摘要目的 探讨循环肿瘤细胞(CTCs)分型对初诊高转移负荷激素敏感性前列腺癌(mCSPC)患者激素敏感时间的预测作用.方法 2015年9月至2017年2月收集复旦大学附属肿瘤医院收治的初诊为mCSPC患者的资料.纳入标准:年龄18 ～ 85岁;前列腺穿刺活检组织或细胞病理学确诊为前列腺腺癌;入组前未接受包括去势、抗雄、放疗、化疗或者原发灶手术等治疗;有影像学检查(PET-CT、ECT或MRI等)结果证实为高转移负荷(≥5处骨转移灶或淋巴结转移灶,且至少有1处骨转移灶;或有内脏转移).排除标准:既往接受过去势和/或抗雄药物治疗、化疗,接受过原发灶手术或放疗等;合并其他恶性肿瘤病史者.本研究同时入组既往无恶性肿瘤病史的健康男性志愿者作为对照组.mCSPC患者入组后接受戈舍瑞林(3.6 mg皮下注射,每月1次)+比卡鲁胺(50 mg口服,每天1次)治疗.采用CanPatrol系统计数患者外周血CTC数量,并根据CTC表面上皮型标志物上皮细胞黏附分子(EpCAM)和细胞角蛋白(CK) 8/CK18/CK19,以及间质型标志物波形蛋白和扭曲蛋白的表达情况将CTC分型.研究终点为患者进展为去势抵抗性前列腺癌(CRPC).Kaplan-Meier法分析患者生存曲线,采用Cox比例风险回归模型进行单因素和多因素分析.结果 本研究共纳入108例患者.中位年龄68岁(51 ～ 85岁).中位PSA为196.2 ng/ml(5.8 ～5 011.9 ng/ml).中位血红蛋白132g/L(9 ～172g/L),中位碱性磷酸酶123.5 U/L(23.0 ～2 519.2 U/L),中位乳酸脱氢酶179 U/L(49 ～630 U/L).美国东部肿瘤协作组(ECOG)评分0～1分94例(87.0％),2分14例(13.0％).穿刺Gleason评分6～7分20例(18.5％),≥8分88例(81.5％).转移灶数量5～ 10个67例(62.0％),＞10个41例(38.0％).伴内脏转移6例(5.6％),四肢骨转移30例(27.8％).患者中位CTC计数为4个(0～35个).间质型CTC阳性58例(53.7％),间质型CTC阴性(包括CTC阴性、上皮型CTC阳性和混合型CTC阳性)50例.CTC分型与患者年龄、基线PSA、Gleason评分、碱性磷酸酶等各临床指标无相关性(P＞0.05).对照组10例,中位年龄26岁(20 ～ 31岁),均未检测到CTC.108例患者中位随访24个月(18 ～32个月),90例(83.3％)进展为CRPC.间质型CTC阳性和阴性患者的中位激素敏感时间分别为(10.5±1.4)个月和(14.0±3.4)个月,差异有统计学意义(P＜0.001).单因素生存分析结果显示,CTC分型(HR=1.647,P=0.003)、转移灶数量(HR=1.624,P=0.025)和四肢骨转移(HR=1.706,P=0.019)是激素敏感时间的影响因素.多因素分析结果显示,间质型CTC阳性(HR=1.562,95％CI1.123 ～2.174,P=0.008)是初诊高转移负荷CSPC患者激素敏感时间的独立预后不良因素.结论 CTC分型能够预测初诊高转移负荷CSPC患者激素敏感时间,基线间质型CTC阳性患者更易进展至CRPC.

abstractsObjective To explore the predictive value of circulating tumor cells (CTCs) characterization for time to castration resistance of newly diagnosed high volume metastatic castration sensitive prostate cancer (mCSPC) patients.Methods Newly diagnosed high volume mCSPC patients were prospectively enrolled in this study from September 2015 to February 2017.The inclusion criteria include that the patients'age should be between 18 to 85 years old.The Prostate cancer should be diagnosed by biopsy or cytopathology.No endocrinological therapy,radiative therapy or chemotherapy was used before the study.High-volume metastatic lesion was confirmed by imaging.Those patients who accepted previous endocrinological therapy,radiative therapy or chemotherapy were excluded in this study.Those patients combined with concomitant tumor were also excluded.The health males were enrolled in the control group.All patients received androgen deprivation therapy (ADT) with goserelin plus bicalutamide (goserelin 3.6 mg subcutaneous injection,once a month plus bicalutamide 50mg orally,once a day).CanPatrol system was used to count CTCs in peripheral blood of patients and characterize CTCs based on expressions of epithelial markers(EpCAM and CK8/18/19) and mesenchymal markers (vimentin and twist).Primary endpoint was time to castration resistance.Survival analysis was conducted using Kaplan-Meier method and log-rank test was used to assess the difference of survival between groups,and univariate and multivariate analyses of prognostic factors were conducted using the Cox proportional hazards model.Results A total of 108 newly diagnosed high volume mCSPC patients were enrolled in this study.The median age of enrolled patients was 68 years old (ranging 51-85 years old),and median PSA was 196.2 ng/ml (ranging 5.8-5 011.9 ng/ml) . The median level of hemoglobin was 32 g/L(ranging 9-172 g/L).The median level of LDH was 179 U/L(ranging 49-630 U/L).The ECOG scores was 0-1 score in 94 cases(87.0％),2 scores in 14 cases (13.0％).The Gleason scores was 6-7 in 20 cases (18.5％) and more than 8 in 88 cases (81.5％).All patients had bone metastatic lesions,among which 41 (38.0％) patients had more than 10 metastatic lesions and 6 (5.6％) patients with visceral metastasis,30 (27.8％) patients with limb bone metastasis.The median CTCs count was four,and ranging 0-35.Mesenchymal CTCs positive and negative (negative included CTCs negative,epithelial CTCs positive and biophenotypic CTCs positive) patients were 58 (53.7％) and 50,respectively.There was no correlation between CTCs characterization with age,baseline PSA,Gleason score,ALP and other clinical parameters (P ＞ 0.05).In control group,the mean age was 26 years old (ranging 20-31 years old).No CTCs were detected among those people.After a median follow-up of 24 months (ranging 18-32 months),90 patients (83.3％) progressed to castration resistant prostate cancer (CRPC).The median time to CRPC for patients of mesenchymal CTCs positive and negative was (10.5 ± 1.4) and (14.0 ± 3.4) months,respectively (P ＜ 0.001).Univariate analysis revealed CTCs characterization(HR =1.647,P =0.003),the number of metastatic lesions (HR =1.624,P =0.025) and limb bone metastasis(HR =1.706,P =0.019) were prognostic factors of time to CRPC;further multivariate analysis showed that only baseline mesenchymal CTCs positive (HR =1.562,P =0.008) was independent prognostic factors of unfavorable time to CRPC.Conclusions CTCs characterization can predict time to CRPC of newly diagnosed high volume mCSPC patients receiving ADT,and patients of baseline mesenchymal CTCs positive are more likely to progress to CRPC.