乳腺癌原发灶和转移灶激素受体与HER2表达差异及其影响因素

目的 乳腺癌的治疗已经进入分子分型时代,雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone receptor,PR)和人类表皮生长因子受体-2(human epidermal growth factor receptor 2,HER2)的表达对指导制订乳腺癌治疗方案及评价患者预后等尤为重要.许多研究证实,部分乳腺癌患者原发灶及转移灶激素受体与HER2表达存在差异,影响术后辅助及解救治疗方案的制订,进而影响患者的治疗效果及预后.本研究探讨乳腺癌原发灶与腋窝及远处转移灶之间激素受体与HER2表达的差异及其临床意义,同时分析了造成差异的影响因素.方法 以乳腺癌、激素受体(ER和PR)、HER2、原发灶和转移灶为关键词,检索PubMed、CNKI数据库和万方数据库1995-01-2016-10的相关文献.共505篇文章被检索到.纳入标准:原发灶与腋窝转移灶激素受体及HER2表达差异情况,原发灶与远处转移灶激素受体及HER2表达差异情况,原发灶与转移灶激素受体及HER2表达差异情况的临床意义.根据纳入标准最终纳入分析38篇文献.结果 在部分乳腺癌患者中,原发灶与腋窝转移灶及远处转移灶激素受体及HER2表达情况存在差异,多数文献报道,乳腺癌原发灶与转移灶ER表达状况变化(阳性转阴性或阴性转阳性)比例约为20％,PR约为20％,HER2约为15％.“肿瘤异质性、抗肿瘤治疗和检测方法”等是影响其表达差异的影响因素.结论 推荐对于存在局部及远处转移的乳腺癌患者,同时检测并综合原发灶及转移灶的激素受体及HER2表达情况制订治疗方案.     

细胞紧密连接蛋白与乳腺癌侵袭转移相关性研究的现状分析

目的:总结国内外关于细胞间紧密连接的破坏在乳腺癌浸润与转移中的作用.方法:应用Medline及CNKI期刊全文数据库系统以"乳腺癌、转移和紧密连接"为关键词检索1997-2010年的相关文献,分析文献30篇.纳入标准:1)乳腺癌的转移机制;2)紧密连接的结构及功能;3)紧密连接的破坏与乳腺癌转移的相关性.结果:紧密连接...     

保留乳头乳晕的改良根治术和重建荟萃分析

目的探讨保留乳头乳晕复合体的乳腺切除及乳房即刻重建手术在中国的临床应用情况,以及对预后的影响。方法检索Pub Med、中国知网、维普、万方数据库中关于保留乳头乳晕复合体和乳房重建相关的文献,没有时间和语言限制。对符合入选标准的文献进行质量评价与荟萃分析。结果共有16篇随机对照试验纳入分析。11篇研究分析得出乳腺癌改良根治术后进行Ⅰ期重建术增加了术后并发症,但差异没有统计学意义(P=0.106),4篇文献分析结果显示保留乳头乳晕复合体后增加了术后并发症(P=0.026)。5篇研究分析显示乳腺癌改良根治术后进行Ⅰ期重建术并没有增加局部复发的概率(P=0.735),3篇研究提示乳腺癌改良根治术后进行Ⅰ期重建术并没有增加远处转移的概率(P=0.905),3篇文献显示保留乳头乳晕复合体后增加了远处转移的概率,但差异没有统计学意义(P=0.523)。7篇研究证实乳腺癌改良根治术后进行Ⅰ期重建术加强了患者对外观的满意度(P=0.000)。结论保留乳头乳晕复合体的乳腺癌改良根治术+Ⅰ期重建术并不增加术后并发症、局部复发和远期转移的发生,却增强了术后满意度,可以作为早期年轻乳腺癌患者的首选术式。     

MACC1表达与乳腺癌临床病理学特征相关性的Meta分析

目的:探讨MACC1表达与乳腺癌临床病理学特征的相关性。方法:检索2020年05月13日前发表于PubMed、Cochrane Library等数据库中关于MACC1表达与乳腺癌的相关性研究，依次通过浏览标题、摘要和全文进行文献筛选，由2名研究者对符合纳入标准的文献进行Meta分析。结果:经筛选后采纳8项研究，共收集乳腺癌组织911例及癌旁正常组织429例。Meta分析结果示:MACC1在乳腺癌组织中阳性表达显著高于癌旁正常组织（OR=10.14，95%CI 5.32~19.32，P＜0.000 01）。MACC1在乳腺癌组织中阳性表达与肿瘤大小、远处转移、HER-2表达阳性、组织学分级显著相关，与ER、PR表达水平、患者是否绝经无统计学差异。结论:MACC1在乳腺癌中阳性表达明显高于癌旁正常组织，MACC1与肿瘤大小、组织学分级、远处转移及HER-2过表达相关，提示MACC1可作为乳腺癌患者预后不良的指标，尤其在HER-2型乳腺癌中有更重要的意义。     

2000~2010年我国前列腺癌和乳腺癌流行状况的系统性综述

[目的]对2000～2010年我国前列腺癌和乳腺癌的流行状况作一系统性综述.[方法]通过检索中国生物医学文献数据库、中国知网和PubMed,按照纳入排除标准筛选,对最终入选的22篇文献进行系统分析.[结果]我国前列腺癌粗发病率为2.98/10万～17.69/10万.我国女性乳腺癌粗发病率为6.96/10万～71.46/10万,粗死亡率为2.68/10万～11.85/10万.[结论]我国前列腺癌、乳腺癌的流行水平低于欧美发达国家,但在亚洲处于较高水平,且在过去10年中总体呈增长趋势.     

乳腺癌循环肿瘤细胞生物学特性的研究进展

目的：总结乳腺癌循环肿瘤细胞生物学特性相关的研究进展。方法：以“乳腺肿瘤、循环肿瘤细胞和微转移”为关键词,系统检索PubMed、Ovid、EMBASE、WebofScience的中国生物医学文献数据库等医学数据库（2000-01—2011—12）。纳入标准：乳腺癌循环肿瘤细胞生物学特性。根据纳入标准,符合分析的文献34篇。结果：乳腺癌循环肿瘤细胞具有高度异形性,细胞增殖活性低,表达激素受体、血管生成相关分子等多种标志,且与上皮细胞间质化、肿瘤干细胞及肿瘤自身种植等密切相关。循环肿瘤细胞具有与原发灶、转移灶内肿瘤细胞明显不同的生物学特征。结论：乳腺癌循环肿瘤细胞具有自身独特的生物学特性,进一步深入研究其生物学特性有助于加深对肿瘤播散和转移机制的认识。     

实体瘤外周血循环肿瘤细胞与转移相关性的研究进展

目的:总结实体瘤外周血中循环肿瘤细胞(CTC)和转移相关性的研究进展。方法:以"循环肿瘤细胞、实体瘤、转移"为关键词,检索2000-01-2010-10 PubMed、Science Direct、Ovid、Springer、CNKI和维普等数据库的相关文献。纳入标准:关于实体瘤CTC与转移密切相关的分子机制、临床相关性的文献。共纳入分析42篇文献。结果:随着分子生物学和材料技术的发展,越来越多的方法有效地富集和鉴定不同类型实体瘤外周血CTC。细胞基因水平证实CTC具有恶性生物学特性,CTC自身基因和转移相关蛋白谱的表达、肿瘤微环境、免疫系统等因素影响着CTC远处器官转移灶的形成。CTC数目、特定基因、蛋白的表达与治疗疗效、预后等具有相关性。结论:研究CTC参与血液播散转移的机制,为全面、准确地阐明恶性实体瘤转移的机制、个体化的治疗提供新的工具。     

乳腺癌nm23基因和雌、孕激素受体表达及其临床意义

[目的]研究nm23基因,雌激素受体(ER)、孕激素受体(PR)在乳腺癌中的表达及临床意义.[方法]应用免疫组化SP法检测60例临床及随访资料完整的乳腺癌患者标本nm23、ER、PR的表达,结合临床表现及随访结果作统计学分析.[结果]nm23、ER、PR阳性表达率分别为60.0%、73.3%、66.7%.nm23阳性表达与临床分期相关(P＜0.05).nm23基因的表达与乳腺癌远处转移及腋淋巴结转移呈显著负相关(P＜0.05),与生存率呈正相关(P＜0.05).ER、PR阳性表达率与年龄、临床分期和淋巴结转移无关(P＞0.05).ER、PR的阳性表达与乳腺癌远处转移呈显著负相关(P＜0.05),与生存率呈正相关(P＜0.05).在判断转移和预后方面,ER( )PR( )与nm23基因阳性表达之间存在着正相关性.[结论]检测乳腺癌组织nm23、ER、PR对评价乳腺癌患者的预后和指导临床治疗有重要价值.     

BRMS1对肿瘤转移抑制机制研究进展

目的:综述乳腺癌转移抑制基因1(BRMS1)在抑制肿瘤转移中的作用机制的研究进展.方法:应用Medline及CNKI期刊全文数据库系统,以“基因、转移抑制和BRMS1”为关键词,检索1996-01-2011-12的相关文献.纳入标准:1) BRMS1的发现及其名称来源;2)BRMS1的结构及其功能;3)BRMS1在肿瘤中的表达;4)BRMS1与肿瘤细胞远处转移关系.根据纳入标准符合分析的文献26篇.结果:BRMS1与其他肿瘤转移抑制基因一样,主要抑制肿瘤的转移,并不影响肿瘤的生长,通过许多复杂的机制,如调节细胞间的缝隙连接信号转导及其他转移抑制基因的表达来抑制转移.结论:对BRMS1基因的深入研究有助于进一步深化对肿瘤转移的认识,为恶性肿瘤的分子诊断和基因治疗提供新的思路.     

根治性放疗与根治性手术治疗肌层浸润性膀胱癌的Meta分析

[目的]系统评价根治性放疗与根治性手术治疗膀胱癌临床效果.[方法]应用END-NOTE软件全面检索Pubmed(1973～2013年)数据库,对符合纳入标准的临床对照试验,采用RevMan 4.3软件进行Meta分析.对于无对照临床研究资料,采用同质合并分析.[结果]共纳入6个临床对照试验,共1 264例患者,Meta分析结果显示,根治性放疗与根治性手术切除治疗膀胱癌患者的5年生存率无统计学差异(P=0.36),合并比值比(OR)为1.10 (95％CI:0.86～1.40).18篇无对照临床研究共纳入根治性放疗治疗膀胱癌患者1 749例,多数文献采用全膀胱放疗40～60Gy,联合以顺铂为基础的化疗方案,完全反应率达到65％以上,平均5年总生存率在50％以上,最低为37％,最高可达82％.[结论]根治性放疗不会降低膀胱癌患者生存率,且能维持正常膀胱功能,提高了患者生存质量.     

Significance of micrometastasis in bone marrow and blood of operable breast cancer patients: research tool or clinical application?

Approximately 25% of breast cancer patients without lymph node metastases develop systemic relapse. A growing body of data supports the notion that hematogenous dissemination of breast cancer cells occurs independently of lymphatic spread of disease; however, current clinical practice does not involve routine analysis of circulating or disseminated cells. Recent studies have documented that both circulating tumor cells (CTCs) within the blood and disseminated tumor cells (DTCs) in bone marrow can be identified using a variety of techniques. It is now clear that the presence of DTCs correlates with subsequent development of clinically evident bone metastases, and a worse outcome from breast cancer. While there are data identifying prognostic significance of CTCs in patients with metastatic breast cancer, there are few data regarding CTCs in operable patients. Factors such as presence of a cancer stem cell phenotype and/or certain microenvironmental conditions are involved in the establishment of distant metastases from a primary breast cancer, emphasizing the need for further studies within this area. The purpose of this report is to review the data regarding CTCs and DTCs in patients with operable breast cancer.     

Significance of micrometastasis in bone marrow and blood of operable breast cancer patients: research tool or clinical application?

Approximately 25% of breast cancer patients without lymph node metastases develop systemic relapse. A growing body of data supports the notion that hematogenous dissemination of breast cancer cells occurs independently of lymphatic spread of disease; however, current clinical practice does not involve routine analysis of circulating or disseminated cells. Recent studies have documented that both circulating tumor cells (CTCs) within the blood and disseminated tumor cells (DTCs) in bone marrow can be identified using a variety of techniques. It is now clear that the presence of DTCs correlates with subsequent development of clinically evident bone metastases, and a worse outcome from breast cancer. While there are data identifying prognostic significance of CTCs in patients with metastatic breast cancer, there are few data regarding CTCs in operable patients. Factors such as presence of a cancer stem cell phenotype and/or certain microenvironmental conditions are involved in the establishment of distant metastases from a primary breast cancer, emphasizing the need for further studies within this area. The purpose of this report is to review the data regarding CTCs and DTCs in patients with operable breast cancer.     

Increased serum interleukin-8 in patients with early and metastatic breast cancer correlates with early dissemination and survival.

PURPOSE: The prognostic significance of serum interleukin (IL)-8 was evaluated in patients with metastatic breast cancer. The predictive value of serum IL-8 for the presence of occult metastatic tumor cells in bone marrow aspirates was evaluated in patients with operable and metastatic breast cancer. EXPERIMENTAL DESIGN: Serum IL-8 was measured in healthy controls, patients with operable breast cancer, and patients with untreated, progressive metastatic breast cancer. In 69 patients with either operable or advanced breast cancer, occult cytokeratin-positive cells were counted in bone marrow aspirates. RESULTS: Serum IL-8 levels are increased in 67% (52 of 77) of patients with advanced breast cancer. Overall, these levels are significantly higher in patients with breast cancer compared with healthy volunteers (P < 0.001). The IL-8 levels increase significantly in patients with more advanced disease. An elevated serum IL-8 is related to an accelerated clinical course, a higher tumor load, and the presence of liver or lymph node involvement. A multivariate analysis indicates that serum IL-8 is an independent significant factor for postrelapse survival. There was a significant difference between serum IL-8 levels in patients with or without occult cytokeratin-positive bone marrow cells (P < 0.04). Serum IL-8 levels also showed an association with the number of these cells (P < 0.01). CONCLUSIONS: Serum IL-8 is increased in patients with breast cancer and has an independent prognostic significance for postrelapse survival. The observations on the relationship between occult cytokeratin-positive bone marrow cells corroborate the concept of IL-8 acting as a contributor to the process of tumor cell dissemination. Similarly, the relationship between serum IL-8 and nodal stage at presentation deserves further study. These results further expand the concept that inflammation and inflammatory cytokines are critical components of tumor progression.     

Angiogenesis in the bone marrow of patients with breast cancer.

PURPOSE: Pathologic angiogenesis has been correlated with tumor growth, dissemination, metastasis, and prognosis in solid tumors including breast cancer. Angiogenesis has also been implicated in the pathophysiology of, and shown to be a therapeutic target in tumors arising in the bone marrow. The status of angiogenesis in the bone marrow of breast cancer patients is unknown. The aim of this study was to estimate the extent of bone marrow angiogenesis in this subset of patients. EXPERIMENTAL DESIGN: We studied 42 women with breast cancer in whom a bone marrow biopsy was done. Bone marrow samples were sorted according to their infiltration status by breast cancer cells. In all bone marrow sections, blood vessels were highlighted by staining endothelial cells with an antibody directed against the CD34-related antigen. A hematopathologist blind to the status of infiltration of breast cancer did the bone marrow vessel count. RESULTS: Nineteen patients (45%) had bone marrow metastasis. The bone marrow microvessel density was significantly higher in patients with bone marrow metastases compared with patients without bone marrow metastases (P < 0.0005). Median bone marrow microvessel density was 2 for the negative bone marrow group, and 15 for the positive bone marrow group. An increased microvessel density was correlated with presence of disease at last follow-up. CONCLUSIONS: This is the first study showing that bone marrow microvessel density is significantly higher in breast cancer patients with bone marrow metastases, when compared with breast cancer patients without evidence of bone marrow metastatic disease. Further research is needed to shed light into the prognostic and therapeutic relevance of this finding.     

Cyclooxygenase-2 expression in primary breast cancers predicts dissemination of cancer cells to the bone marrow

Purpose Cyclooxygenase-2 (COX2) plays a role in breast cancer progression at various stages starting from pre-malignant phenotype to clinical metastasis. Breast cancer metastasizes commonly to the bone and preclinical studies suggest an involvement of COX2 in this process. Detection of disseminated tumor cells in the bone marrow of patients at the time of surgery correlates with the subsequent development of clinical bone metastasis. Therefore, to investigate whether COX2 is important for breast cancer metastasis in humans, we analyzed COX2 protein expression by immunostaining of primary tumors from 112 operable stages I, II, or III patients and determined its correlation with bone marrow micrometastasis (BMM). Methods We detected COX2 protein in primary tumors by immunostaining with a monoclonal antibody, and tumor cells present in the bone marrow by immunostaining for epithelial cytokeratins and by morphological criteria. Results COX2 expression in primary breast cancer correlated with BMM in a highly statistically significant manner (P = 0.006). Our statistical analyses of correlations of the COX2 positivity in primary tumor with other clinically relevant indicators revealed that COX2 positivity correlates with high nuclear grade (P = 0.0004). Furthermore, we were able to detect COX2 protein in BMM by immunostaining. Conclusions These studies indicate that COX2 produced in primary breast cancer cells may be vital to the initial development of BMM that may subsequently lead to osteolytic bone metastases in patients with breast cancer, and that COX2 inhibitors may be useful in halting this process.     

Detection of bone metastases in patients with breast cancer

Various methods have been evaluated for their ability to detect bone metastases in patients with breast cancer. Bone scanning and hydroxyproline measurements are insensitive and showed metastases in few patients with primary breast cancer despite the fact that most will develop bone metastases. We have therefore investigated the value of examining the bone marrow with immunocytochemical staining for breast carcinoma cells. Initial results in 68 patients with no evidence of bone metastases by conventional means indicated (a) that some patients have breast cancer cells in bone marrow despite having no evidence of dissemination using other tests, and (b) that patients with micrometastases relapse sooner than those patients with normal bone marrows.     

Perioperative Screening for Metastatic Disease is not Indicated in Patients with Primary Breast Cancer and no Clinical Signs of Tumor Spread

Background. Is a perioperative metastatic screening program indicated in patients presenting with primary operable breast cancer and no signs of distant metastases? Patients and methods. The impact of staging results (chest X-ray, bone scanning, liver ultrasound) for prognosis, treatment, quality of life and costs was retrospectively analyzed in 1076 patients with an operable breast cancer and no clinical signs of metastases. Results. Staging examinations revealed 30 (2.8%) distant metastases, 130 (12.1%) suspect findings and excluded metastases in 916 (85.1%) patients. Further diagnostic procedures confirmed distant metastases in 7 (5.4%) and excluded them in 123 (94.6%) out of 130 patients with suspect findings. Distant metastases were detected more frequently with increasing pathological tumor size (pT ≤q 2.0 cm: 1.6%, pT 2.1–5.0 cm: 3.0%, respectively pT > 5.0 cm: 15.1%; p < 0.001) and increasing number of involved axillary lymph nodes (pN0: 1.9%, pN1–3+: 1.8%, pN4–9+: 4.0%, pN ≥ 10+: 18.7%; p < 0.001). Due to false positive findings 123 (11.4%) patients had to live for a significant period of time with the psychological distress of suspected metastatic disease. The abandonment of a perioperative screening in 1076 patients saves costs of at least Euro 259,367.68. Conclusions. In breast cancer patients without clinical signs of tumor spread perioperative screening for metastases is not warranted because of low frequency of metastases, false positive findings, missing therapeutic consequences and high costs.     

Analysis of and prognostic information from disseminated tumour cells in bone marrow in primary breast cancer: a prospective observational study

ABSTRACT: BACKGROUND: Disseminated tumour cells (DTCs) in the bone marrow of patients with breast cancer have been identified as an independent predictor of poor prognosis in patients with non-metastatic disease. This prospective study aimed to evaluate the presence and prognostic value of DTCs in the bone marrow of female patients with primary breast cancer. METHODS: Between 1999 and 2003, bone marrow aspirates were obtained from patients at the time of surgery for primary invasive breast cancer. DTCs in bone marrow were identified using monoclonal antibodies against cytokeratins for detection of epithelial cells. The detection of DTCs was related to clinical follow-up with distant disease-free survival (DDFS) and breast cancer-specific survival as endpoints. Bone marrow aspirates from adult healthy bone marrow donors were analysed separately. RESULTS: DTCs were analysed in 401 patients, and cytokeratin-positive cells were found in 152 of these (38%). An immunofluorescence (IF) staining procedure was used in 327 patients, and immunocytochemistry (IC) was performed in 74 patients. The IF-based method resulted in 40% DTC-positive cases, whereas 30% were positive using IC (p = 0.11). The presence of DTCs in bone marrow was not significantly related to patient or tumour characteristics. The presence of DTCs was not a prognostic factor for DDFS (IF: hazards ratio [HR], 2.2; 95% confidence interval [CI], 0.63--2.2; p = 0.60; IC: HR, 0.84; 95% CI, 0.09--8.1; p = 0.88). Significant prognostic factors were lymph node metastases, oestrogen receptor positivity, Nottingham histological grade, and tumour size using Cox univariate analysis. The analyses were positive for epithelial cells in bone marrow from adult healthy donors in 19 (25%) samples. CONCLUSIONS: The detection of DTCs in bone marrow in primary breast cancer was previously shown to be a predictor of poor prognosis. We were not able to confirm these results in a prospective cohort including unselected patients before the standard procedure was established. Future studies with a standardised patient protocol and improved technique for isolating and detecting DTCs may reveal the clinical applications of DTC detection in patients with micrometastases in the bone marrow.