit (p = 0.05), whereas nuclear ARV7 presence and 20 or more bone lesions at baseline with primary resistance (p = 0.04 and p = 0.0006, respectively).
CONCLUSION
Testing of a prespecified androgen signalling signature was highly supportive of its predictive value in maximal androgen deprivation strategies in mCRPC. Further validation is under way.
TRIAL REGISTRATION
ClinicalTrials.gov NCT01254864.
背景
转移性去势抵抗性前列腺癌（mCRPC）中雄激素信号抑制的反应模式不可预测，因此出现了对预测性生物标志物的未满足需求。在此，我们报告了对先前确定的与雄激素信号抑制反应相关的候选雄激素信号特征的检测结果。
患者和方法
我们报告了醋酸阿比特龙（AA）后继以达沙替尼或舒尼替尼联合治疗的 II 期试验第一模块的结果。基线和进展时采集骨髓活检（BMB）与骨髓抽吸和血液样本。终点包括评估预先指定的分子特征，该特征由核雄激素受体（AR）过表达、细胞色素 P450 家族 17 亚家族 A 多肽 1（CYP17）表达和免疫组织化学（IHC）中 AR-C/N 端表达比≥0.8 组成，用于对 AA 有获益与原发性耐药的患者（即 4 个月内进展）。肿瘤标志物还包括 v-ets 禽红细胞白血病病毒 E26 癌基因同源物（ERG）、雄激素受体剪接变体（ARV7）通过 IHC 和通过液相色谱-串联质谱法检测类固醇。
结果
从 2011 年 3 月至 2015 年 2 月共入组 170 例患者，其中 44 例（26%）对 AA 原发性耐药。48 例患者基线时有肿瘤浸润的 BMB。预处理雄激素信号特征与 AA 获益相关（p<0.001）。存在 ERG 与获益相关（p=0.05），而核 ARV7 存在和基线时 20 个或更多骨病变与原发性耐药相关（p=0.04 和 p=0.0006）。
结论
对预先指定的雄激素信号特征的检测高度支持其在 mCRPC 最大雄激素剥夺策略中的预测价值。正在进行进一步验证。
试验注册
ClinicalTrials.gov NCT01254864。
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