循环肿瘤细胞基因表达和血浆 AR 基因拷贝数作为卡巴他赛治疗去势抵抗性前列腺癌患者的生物标志物。
Circulating tumor cell gene expression and plasma AR gene copy number as biomarkers for castration-resistant prostate cancer patients treated with cabazitaxel.
机构信息
Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy.
Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", Meldola, Italy.
出版信息
BMC Med. 2022 Jan 31;20(1):48. doi: 10.1186/s12916-022-02244-0.
BACKGROUND
Cabazitaxel improves overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients progressing after docetaxel. In this prospective study, we evaluated the prognostic role of CTC gene expression on cabazitaxel-treated patients and its association with plasma androgen receptor (AR) copy number (CN).
METHODS
Patients receiving cabazitaxel 20 or 25 mg/sqm for mCRPC were enrolled. Digital PCR was performed to assess plasma AR CN status. CTC enrichment was assessed using the AdnaTest EMT-2/StemCell kit. CTC expression analyses were performed for 17 genes. Data are expressed as hazard ratio (HR) or odds ratio (OR) and 95% CI.
RESULTS
Seventy-four patients were fully evaluable. CTC expression of AR-V7 (HR=2.52, 1.24-5.12, p=0.011), AKR1C3 (HR=2.01, 1.06-3.81, p=0.031), AR (HR=2.70, 1.46-5.01, p=0.002), EPCAM (HR=3.75, 2.10-6.71, p< 0.0001), PSMA (HR=2.09, 1.19-3.66, p=0.01), MDK (HR=3.35, 1.83-6.13, p< 0.0001), and HPRT1 (HR=2.46, 1.44-4.18, p=0.0009) was significantly associated with OS. ALDH1 (OR=5.50, 0.97-31.22, p=0.05), AR (OR=8.71, 2.32-32.25, p=0.001), EPCAM (OR=7.26, 1.47-35.73, p=0.015), PSMA (OR=3.86, 1.10-13.50, p=0.035), MDK (OR=6.84, 1.87-24.98, p=0.004), and HPRT1 (OR=7.41, 1.82-30.19, p=0.005) expression was associated with early PD. AR CN status was significantly correlated with AR-V7 (p=0.05), EPCAM (p=0.02), and MDK (p=0.002) expression. In multivariable model, EPCAM and HPRT1 CTC expression, plasma AR CN gain, ECOG PS=2, and liver metastases and PSA were independently associated with poorer OS. In patients treated with cabazitaxel 20 mg/sqm, median OS was shorter in AR-V7 positive than negative patients (6.6 versus 14 months, HR=3.46, 1.47-8.17], p=0.004).
CONCLUSIONS
Baseline CTC biomarkers may be prognosticators for cabazitaxel-treated mCRPC patients. Cabazitaxel at lower (20 mg/sqm) dose was associated with poorer outcomes in AR-V7 positive patients compared to AR-V7 negative patients in a post hoc subgroup analysis.
TRIAL REGISTRATION
Clinicaltrials.gov NCT03381326 . Retrospectively registered on 18 December 2017.
背景
卡巴他赛可提高转移性去势抵抗性前列腺癌（mCRPC）患者的总生存期（OS），这些患者在接受多西他赛治疗后病情进展。在这项前瞻性研究中，我们评估了 CTC 基因表达对接受卡巴他赛治疗的患者的预后作用及其与血浆雄激素受体（AR）拷贝数（CN）的关系。
方法
招募接受卡巴他赛 20 或 25mg/sqm 治疗 mCRPC 的患者。采用数字 PCR 评估血浆 AR CN 状态。使用 AdnaTest EMT-2/StemCell 试剂盒评估 CTC 富集情况。对 17 个基因进行 CTC 表达分析。数据以危险比（HR）或优势比（OR）和 95%置信区间（CI）表示。
结果
74 例患者可进行全面评估。AR-V7（HR=2.52，1.24-5.12，p=0.011）、AKR1C3（HR=2.01，1.06-3.81，p=0.031）、AR（HR=2.70，1.46-5.01，p=0.002）、EPCAM（HR=3.75，2.10-6.71，p<0.0001）、PSMA（HR=2.09，1.19-3.66，p=0.01）、MDK（HR=3.35，1.83-6.13，p<0.0001）和 HPRT1（HR=2.46，1.44-4.18，p=0.0009）的 CTC 表达与 OS 显著相关。ALDH1（OR=5.50，0.97-31.22，p=0.05）、AR（OR=8.71，2.32-32.25，p=0.001）、EPCAM（OR=7.26，1.47-35.73，p=0.015）、PSMA（OR=3.86，1.10-13.50，p=0.035）、MDK（OR=6.84，1.87-24.98，p=0.004）和 HPRT1（OR=7.41，1.82-30.19，p=0.005）的表达与早期 PD 相关。AR CN 状态与 AR-V7（p=0.05）、EPCAM（p=0.02）和 MDK（p=0.002）的表达显著相关。在多变量模型中，EPCAM 和 HPRT1 CTC 表达、血浆 AR CN 增益、ECOG PS=2 和肝转移和 PSA 是 OS 较差的独立预测因素。在接受卡巴他赛 20mg/sqm 治疗的患者中，AR-V7 阳性患者的中位 OS 短于 AR-V7 阴性患者（6.6 与 14 个月，HR=3.46，1.47-8.17，p=0.004）。
结论
基线 CTC 生物标志物可能是接受卡巴他赛治疗的 mCRPC 患者的预后标志物。在事后亚组分析中，与 AR-V7 阴性患者相比，卡巴他赛较低（20mg/sqm）剂量与 AR-V7 阳性患者的结局较差相关。
试验注册
Clinicaltrials.gov NCT03381326。于 2017 年 12 月 18 日回顾性注册。
Zotero 插件