ctDNA在转移性去势抵抗性前列腺癌诊断中的应用现状

转移性去势抵抗性前列腺癌（metastatic castration-resistant prostate cancer,mCRPC）是不可治愈的,严重威胁着男性患者的健康,也是人类恶性肿瘤治疗的一个重要难题。循环肿瘤DNA（circulating tumor DNA,ctDNA）是一种非侵入性、可重复的评估肿瘤基因组的工具,具有全面了解恶性肿瘤的潜力,在mCRPC中也进行了深入研究。本文将对ctDNA在mCRPC中的检测情况,以及用于mCRPC患者监测及对耐药性机制等相关研究现状进行综述,并提出对未来可能有参考价值的研究方向。      

去势抵抗性前列腺癌的药物治疗现状

雄激素剥夺疗法(ADT)一直是晚期前列腺癌的代表性疗法。当前列腺癌进展为去势抵抗性前列腺癌(CRPC)时,ADT的抗性也随之出现。目前,多西他赛是首个被美国食品药品监督管理局(FDA)批准用于CRPC的细胞毒性化疗药物。另外,还有阿比特龙、恩杂鲁胺等药物也获得FDA批准,且这些药物都显示出良好的生存获益。本文对这些疗法的临床试验和生存获益进行了回顾,并对这一领域的新兴药物进行了讨论。本综述将对CRPC的药物治疗现状进行陈述,并为临床用药提供参考。     

甲磺酸阿帕替尼靶向治疗转移性去势抵抗性前列腺癌的临床疗效观察

  目的  评价甲磺酸阿帕替尼单药靶向治疗常规治疗失败的转移性去势抵抗性前列腺癌（metastatic castration-resistant prostatecancer,mCRPC）的近期疗效和不良反应。  方法  收集天津医科大学第二医院2016年6月至2017年12月收治的25例常规治疗失败的mCRPC患者临床资料,观察口服甲磺酸阿帕替尼后的影像学检查,根据最新修订的实体瘤疗效评价标准（m-RECIST）、癌痛评分和前列腺特异性抗原（prostate specific antigen,PSA）的变化,回顾性分析阿帕替尼靶向治疗4个疗程（平均约112 d）后患者的近期疗效,并对靶向治疗后出现的不良反应进行初步分析。  结果  25例患者平均发病年龄72（53~81）岁,病理类型均为腺癌,除3例失访,无完全缓解（complete response,CR）,部分缓解（povtial response,PR）11例（44%）,疾病稳定（stable disease,SD）8例（32%）,疾病进展（progresive disease,PD）3例（12%）。客观缓解率（objective remission rate,ORR）为44%,疾病控制率（disease control rate,DCR）为76%。25例患者治疗中出现一系列不良反应,其中乏力22例（88%）、胃肠道反应15例（60%）,血压升高7例（28%）,手足综合征6例（24%）,头晕不适、蛋白尿等其他不良反应,经对症处理后好转。  结论  甲磺酸阿帕替尼治疗常规治疗失败的mCRPC近期疗效满意,治疗过程中不良反应的发生率较高,但多为轻中度反应,需要积极对症处理。今后仍需进一步探索该药治疗mCRPC的机制,为更多患者寻求更为有效的治疗策略。      

去势抵抗性前列腺癌精准医学研究的探索*

我国前列腺癌发病率呈逐年上升趋势,且大多数前列腺癌患者就诊时已处于中晚期,虽然内分泌治疗可使多数患者的病情在一定程度上能得到控制和改善,但其中绝大多数患者发展为去势抵抗性前列腺癌（castration resistant prostate cancer ,CRPC）。 此类患者预后极差,治疗颇为棘手,因此迫切需要新的治疗策略。精准医学能够根据每位患者的基因特征指导临床个体化治疗。本文就CRPC发病机制和靶向治疗药物的研发、指导个体化治疗的临床试验进行综述,以总结和探讨CRPC精准医学研究的进展。     

去势抵抗性前列腺癌药物治疗现状与进展

前列腺癌发病率、死亡率逐年升高,是肿瘤防治最受关注的恶性肿瘤之一。去势抵抗性前列腺癌(castration-resistant prostate cancer,CRPC)患者的规范化药物治疗是提高患者生存时间、改善生存质量的关键方法。本文将就近年来有关CRPC药物治疗的现状及最新进展进行综述。     

多西他赛再挑战治疗转移性去势抵抗性前列腺癌的疗效及预后因素

目的 评价多西他赛再挑战治疗一线多西他赛治疗有效的转移性去势抵抗性前列腺癌（mCRPC）患者的疗效，并分析预后因素。方法 回顾性分析120例mCRPC患者的临床资料，观察终点为第一序列多西他赛化疗后前列腺特异性抗原无疾病进展生存期（PSA PFS）和多西他赛再挑战后前列腺特异性抗原无疾病进展生存期（Rechallenge PSA PFS）以及mCRPC患者总生存期（OS）。采用Cox单因素和多因素回归模型对患者PSA PFS、Rechallenge PSA PFS和OS相关的预后因素进行分析。结果 中位随访时间32.73（13.27~98.56）月，30例（25%）患者仍存活。中位PSA PFS 13.89（7.67~39.00）月，中位Rechallenge PSA PFS 5.29（1.25~20.00）月，中位OS 27.13（12.40~60.50）月。多因素回归分析显示：第一序列多西他赛化疗与多西他赛再挑战之间的治疗间歇期（>6月vs.≤6月）与患者的PSA PFS显著相关，对多西他赛再挑战治疗反应性（获得部分反应vs.未获得部分反应）与Rechallenge PSA PFS显著相关，mCRPC患者就诊时基础血清PSA值及对多西他赛再挑战治疗反应性（获得部分反应vs.未获得部分反应）与OS显著相关。结论 多西他赛在一线使用多西他赛有效的mCRPC患者中再次使用疗效尚可，可作为此类患者后期治疗的一种选择。     

PARP抑制剂治疗转移性去势抵抗性前列腺癌的机制及其临床研究进展

多聚腺苷二磷酸核糖聚合酶（PARP）抑制剂是治疗转移性去势抵抗性前列腺癌（mCRPC）的新型靶向药物,其对DNA损伤修复基因突变的mCRPC患者具有较高的药物敏感性,多项临床试验结果显示,PARP抑制剂单一疗法及联合疗法在mCRPC患者中具有明显优势,有望为mCRPC患者个体化、精准化治疗带来希望。然而,PARP抑制剂治疗仍有许多问题需纳入考虑,如安全性、耐药性等。对PARP抑制剂在mCRPC中的作用机制及相关临床研究现状进行讨论,可为mCRPC患者提供新的治疗思路。     

转移性去势抵抗性前列腺癌化疗后预后的影响因素

目的探讨采用多西紫杉醇化疗的转移性去势抵抗性前列腺癌(metastatic castration-resistant prostate cancer,MCRPC)患者预后影响因素。方法以转移性去势抵抗性前列腺癌患者46例作为观察对象,记录患者化疗前年龄、Gleason评分、前列腺特异抗原(prostate-specific antigen,PSA)值、血常规等基线情况及激素敏感时间。结果患者总生存时间为3~45个月,平均生存期为(21.34±2.13)个月,中位生存时间为19.36个月;Cox回归结果提示,Gleason评分、血红蛋白水平、激素敏感时间与患者生存时间相关,RR值分别为1.782、2.363和2.012,且P<0.05。结论多西他赛化疗前Gleason评分、血红蛋白浓度及激素敏感时间,是转移性去势抵抗性前列腺癌患者的预后因素。     

个体化多肽疫苗在去势抵抗性前列腺癌免疫治疗中应用的研究进展

[摘要] 个体化多肽疫苗（personalized peptide vaccines,PPVs）是指根据肿瘤患者的个体遗传基因结构和功能差异,从一系列候选多肽中选出至多４种与人类白细胞抗原A1 亚型（HLA-A1）匹配的多肽,制作成的肿瘤疫苗。与常规多肽疫苗相比较,PPVs能诱导更强大和更快捷的抗肿瘤免疫力。现有临床研究结果显示,PPVs 在去势抵抗性前列腺癌(castration-resistant prostate cancer,CRPC)免疫治疗中具有良好的应用前景,可明显改善无进展生存期和总体生存期。目前,PPVs仍处于临床研究阶段,与真正的临床应用尚存在一定距离,对于治疗对象的选择、疗效的评估以及联合用药的价值等问题均有待进一步的探索。     

去势抵抗性前列腺癌的治疗进展*

去势抵抗性前列腺癌是一种致死性疾病,进展快,常伴随着转移,预后极差,死亡率接近100% ,患者中位生存时间少于20个月,是前列腺癌治疗的热点和难题,其发生发展机制尚不明确。近些年来涌现出许多治疗去势抵抗性前列腺癌的新方法,包括新型雄激素受体拮抗剂、免疫治疗、紫杉烷类化疗药物、抗血管生成药物、放射性核素、骨靶向药物以及各疗法联合应用等,改善了患者的生存期。本文就去势抵抗性前列腺癌的治疗进展进行综述。     

Systemic therapy and novel agents for metastatic castration resistant prostate cancer

Treatment for metastatic castration resistant prostate cancer (CRPC) represents a critical need. While docetaxel-based chemotherapy has been shown to extend life, relieve pain, and improve the quality of life expanded treatment options are necessary. No standard second line therapy exists and secondary hormonal manipulations before and after docetaxel offer marginal benefits. The increased understanding of the mechanisms of progressive castration resistant prostate cancer has translated into an increasing pipeline of novel therapies such as vaccines, monoclonal antibodies, bone-targeted drugs, antisense oligonucleotides, anti-angiogenic drugs, small molecule receptor tyrosine kinase inhibitors and more specific targets of the androgen receptor. The future treatment for the most advanced prostate cancer patients is encouraging with broadened clinical benefit.     

Building a hit list for the fight against metastatic castration resistant prostate cancer

Identification of genetic alterations in Metastatic Castration Resistant Prostate Cancer (mCRPC) may provide scientists and clinicians with a list of new targets for drug research and development. Recently published in Cell, Robinson et al. present the first look at genetic data from mCRPC lesions gathered over multiple years and from many institutions.     

Developing imaging strategies for castration resistant prostate cancer

Recent advances in the understanding of castrate-resistant prostate cancer (CRPC) have lead to a growing number of experimental therapies, many of which are directed against the androgen-receptor (AR) signaling axis. These advances generate the need for reliable molecular imaging biomarkers to non-invasively determine efficacy, and to better guide treatment selection of these promising AR-targeted drugs. Methods. We draw on our own experience, supplemented by review of the current literature, to discuss the systematic development of imaging biomarkers for use in the context of CRPC, with a focus on bone scintigraphy, F-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET) and PET imaging of the AR signaling axis. Results. The roadmap to biomarker development mandates rigorous standardization and analytic validation of an assay before it can be qualified successfully for use in an appropriate clinical context. The Prostate Cancer Working Group 2 (PCWG2) criteria for "radiographic" progression by bone scintigraphy serve as a paradigm of this process. Implemented by the Prostate Cancer Clinical Trials Consortium (PCCTC), these consensus criteria may ultimately enable the co-development of more potent and versatile molecular imaging biomarkers. Purported to be superior to single-photon bone scanning, the added value of Na(18)F-PET for imaging of bone metastases is still uncertain. FDG-PET already plays an integral role in the management of many diseases, but requires further evaluation before being qualified in the context of CRPC. PET tracers that probe the AR signaling axis, such as (18)F-FDHT and (89)Zr-591, are now under development as pharmacodynamic markers, and as markers of efficacy, in tandem with FDG-PET. Semi-automated analysis programs for facilitating PET interpretation may serve as a valuable tool to help navigate the biomarker roadmap. Conclusions. Molecular imaging strategies, particularly those that probe the AR signaling axis, have the potential to accelerate drug development in CRPC. The development and use of analytically valid imaging biomarkers will increase the likelihood of clinical qualification, and ultimately lead to improved patient outcomes.     

Estradiol suppresses tissue androgens and prostate cancer growth in castration resistant prostate cancer

Background  

Estrogens suppress tumor growth in prostate cancer which progresses despite anorchid serum androgen levels, termed castration resistant prostate cancers (CRPC), although the mechanisms are unclear. We hypothesize that estrogen inhibits CRPC in anorchid animals by suppressing tumoral androgens, an effect independent of the estrogen receptor.     

去势抵抗性前列腺癌化疗耐药机制的研究进展

前列腺癌的发病率和死亡率逐年上升,去势治疗是中晚期前列腺癌的最主要治疗方法,但去势抵抗性前列腺癌为临床治疗难点,化疗虽为后续主要治疗手段,但易出现耐药。最新研究表明,去势抵抗性前列腺癌患者化疗后再使用抗雄激素药物能提高总生存率。本文就近年来去势抵抗性前列腺癌化疗耐药相关机制做一综述,探讨雄激素受体、自噬、JAK/STAT3信号通路在去势抵抗性前列腺癌发生化疗耐药过程中所发挥的调控作用。     

Maximal androgen blockade versus castration alone in patients with metastatic prostate cancer

Maximum androgen blockade （MAB）, consisting of an antiandrogen plus either a luteinizing hormone- releasing hormone agonist （LHRHA） or orchiectomy, is a standard care for patients with prostate cancer. Although, clinical trial results have been equivocal, none has shown a significant advantage in favor of MAB over castration alone in metastatic prostate cancer and MAB has been the subject of considerable controversy. The aim of this study was to compare MAB （orchiectomy or LHRHA＂Goserelin＂） and anti-androgen ＂Bicalutamide＂ with castration alone （orchiectomy or LHRHA） in previ- ously untreated metastatic prostate cancer patients. Methods： Hundred eligible patients with adequate performance status and adequate hematologic, hepatic and renal functions were included. MAB arm, fifty patients underwent castration either surgically by orchiectomy or medically by receiving Goserelin （3.6 rag） depot, which was injected subcutaneously every 28 days plus bicalutamide 50 mg once daily. Castration alone arm, fifty patients underwent castration alone either surgically by orchiectomy or medically by receiving Goserelin （3.6 mg） depot. Results： During the period from January 2011 to January 2013, with a median follow up of 18 months （range 6 to 24 months）, there were eight deaths （16%）, in MAB arm and ten deaths （20%） in castration alone arm. At three months, there were 35 patients （70%） with prostate specific antigen （PSA） normalization （-〈 4 mg/dL） in MAB arm versus 17 patients （34%） with PSA normalization in castration alone arm （P = 0.001）. The median progression free survival （PFS） times were 22.18 months （95% CI, 19.7 to 24.2 months） for MAB arm versus 22 months in castration alone arm （95% CI, 18 to 25.9 months; P = 0.045）. The survival rates for MAB arm were 82% at 18 months and 70.6% at 24 months versus 78.7% at 18 months and 75.1% at 24 months in castration alone arm （P 〉 0.05）. The median overall survival （OS） was not reached i     

Molecular alterations and emerging targets in castration resistant prostate cancer

Prostate cancer is the most common malignancy in Western Europe, of which approximately 10–20% presents with advanced or metastatic disease. Initial response with androgen deprivation therapy is almost universal, but progression to castration resistant prostate cancer (CRPC), an incurable disease, occurs in approximately 2–3 years.In recent years, the novel taxane cabazitaxel, the hormonal agents abiraterone and enzalutamide, the immunotherapeutic agent sipuleucel-T and the radiopharmaceutical radium-223 have been shown to prolong survival in large randomised trials, thus widely increasing the therapeutic armamentarium against the disease. Despite these advances, the median survival in the first-line setting of metastatic castration-resistant prostate cancer (mCRPC) is still up to 25 months and in the post-docetaxel setting is about 15–18 months.There is an urgent need for the development of biomarkers of treatment response, and for a deeper understanding of tumour heterogeneity and the molecular biology underlying the disease. In this review, we attempt to provide insight into the novel molecular targets showing promise in clinical trials.     

Tpl2 induces castration resistant prostate cancer progression and metastasis

Progression to metastatic castration resistant prostate cancer (CRPC) is the major lethal pathway of prostate cancer (PC). Herein, we demonstrated that tumor progression locus 2 (Tpl2) kinase is the fundamental molecule provoking progression and metastasis of CRPC. Tpl2 upregulates CXCR4 and focal adhesion kinase (FAK) to activate CXCL12/CXCR4 and FAK/Akt signalling pathway. Consequently, epithelial–mesenchymal transition (EMT) and stemness of androgen depletion independent (ADI) PC cells are induced, which is dependent on the kinase activity of Tpl2. In vitro, proliferation, clonogenicity, migration, invasion and chemoresistance of ADI PC cells were enhanced by Tpl2. In vivo, Tpl2 overexpression and downregulation showed significant stimulatory and inhibitory effects on tumorigenic and metastatic potential of ADI PC cells, respectively. Moreover, the prognostic effects of Tpl2 and expressional correlation between Tpl2 and EMT‐related molecules/CXCR4 were validated in clinical PC databases. Since Tpl2 exerts metastatic progression promoting activities in CRPC, Tpl2 could serve as a novel therapeutic target for metastatic CRPC.     

多西他赛联合雄激素剥夺治疗高肿瘤负荷移性激素敏感性前列腺癌的疗效及不良反应

目的 比较多西他赛联合雄激素剥夺治疗(ADT)高肿瘤负荷移性激素敏感性前列腺癌(mHSPC)的疗效及不良反应.方法 依据治疗方式不同将154例高肿瘤负荷mHSPC患者分为联合组(n=101)和对照组(n=53),联合组患者给予多西他赛+ADT治疗,对照组患者给予单纯ADT治疗.随访4.0～85.0个月,观察记录两组患者前列腺特异性抗原(PSA)-无进展生存期(PFS)、影像学无进展生存期(rPFS)、总生存期(OS)、不良反应发生情况.结果 接受多西他赛+ADT治疗的联合组高肿瘤负荷mHSPC患者的中位PSA-PFS、中位OS分别为19个月、未到达,均明显长于对照组患者的9个月、30个月(P﹤0.01);联合组患者的中位rPFS为20个月,与对照组患者的17个月无明显差异.治疗7个月时,联合组PSA水平降至0.2 ng/ml的患者比例为49.50％(50/101),明显高于对照组患者的15.09％(8/53)(P﹤0.01).101例联合组患者中,2例患者的不良反应信息缺失,其余99例患者发生中性粒细胞减少和胃肠反应较为常见,发生率分别为34.34％和24.24％,总3～4级化疗相关不良反应发生率为14.14％(14/99),整体不良反应较轻,经对症治疗容易控制,无相关死亡不良事件.结论 多西他赛联合ADT治疗高肿瘤负荷mHSPC的疗效明显优于单独ADT治疗,7个月时PSA更易降至0.2 ng/ml,安全性良好.