循环肿瘤细胞预测乳腺癌骨转移进展一例

晚期肿瘤的疗效评价目前仍主要依靠影像学,肿瘤血清标志物仅作为参考。然而骨转移灶作为不可测量病灶,评价疗效存在一定困难,以至于临床不易及时发现疾病恶化。基于肿瘤细胞播散理论,检测循环肿瘤细胞（CTC）可发现肿瘤的早期复发转移。本文报告1例CTC升高预测乳腺癌骨转移早期进展并帮助指导临床治疗的病例。     

循环肿瘤细胞在转移性乳腺癌中的表达及其与多种血清肿瘤标志物的关系

目的 探讨转移性乳腺癌的循环肿瘤细胞(CTC)和血清肿瘤标志物(CEA、CA153和CA125)的表达水平以及两者之间的相关性。方法 采用CellSearch自动检测系统检测93例转移性乳腺癌患者开始新治疗前的循环肿瘤细胞(CTC),同时采用电化学发光法检测这些患者血清肿瘤标志物(CEA、CA153和CA125)的表达水平。结果 CTC阳性率为60%(56/93),与患者激素受体的状态、Her-2的状态、既往治疗的线数以及内脏转移无关。CEA的阳性率为56%(52/93),ER或PR阳性的患者CEA的阳性率更高(χ²=4.550,P=0.045),与Her-2的状态、既往治疗的线数以及内脏转移无关;CA153的阳性率为47%(44/93),与患者激素受体的状态、Her-2的状态、既往治疗的线数以及内脏转移无关;CA125的阳性率为41%(38/93);既往治疗大于等于二线的患者CA125的阳性率更高(χ²=4.501,P=0.038),与患者激素受体的状态、Her-2的状态以及是否有内脏转移无关。CTC和CEA之间呈正相关(r=0.296,P=0.004);CTC和CA153之间呈正相关(r=0.286,P=0.005);CTCs和CA125两者之间无相关性(r=0.184,P=0.077)。结论 转移性乳腺癌患者的循环肿瘤细胞(CTC)检出率高,而且与血清肿瘤标志物(CEA和CA153)有明显相关性,提示联合检测转移性乳腺癌的循环肿瘤细胞(CTC)和血清肿瘤标志物(CEA和CA153)可能会对其治疗决策有所帮助,同时CTC有可能成为转移性乳腺癌新的治疗靶点。     

乳腺癌循环肿瘤细胞

循环肿瘤细胞的播散是乳腺癌转移与复发的重要事件.检测循环肿瘤细胞,对判断患者预后、评价治疗效果、监测转移复发、指导治疗等有着重要的临床意义.完善循环肿瘤细胞的检测技术,研究循环肿瘤细胞的生物学特性及其机制,是乳腺癌循环肿瘤细胞研究需要解决的主要难题.目前,乳腺癌循环肿瘤细胞研究在检测技术及其指标的联合应用、低增殖活性循环肿瘤细胞研究等方面均取得了一定进展.     

循环肿瘤细胞及循环肿瘤DNA检测在乳腺癌中的研究进展

乳腺癌是中国女性最常见的癌症,其早期检测、个体化治疗及实时疾病监测一直是科研及临床工作者关注的重点。癌症患者血液中循环肿瘤细胞(CTC)和循环肿瘤DNA(ctDNA)的检测微创、简便,易实时获取信息。目前,有关CTC富集鉴定方法多种多样,CTC及ctDNA检测的敏感度和特异度较前有所提高,未来研究面临的最大挑战为肿瘤细胞特异性标志物的开发以及ctDNA临床意义的研究。CTC及ctDNA在基础研究、检测方法、CTC培养、早期肿瘤检测、个体化治疗及临床预后等方面的研究均有开展。笔者对乳腺癌CTC及ctDNA的研究进展作一总结。     

乳腺癌患者循环肿瘤细胞检测及其临床意义

乳腺癌已被证实是一种全身性的疾病,其发展早期即可出现远处播散和转移,血液中检测出肿瘤细胞即是重要证据.而肿瘤细胞进入外周血即是肿瘤远处转移的前提,是肿瘤转移的主要途径之一.在外周血中检测到肿瘤细胞提示存在肿瘤微转移并有可能进一步发展为远处转移.随着循环肿瘤细胞（circulating tumor cells, CTCs）检测技术的敏感性和特异性不断提高,其在外周血中的含量与乳腺癌的诊断﹑治疗和预后有密切的关系, 这一点已被大多数研究者所证实.本文简要综述了目前对乳腺癌患者的CTCs检测方法以及其对临床的指导意义,并对其临床运用前景进行了展望.     

检测循环肿瘤细胞(CTC)在临床肿瘤诊断和治疗中的作用

有关循环肿瘤细胞的理论已有很长时间。肿瘤转移及复发的过程均是一个循环肿瘤细胞定植生长的级连放大的瀑布反应。目前肿瘤的发现和诊断仍高度依赖于影像学及肿瘤特异性血清标志物的方法,不能及时发现肿瘤的转移和复发。基于肿瘤细胞播散理论,检测循环肿瘤细胞可更早期有效发现肿瘤的早期转移和复发。本文对文献报道的检测循环肿瘤细胞在临床肿瘤诊断和治疗中的作用进行了总结,并与目前经典的标志物和影像学进行了比较。     

液体肿瘤生物指标检测对乳腺癌患者的临床价值

循环肿瘤标志物在乳腺癌中的应用受到越来越多的关注,研究水平已从蛋白质水平深入到基因水平,相应的检测指标则从传统的肿瘤标志物扩展到相对特异的HER-2蛋白质细胞外段、循环肿瘤细胞、循环肿瘤DNA及循环RNA等。作为“液体检测”,循环肿瘤标志物的检测因其实时动态、操作简便、可重复性好等优势,被广泛应用于协助早期诊断、判断预后、预测疗效、监测疾病复发及病情变化等方面。对循环肿瘤标志物的深入研究,有助于实现患者的个体化治疗。     

癌胚抗原、糖类抗原15-3和细胞角蛋白片段19检测对乳腺癌临床应用的价值

 目的　研究血清肿瘤标志物癌胚抗原（CEA）、糖类抗原15-3 （CA15-3）、细胞角蛋白片段19 （CYFRA21-1）联合检测对乳腺癌的诊断及复发监测中的意义。方法　采用电化学发光免疫法检测62例乳腺癌患者、57例乳腺良性病患者及50名健康对照组CEA、CA15-3和CYFRA21-1水平,并计算上述指标联合检测在乳腺癌诊断中的敏感度、特异度、准确度和约登指数（YI）。结果　乳腺癌组3种肿瘤标志物水平均明显高于乳腺良性疾病组和健康对照组（P＜0.01）。临床分期越大3种血清肿瘤标志物水平越高;复发病例中3种肿瘤标志物水平均有不同程度升高。单项检测各种肿瘤标志物以CA15-3的敏感性最高（56.5 %）,CYFRA21-1特异性最好（89.7 %）,但CA15-3和CYFRA21-1的准确度及YI值都不高,分别为71.1 %、0.35和70.5 %、0.37。联合检测较单项检测敏感性、准确性和YI明显提高,3项联合检测敏感度高达88.7 %,特异度90.8 % ,准确度89.9 %,YI为0.80。结论　单项检测对乳腺癌的诊断价值有限,3种血清肿瘤标志物联合检测可显著提高乳腺癌的敏感性和准确性,在术后随访和监测复发中可发挥重要作用。     

早期乳腺癌患者外周血CK19 mRNA阳性循环细胞检测及其临床意义

 目的　探讨早期乳腺癌患者外周血CK19 mRNA阳性细胞检测的临床意义及其预后价值。方法　应用RT-PCR检测50例早期乳腺癌患者、24例良性乳腺病变患者及20名健康体检志愿者外周血有核细胞CK19 mRNA的表达,并根据基因标志物结果随访。结果　早期乳腺癌患者术后辅助治疗前外周血有核细胞CK19 mRNA阳性率40.0 %（20／50）,与良性乳腺疾病患者[12.5 %（3／24）]及健康体检志愿者[5 %（1／20）]比较,差异均有统计学意义（P＝0.018,P＝0.004）;外周血有核细胞CK19 mRNA阳性率与患者年龄、月经状况、TNM分期、肿瘤大小、淋巴结转移状况、病理分化、激素受体状况、Her-2、血清CA153、血清CEA水平异常升高无关（P＞0.05）;20例外周血有核细胞CK19 mRNA阳性的患者中有11例随访期出现转移复发（P＝0.002）,中位无瘤生存期明显缩短（P＝0.007）。结论　CK19 mRNA可以作为循环肿瘤细胞基因标志物。检测CK19 mRNA阳性循环肿瘤细胞,可能作为早期乳腺癌术后判断复发转移的辅助指标。     

乳腺癌相关血清肿瘤标志物的临床研究进展

癌胚抗原(CEA)、糖类抗原(CA)15-3、CA125等血清肿瘤标志物异常表达提示肿瘤的发生风险.CA15-3过表达被认为与乳腺癌的疾病进展有关,不同临床分期乳腺癌患者血清CA15-3的阳性检出率对诊断临床分期有显著优势,灵敏度和特异度均较高.但目前认为,某项血清肿瘤标志物单独检测对乳腺癌的阳性检出率较低,对早期筛查及诊断的意义不大,因此,多主张血清肿瘤标志物联合检测以对乳腺肿瘤进行早期筛查和早期诊断.本文对CEA、CA15-3、CA125等已在临床一定范围内得到应用的肿瘤标志物,以及新发现、潜在可能用于指导乳腺癌临床决策及治疗方案的肿瘤生物标志物与乳腺癌诊断、治疗及预后相关的临床研究进行综述.     

Role of circulating tumor cells and disseminated tumor cells in primary breast cancer

Metastasis remains a main cause of death in patients with breast cancer regardless of improvements in treatment. Prospective clinical studies of this minimal residual disease have shown disseminated tumor cells (DTCs) in bone marrow and circulating tumor cells (CTCs) in peripheral blood, neither of which can be detected by conventional imaging, to be prognostic and predictive markers for responsive treatment in patients with metastatic breast cancer. However, the guideline from the American Society of Clinical Oncology does not recommend measuring CTCs for clinical decisions because of a lack of evidence for an established, sound methodology and with proven clinical relevance. The Southwest Oncology Group trial S0500 to validate the clinical relevance of CTCs for treatment decisions in patients with metastatic breast cancer is ongoing. In patients with primary breast cancer, the low detection rate of CTCs has been overcome by recent advances in technology. Although generally DTCs were more detectable than CTCs and the association between presence of DTCs and poor prognosis has been shown, the invasiveness of sample collection of DTCs from bone marrow is generally hard for patients to accept. In this review, we concentrate on the question of whether we need to consider CTCs and DTCs in the management of primary breast cancer on the basis of the evidence of the clinical relevance of CTCs and DTCs. The promising role of the molecular characterization of CTCs, which does have the potential for being a predictor for tumor behavior and development, is suggested as a new targeting strategy.     

Bone marrow micrometastases and circulating tumor cells: current aspects and future perspectives

Early tumor cell dissemination at the single-cell level can be revealed in patients with breast cancer by using sensitive immunocytochemical and molecular assays. Recent clinical studies involving more than 4000 breast cancer patients demonstrated that the presence of disseminated tumor cells in bone marrow at primary diagnosis is an independent prognostic factor. In addition, various assays for the detection of circulating tumor cells in the peripheral blood have recently been developed and some studies also suggest a potential clinical relevance of this measure. These findings provide the basis for the potential use of disseminated tumor cells in bone marrow or blood as markers for the early assessment of therapeutic response in prospective clinical trials.     

循环肿瘤细胞的异质性在转移性乳腺癌中的作用研究进展

循环肿瘤细胞（CTC）的计数可以预测转移性乳腺癌的预后,但其改善患者预后的能力在临床试验中尚未得到证实。目前研究专注于CTC的分子表征,作为肿瘤组织的“替代物”以非侵入性地方式评估癌症基因组表达及其在治疗过程中的演变。CTC中存在上皮-间质转化过程（EMT）,其特点为上皮标志物的缺失。EMT过程可以存在于侵袭性及耐药性较强的细胞,其计数和表征,能够引起肿瘤的复发和进展,具有较高的临床价值。本文深入探讨循环肿瘤细胞的异质性及在转移性乳腺癌上皮-间质转化过程中的作用。使其成为乳腺癌患者监测转移和预后的常规的检测指标,并有助于明确转移的机制,更有望发现乳腺癌转移治疗的新靶点。     

Recent translational research: circulating tumor cells in breast cancer patients

In breast cancer patients, hematogenous tumor cell dissemination can be detected, even at the single cell level, by applying immunocytochemical and molecular assays. Various methods for the detection of circulating tumor cells in the peripheral blood have been described. Results from recently reported studies suggest that circulating tumor cell levels may serve as a prognostic marker and for the early assessment of therapeutic response in patients with metastatic breast cancer. However, in early-stage breast cancer, the impact of circulating tumor cells is less well established than the presence of disseminated tumor cells in bone marrow; several clinical studies have demonstrated that cells of the latter type are an independent prognostic factor at primary diagnosis. In this article we briefly summarize recent studies examining the presence of circulating tumor cells in the blood and discuss further clinical applications.     

Circulating tumor markers in breast cancer (review)

The clinical application of circulating tumor markers remains a controversial subject in terms of useful methods and correct interpretation of findings. In particular and despite numerous investigations in the field, we do not have as yet specific or highly sensitive biological markers in breast cancer. Nevertheless, many oncologists often utilize circulating tumor markers in various phases of this malignancy to obtain additional information about disease extent and clinical course. For this reason, we have reviewed the present status of the most widely used serum tumor markers in this neoplasm. Both CEA and TPA are well known, but their organ specificity is not related to breast. Among novel biological markers identified by monoclonal antibodies, special attention has been devoted to circulating agents that are recognized by immunoreagents and that were obtained by immunization with breast-derived products. Both CA 15.3 and MCA are now being validated at the clinical level. From the present review it is clear that today we are still far from being able to make the diagnosis of breast cancer on the sole basis of laboratory findings. On the contrary, some of the available markers can be utilized as prognostic indicators of disease extent and treatment response. Their value greatly increases when combined with conventional diagnostic methods that can be prescribed on the basis of abnormal laboratory findings to confirm or rule out disease recurrence.     

Clinical Utility of Serum Tumor Markers and Circulating Tumor Cell Assays in the Treatment of Breast Cancer

Though serum tumor markers and circulating tumor cells (CTCs) have been available to the oncologist for many years, their place in the management of breast cancer remains unclear. Due to issues with sensitivity and specificity, tumor markers are unreliable for the detection of metastases in early stage breast cancer. For patients with metastatic breast cancer without measurable disease (e.g., bone-only disease, pleural effusions, or ascites), it is reasonable to obtain baseline values of serum tumor markers and attempt to correlate them with the first set of scans. In patients with elevated markers at baseline whose tumor marker levels decrease in correlation with an improvement in clinical symptoms, it may be reasonable to use them in conjunction with imaging to help determine whether there is progression of disease. CTCs have been found to hold strong prognostic value for breast cancer in both the early stage and metastatic settings. No large prospective studies to date, however, have shown any predictive value for CTCs and their clinical utility is therefore limited. Whether changing treatment in response to an increase in CTCs without radiologic progression results in improvements in quality of life or survival remains to be seen. CTCs hold great promise in the management of breast cancer and future studies will help delineate their role more appropriately.     

Expected clinical applications of circulating tumor cells in breast cancer

Tumor cell invasion and intravascular filtration lead to the presence of circulating tumor cells (CTCs) in peripheral blood. CTCs have, thus, been counted in patients with cancer to analyze metastatic mechanisms or in the hope of developing clinical applications for diagnosis and therapy; various CTC-related studies have been performed. However, the clinical significance of CTCs remains to be established because of the extremely small number of CTCs in peripheral blood as compared with the number of blood cells. Technical problems (e.g. reproducibility and reliability) in the detection of CTCs also remain to be solved. The use of flow cytometric analysis, which can be performed with tumor-cell markers such as anti-epithelial cell adhesion molecule antibodies and anti-cytokeratin antibodies and non-tumor-cell markers such as anti-CD45 antibodies has enhanced specificity for the detection of tumor cells. The CellSearch System^® can detect 1 CTC in 7.5 mL of peripheral blood, with high reproducibility. Its detection rate and accuracy for CTCs have been confirmed. In the United States, clinical trials have used this system to detect CTCs in patients with metastatic breast cancer, metastatic colorectal cancer, and metastatic prostate cancer, and CTCs have been confirmed to be a useful prognostic factor. This system was also suggested to be useful for monitoring treatment response in patients with metastatic breast cancer and was approved by the United States Food and Drug Administration in 2004. Measuring CTC counts can facilitate the early prediction of treatment response and thereby avoid unnecessary therapy. CTCs may also be a useful biomarker for molecular targeted agents, enabling the identification of patients most likely to respond to a given treatment and facilitating treatment selection. However, the widespread use of CTC monitoring as a routine examination requires a further improvement in measurement sensitivity, the establishment of criteria for quantitative and qualitative evaluations, and additional clear-cut evidence supporting the clinical significance of CTCs. We expect that CTCs will be established to be a new diagnostic and therapeutic index for breast cancer.     

TIMP-1 as a tumor marker in breast cancer--an update

Improvement of the management of breast cancer patients has high priority. In this regard, prognostic stratification needs to be improved in order to ensure proper medical treatment of all patients and furthermore predictors of response to chemotherapy are urgently needed. As new treatment opportunities emerge in the future this need will continue to grow. Thus, the search for molecular markers of prognosis and prediction is ongoing. Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) has been suggested as a marker of both prognosis and response to treatment. Several studies have demonstrated the association between TIMP-1 and prognosis in breast cancer and new studies within this area have focused on the possibility of using blood samples or paraffin embedded tissue instead of tumor tissue extracts for measurements of TIMP-1. Interestingly, recent studies have investigated the association between TIMP-1 and response to treatment showing that TIMP-1 may also carry predictive information on response to treatment. In this regard, results from studies of the molecular functions of TIMP-1 point to a role of TIMP-1 in the inhibition of tumor cell apoptosis as an explanation for the clinical findings. This review gives an update on the ongoing investigation of the potential role of TIMP-1 as a tumor marker in breast cancer. Furthermore, we link the clinical findings with studies of the molecular actions of the TIMP-1 protein, raising hypotheses that may explain why TIMP-1 could play an important role in future management of breast cancer patients.