血清肿瘤标志物预测乳腺癌骨转移的价值

目的探讨血清肿瘤标志物预测乳腺癌骨转移的临床价值。方法应用化学发光免疫检测技术检测174例乳腺癌患者血清CA153、CA125、CEA、FER等四种肿瘤标志物,同时应用SPECT对所有患者行全身骨扫描检查,以明确有无骨转移。结果174例患者中55例临床诊断为乳腺癌骨转移。CA153、CA125、CEA、FER对诊断骨转移的阳性预测价值分别为68.0%(34/50),70.0%(14/20),88.9%(8/9),53.8%(14/26),阴性预测价值分别为86.2%(106/123),89.0%(130/146),73.2%(115/157),75.9%(85/112)。一种以上标志物同时阳性或阴性者,其阳性或阴性预测价值增加。结论CA153、CA125、CEA、FER具有预测乳腺癌骨转移的临床价值,联合检测CA153、CA125、CEA、FER能提高其预测乳腺癌骨转移的准确性。     

白细胞介素-11结缔组织生长因子对乳腺癌骨转移的诊断价值分析

目的:研究白细胞介素-11（IL- 11）和结缔组织生长因子（CTGF）对乳腺癌的诊断价值,探索新的乳腺癌早期诊断的标志物。方法:对180 例经病理证实的乳腺癌及45例其他癌骨转移患者的外周血标本进行研究,以20例健康女性外周血标本作对照,应用酶联免疫法定量检测血中IL- 11与CTGF的含量。结果:IL- 11在乳腺癌骨转移组、未发生骨转移组与正常对照组之间差异均有统计学意义（P<0.05）,在乳腺癌骨转移组明显升高,而CTGF在各组间比较差异无统计学意义（P>0.05）。 两两进行比较发现IL- 11在乳腺癌骨转移组明显升高（P<0.05）,但在乳腺癌未发生骨转移组与健康对照组比较差异无统计学意义（P>0.05）。IL- 11在乳腺癌骨转移中的水平与其他肿瘤骨转移的表达水平相比差异有统计学意义（P<0.05）。 IL- 11与乳腺癌骨转移患者的年龄、骨痛程度及骨转移程度密切相关（P<0.05）。 结论:IL- 11的定量检测有助于乳腺癌骨转移的诊断,有望成为乳腺癌骨转移的血清标志物。      

骨代谢标志物及其在转移性骨癌中的表达和临床应用

骨转移在晚期肿瘤患者中约占25％～85％，及时和有效的治疗有赖于骨转移状态的临床评估和疗效的监测。现介绍常用骨代谢标志物的临床生化特点、检测方法、在骨转移的诊断和早期诊断中的应用及其在骨转移状态监测和疗效评估中的应用，并提出需要进一步研究解决的问题。     

乳腺癌肿瘤标志物新的研究进展

目前乳腺癌已成为危害女性健康的第一大恶性肿瘤, 且发病率呈逐年递增趋势, 其早期诊断、治疗及预后成为当下研究的热点。乳腺癌肿瘤标志物对于其早期诊断、个体化治疗及预后均具有重要的临床实践指导意义。分子生物学的不断发展, 为乳腺癌肿瘤标志物的基础与临床研究奠定了良好的基础。近年来, 乳腺癌的诊断治疗手段逐渐增多, 肿瘤标志物的应用也不断受到青睐, 经典的肿瘤标志物已不足以更好的指导临床实践, 因此不断有新的肿瘤标志物出现。为了解乳腺肿瘤标志物在乳腺癌诊治中的重要作用及其相关最新研究, 本文结合国内外最新研究报道, 对乳腺肿瘤标志物新的研究进展做一简要综述。      

Dickkopf-1与骨转移癌

 研究显示DKK-1(dickkopf-1)异常与乳腺癌、前列腺癌、多发性骨髓瘤及神经母细胞瘤等骨转移的发生及治疗效果密切相关,亦与非小细胞肺癌密切相关。进一步进行血清DKK-1水平与常见肿瘤骨转移关系的大样本临床研究,对评价DKK-1作为骨转移癌临床生物标志物的价值、了解骨转移肿瘤机制具有重要临床意义。     

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.     

乳腺癌脑转移的潜在生物标志物研究进展

摘 要：脑转移是乳腺癌病情严重化和预后恶化的重要因素之一。近年来，越来越多的研究集中在寻找乳腺癌脑转移的潜在生物标志物，以便更好地理解其发生及进展机制，并为预防、诊断和治疗提供新的靶点。全文对近年来乳腺癌脑转移的潜在生物标志物进行了综述，重点讨论循环肿瘤细胞、细胞外囊泡以及蛋白质等生物标志物，以期为早期诊断乳腺癌脑转移提供参考依据。     

乳腺癌转移复发肿瘤标志物研究进展

肿瘤标志物是指与肿瘤发生相关的物质，主要包括两部分大分子蛋白质肿瘤标志物和基因肿瘤标志物，可用于肿瘤的早期发现、预后判断、定位和治疗。目前有多种肿瘤标志物与乳腺癌转移相关，但erb-2可在20％～30％侵袭性乳腺癌患者中扩增表达，被认为是首选的肿瘤标志物，并成为抗乳腺癌治疗的靶点。研究认为，肿瘤的转移潜能与多药耐药(MDR)表型相关。因此从MDR相关基因和蛋白质中寻找肿瘤标志物，可成为克服乳腺癌转移的新策略。     

骨标志物在乳腺癌骨转移诊断与疗效观察中的作用

目的 探讨I型胶原交联羧基氨基端肽(β-Cross Laps)和总骨1型前胶原氨基端延长肽(P1NP)在乳腺癌骨转移诊断与疗效观察中的临床价值。方法 运用电化学发光法对β-Cross Laps、P1NP、CA15-3进行定量检测。57例乳腺癌骨转移患者按转移灶多少分为2组,分别为骨显像轻度异常组(Ⅰ组)36例与骨显像明显异常组(Ⅱ组)21例。结果 骨转移组β-Cross Laps、P1NP两种血清标志物较无骨转移组与对照组明显升高,差异具有统计学意义(P＜0.01),且治疗后两种指标明显低于治疗前水平(P＜0.05),随转移灶增加两种标志物水平也有升高趋势,差异具有统计学意义(P＜0.01)。而各组间及治疗前后CA15-3无显著变化(P＞0.05)。骨标志物β-Cross Laps、P1NP对乳腺癌骨转移的诊断灵敏度分别达到71.25%与64.05%,特异性分别达到88.00%与81.99%,均高于骨显像所显示结果的50.32%和61.17%。结论 血清骨标志物β-Cross Laps、P1NP水平可以反映乳腺癌骨转移患者病情变化,并可以运用于疗效监测,有较好的临床应用价值。     

血清TRACP5b、CA15-3水平预测乳腺癌术后骨转移的临床意义

研究表明,乳腺癌骨转移中10%为成骨型,10%为混合型,80%均为以破骨细胞活动为主的溶骨性转移,而血清抗酒石酸盐酸性磷酸酶5b(Serum tartrate resistant acid phosphatase,TRACP5b)主要来源于破骨细胞,是一个反映破骨细胞功能的指标[1],故在众多乳腺癌骨转移标志物中显示出很高的特异性.肿瘤相关抗原15-3(Cancer antigen15-3,CA15-3)为乳腺癌相关抗原,被认为是一种相关性较高的乳腺癌标志物.文献报道,CA15-3在两处及两处以上骨转移灵敏性为100%;同时其值大于100U/ml时,应高度怀疑骨转移[2].本研究乳腺癌术后骨转移患者血清TRACP5b及CA15-3水平,旨在探讨早期预测乳腺癌术后骨转移的良好标志物,从而指导临床及早发现患者骨转移倾向,做到早发现,早治疗,提高患者的生存期和生活质量.     

Breast cancer with osteoblastic bone metastasis treated successfully with bisphosphonate: a case report]

A 52-year-old woman with painful osteoblastic bone metastasis received pamidronate therapy which resulted in marked pain relief with a normalization of elevated tumor marker levels. However, the patient complained of increased pain after the 26th pamidronate infusion. Although a change from pamidronate to alendronate therapy did not relieve bone pain, a second change from alendronate to incadronate therapy resulted in pain relief with a decrease in re-elevated tumor marker levels. These findings suggest that bisphosphonate therapy is effective against osteoblastic bone metastasis in breast cancer, and that sequential therapy with bisphosphonates may be effective against bone metastasis in some cases.     

乳腺癌组织中Cath-D、c-erbB-2的表达及其与肿瘤标志物水平、淋巴结转移的相关性

目的观察乳腺癌患者病理组织中Cath-D、c-erbB-2的表达情况,并分析其与淋巴结转移、肿瘤标志物水平的相关性。方法选取接受手术治疗的乳腺癌患者为研究对象,同时选取同期接受手术治疗的乳腺纤维腺瘤患者为对照。观察乳腺癌(有、无淋巴转移组)、乳腺纤维腺瘤患者组织切片Cath-D、c-erbB-2阳性表达情况,比较乳腺癌(有、无淋巴转移组)、乳腺纤维腺瘤患者血清肿瘤标志物水平的差异,分析淋巴结转移的乳腺癌患者Cath-D、c-erbB-2阳性表达与肿瘤标志物水平的相关性。结果乳腺癌组患者的组织切片Cath-D、c-erbB-2阳性表达率均高于乳腺纤维腺瘤组(χ²=51.796、70.090,P均<0.001);有淋巴结转移的乳腺癌患者组织切片Cath-D、c-erbB-2阳性表达率高于无淋巴结转移组。乳腺癌组患者血清CEA、CA15-3、CA125水平高于乳腺纤维腺瘤组(t=52.270、58.784、76.349,P<0.001);乳腺癌组有淋巴结转移组患者血清CEA、CA15-3、CA125水平高于无淋巴结转移组(t=16.681、27.880、23.216,P<0.001)。有淋巴结转移的乳腺癌患者Cath-D、c-erbB-2阳性表达率与血清CEA、CA15-3、CA125水平正相关。结论乳腺癌患者病理组织中Cath-D、c-erbB-2阳性表达率较高,且与淋巴结转移和肿瘤标志物水平相关。     

Study on the safety of rapid infusion and the efficacy of incadronate against bone metastasis of breast cancer]

To assess the safety of rapid infusion of incadronate and its efficacy against bone metastasis of breast cancer, we conducted a trial using incadronate therapy for breast cancer patients with bone metastasis. Of the 12 patients, 6 had undergone pamidronate or alendronate therapy. Rapid infusion of incadronate consisted of administration of 10 mg incadronate diluted in 100 ml saline in 30 minutes, and was repeated every two weeks. Each patient underwent 2 to 20 incadronate administrations. With the incadronate therapy, no patients showed hypocalcemia, but 3 patients showed asymptomatic hypophosphoremia. Of the 11 patients with bone pain, 5 patients (45%) experienced pain relief. A decrease in tumor marker levels in serum was found in 5 (56%) of the 9 patients with elevated marker levels. The side effects of incadronate administration were general fatigue (25%), pyrexia (17%) and transient pain increase (17%), but no renal dysfunction was found. In conclusion, rapid infusion of incadronate was a safe treatment and the incadronate therapy was effective against bone metastasis of breast cancer.     

检测乳腺癌患者骨髓中CK19的表达及其临床意义

背景与目的:乳腺癌早期即可发生播散和转移,远处转移尤其骨转移是影响患者预后的主要因素之一,而骨髓微转移用常规方法又难以检测出来。本研究旨在探讨检测乳腺癌患者骨髓中CK19mRNA的表达及其临床意义。方法:应用RT鄄PCR技术,同时对照检测65例乳腺癌患者、15例乳腺良性病变患者和8例健康人骨髓中的CK19mRNA表达,并分析CK19mRNA表达与临床病理因素的关系。结果:65例乳腺癌患者中,22例CK19mRNA阳性,阳性率为33.8%;乳腺良性病变患者和健康人骨髓中未检测到CK19mRNA表达。CK19mRNA表达与乳腺癌肿瘤大小和分期有关(P<0.05),与年龄和淋巴结转移状况无显著性相关(P>0.05);与外周血中CEA异常增高呈正相关(r=0.372,P=0.002)。结论:CK19mRNA可作为检测乳腺癌患者骨髓微转移的分子指标之一,可为乳腺癌患者的治疗和预后判断提供帮助。     

Combination of anti‐angiogenic therapies reduces osteolysis and tumor burden in experimental breast cancer bone metastasis

The clinical efficacy of anti‐angiogenic monotherapies in metastatic breast cancer is less than originally anticipated, and it is not clear what the response of bone metastasis to anti‐angiogenic therapies is. Here, we examined the impact of neutralizing tumor‐derived vascular endothelial growth factor (VEGF) in animal models of subcutaneous tumor growth and bone metastasis formation. Silencing of VEGF expression (Sh‐VEGF) in osteotropic human MDA‐MB‐231/B02 breast cancer cells led to a substantial growth inhibition of subcutaneous Sh‐VEGF B02 tumor xenografts, as a result of reduced angiogenesis, when compared to that observed with animals bearing mock‐transfected (Sc‐VEGF) B02 tumors. However, there was scant evidence that either the silencing of tumor‐derived VEGF or the use of a VEGF‐neutralizing antibody (bevacizumab) affected B02 breast cancer bone metastasis progression in animals. We also examined the effect of vatalanib (a VEGF receptor tyrosine kinase inhibitor) in this mouse model of bone metastasis. However, vatalanib failed to inhibit bone metastasis caused by B02 breast cancer cells. In sharp contrast, vatalanib in combination with bevacizumab reduced not only bone destruction but also skeletal tumor growth in animals bearing breast cancer bone metastases, when compared with either agent alone. Thus, our study highlights the importance of targeting both the tumor compartment and the host tissue (i.e., skeleton) to efficiently block the development of bone metastasis. We believe this is a crucially important observation as the clinical benefit of anti‐angiogenic monotherapies in metastatic breast cancer is relatively modest.     

Pain relief with alendronate therapy in a breast cancer patient with bone metastasis

A 66-year-old woman developed a bone metastasis from breast cancer to the sternum in September, 1997. She received alendronate therapy, consisting of biweekly intravenous administrations of 10 mg-alendronate 6 times and monthly 20 mg-alendronate infusions 15 times. The first alendronate administration markedly alleviated her bone pain. She obtained complete pain relief after the 4th alendronate infusion. However, an elevation of tumor marker levels in serum without any pain increase forced us to treat her with medroxyprogesterone acetate and doxifluridine in addition to the alendronate therapy. With these therapies, she has shown an objective response (PR) of the bone metastasis for 8 months. In conclusion, alendronate therapy was effective against bone pain due to metastasis of breast cancer.     

乳腺癌骨转移研究的新进展及展望——从机制到临床

乳腺癌骨转移是晚期乳腺癌患者严重的并发症之一.骨转移后出现的严重骨痛、病理性骨折等并发症,严重影响患者的生活质量并缩短其生存期.近年来,随着对乳腺癌骨转移机制以及肿瘤细胞与骨微环境之间相关调控网络的认知不断深入,许多新药的开发和应用使乳腺癌骨转移的治疗取得重大进展.现就乳腺癌骨转移机制及目前治疗研究进展进行综述.     

The bisphosphonate incadronate for bone metastases of breast cancer

Background. Bisphosphonates are bone resorption inhibitors which are effective in the treatment of diseases of increased bone turnover, such as hypercalcemia of malignancy and osteolytic bone metastasis. The safety and efficacy of incadronate, a third-generation bisphosphonate, were evaluated in breast cancer patients with bone metastases. Methods. Fifteen breast cancer patients with bone metastasis were enrolled. Incadronate's safety, its effectiveness in relieving bone pain, and its effects on bone metabolic markers and a tumor marker were assessed in 8 patients treated with a 10-mg IV infusion once a week for 5 weeks (10 mg × 5), 3 patients treated with a single 20-mg IV infusion (20 mg × 1), and 4 patients treated with a 20-mg IV infusion once a week for 5 weeks (20 mg × 5). Pain assessment was performed only in the patients with the repeated infusion regimens. Results. All incadronate treatment regimens were administered without any serious adverse reactions. Minimal fever was noted in 6 patients, but it subsided without any treatment. Incadronate relieved bone pain in 10 of the 12 patients who received repeated infusions. Levels of bone resorption markers dropped transiently, but the decreases in the individual markers of bone resorption varied. Levels of bone formation markers did not change significantly. Levels of a tumor marker specific to breast cancer, carbohydrate antigen (CA)15-3 decreased in patients whose metastases were limited to bone. Conclusion. The third-generation bisphosphonate, incadronate, was administered safely at dosages of up to 20 mg once a week for 5 weeks. Incadronate reduced bone pain, bone resorption marker levels, and CA15-3 tumor marker levels in breast cancer patients with bone metastases. Received: November 9, 1999 / Accepted: March 6, 2000     

Hypoxia-induced Jagged2 promotes breast cancer metastasis and self-renewal of cancer stem-like cells

Notch signaling is often and aberrantly activated by hypoxia during tumor progression; however, the exact pathological role of hypoxia-induced Notch signaling in tumor metastasis is as yet poorly understood. In this study, we aimed to define the mechanism of Notch-ligand activation by hypoxia in both primary tumor and bone stromal cells in the metastatic niche and to clarify their roles in tumor progression. We have analyzed the expression profiles of various Notch ligands in 779 breast cancer patients in GEO database and found that the expression of Jagged2 among all five ligands is most significantly correlated with the overall- and metastasis-free survival of breast cancer patients. The results of our immunohistochemical (IHC) analysis for Jagged2 in 61 clinical samples also revealed that both Jagged2 and Notch signaling were strongly upregulated at the hypoxic invasive front. Activation of Jagged2 by hypoxia in tumor cells induced EMT and also promoted cell survival in vitro. Notably, a γ-secretase inhibitor significantly blocked Notch-mediated invasion and survival under hypoxia by promoting expression of E-cadherin and inhibiting Akt phosphorylation. Importantly, Jagged2 was also found to be upregulated in bone marrow stroma under hypoxia and promoted the growth of cancer stem-like cells by activating their Notch signaling. Therefore, hypoxia-induced Jagged2 activation in both tumor invasive front and normal bone stroma has a critical role in tumor progression and metastasis, and Jagged2 is considered to be a valuable prognostic marker and may serve as a novel therapeutic target for metastatic breast cancer.