乳腺癌中COX-2蛋白与HER2基因表达的相关性

目的 探讨浸润性乳腺癌组织中的COX-2蛋白表达与HER2基因扩增的相关性及其临床意义.方法 收集78例浸润性导管乳腺癌患者术后组织学标本,免疫组化(IHC)检测COX-2蛋白的表达,荧光原位杂交(FISH)检测HER2基因突变状态,并结合临床特征资料分析两者的相关性.结果 78例浸润性乳腺癌患者中,COX-2蛋白阳性...     

乳腺癌HER2与IGF-IR和PTEN表达的相关性

目的探讨中国人乳腺癌中HER2与IGF-IR和PTEN之间的相关性。方法分别在65例HER2(+)和108例HER2(-)的乳腺浸润性导管癌中,用免疫组化EnVision法检测IGF-IR和PTEN蛋白的表达。结果 HER2(+)组中,IGF-IR和PTEN阳性率分别为78.5%(51/65)和52.3%(34/65);HER2(-)组中,IGF-IR和PTEN阳性率分别为71.3%(77/108)和68.5%(74/108)。阳性组IGF-IR过表达率高于阴性组,但差异不显著(P>0.05);阳性组PTEN表达低于HER2阴性组,差异显著(P<0.05)。HER2阳性和阴性组中,IGF-IR过表达与各临床病理参数间均无相关性(P>0.05);但阳性组中,IGF-IR高表达与淋巴结转移密切相关(P<0.05)。对全部乳腺癌标本分析显示,PTEN表达与癌的组织学分级和淋巴结转移呈负相关(P<0.05),与ER表达呈正相关(P<0.05),与其他临床指标间无相关性(P>0.05)。PTEN表达与IGF-IR和HER2表达呈负相关(P<0.05)。结论 PTEN表达丢失与乳腺癌进展密切相关;HER2阳性的乳腺癌中常见PTEN蛋白表达丢失,且IGF-IR可能参与促进了癌细胞的转移过程。PTEN蛋白缺失与IGF-IR蛋白过表达均与乳腺癌进展相关联,其分子机制和相关意义有待于进一步研究。     

乳腺癌患者血清肿瘤标记物检测的临床应用

目的探讨血清癌抗原153（CA153）、组织多肽特异性抗原（TPS）和癌抗原125（CA125）联合检测对乳腺癌诊断的临床应用价值。方法采用电化学发光法检测患者血清中CA153、TPS、CA125。结果乳腺癌患者组血清三种标记物水平及阳性率均明显高于乳腺良性病变组和正常对照组（P〈0．01）,联合检测的敏感性和诊断准确性均比单项检测高。结论联合检测血清中的CA153、TPS、CA-125对乳腺癌的早期诊断具有重要价值。     

ELISA方法检测乳腺癌患者血清HER2的临床价值

目的：HER2基因扩增和HER2蛋白过表达是乳腺癌患者预后不良的分子标志,是临床指导靶向HER2治疗的标准。肿瘤细胞中HER2蛋白胞外域经蛋白酶裂解脱落入血,血清中HER2水平改变可以用于监测乳腺癌的进展和治疗疗效。本研究旨在分析血清HER2水平与乳腺癌组织HER2表达状态的相关性,并探讨血清HER2水平与临床病理因素的关系,以评价其潜在的临床应用价值。方法：分别采用ELISA和免疫组化方法检测70例乳腺癌患者血清HER2水平和肿瘤组织HER2表达状态,Spearmen秩相关分析二者的相关性,χ2检验分析血清HER2与临床病理因素的关系。结果：乳腺癌患者血清HER2水平和组织HER2表达呈正相关（r=0．686,P〈0．001）;肿瘤直径大于2cm患者血清HER2水平高于小于等于2cm患者（χ2=9．071,P=0．030）;临床II-III期患者血清HER2水平高于I期患者（χ2=9．001,P=0．030）;ER阴性患者血清HER2水平高于ER阳性患者（χ2=16．307,P〈0．0.001）：PR阴性患者血清HER2水平高于PR阳性患者（χ2=16．164,P〈0．001）,而血清HER2水平在不同患者年龄、组织学分级和淋巴结状态等临床病理因素各组间无统计学差异。结论：乳腺癌患者血清HER2水平可以反应肿瘤组织HER2表达状态,其水平升高提示乳腺癌恶性程度高、预后差,是潜在的乳腺癌预后预测和疗效监测的血清学标志,     

复发转移乳腺癌患者血清HER2水平与组织表达状态的相关性

目的探讨复发转移乳腺癌患者血清HER2水平与组织表达状态间的联系,分析血清HER2检测是否可作为组织HER2检测的补充手段。方法采用酶联免疫吸附试验(ELISA)对72例女性复发转移乳腺癌(组织HER2阳性组30例,组织HER2阴性组42例)和30例健康体检女性(健康对照组)进行血清HER2水平检测,将各组的血清HER2水平进行比较,并与组织HER2表达状态进行对比分析。结果组织HER2阳性组的血清HER2水平显著高于组织HER2阴性组和健康对照组,差异有统计学意义(P<0.0001);组织HER2阴性组血清HER2水平与健康对照组比较差异无统计学意义(P=0.163);组织HER2阳性组有22例血清HER2阳性,阳性符合率为73.4%(22/30),组织HER2阴性组有32例血清HER2阴性,阴性符合率为78.6%(32/42)。血清HER2水平与组织HER2表达状态呈正相关(χ2=21.626,r=0.547)。结论血清HER2水平与组织HER2表达状态呈正相关,且血清HER2可以作为组织HER2检测的补充手段。     

血清CA153、CEA水平与乳腺癌骨转移的相关性研究

目的探索血清肿瘤标志物CA153、CEA对乳腺癌患者骨转移的预测价值。方法采用酶联免疫吸附法,测定39例乳腺癌患者骨转移前后肿瘤标志物CA153、CEA的血清水平。结果骨转移前后血清CA153、CEA水平有显著性差异,且与乳腺癌骨转移有显著的相关性。HER-2(-)、绝经前、Ⅲ~Ⅳ期、骨转移区域数>5乳腺癌患者骨转移后CA153水平显著升高(P<0.05)。HER-2(-)、Ⅲ~Ⅳ期、骨转移区域数>5、骨外转移区域数<1、PR阴性乳腺癌患者血清CA153水平与骨转移有显著相关性(P<0.05)。HER-2(-)、绝经后、Ⅱ期、骨转移区域数≤5、骨外转移区域数>5、ER阴性、ER阳性、PR阴性、PR阳性乳腺癌患者,骨转移后CEA水平升高,且与骨转移有显著相关性(P<0.05)。结论血清肿瘤标志物CA153、CEA水平升高与乳腺癌骨转移有一定的相关性,对乳腺癌骨转移有一定的预测价值。     

乳腺癌患者PTPRO、HER2和PIASy表达情况

目的分析乳腺癌患者受体O型蛋白酪氨酸磷酸酶(PTPRO)、表皮生长因子受体2(HER2)、激活的STAT蛋白抑制因子(PIASy)表达情况及其临床意义。方法选取2016年5月至2018年4月我院收治的乳腺癌患者56例为研究对象,采用免疫组织化学EnVision法检测其PTPRO、HER2和PIASy表达水平,并分析其与临床病理参数的关系。结果乳腺癌患者癌组织PTPRO阳性率低于癌旁组织,而HER2、PIASy阳性率高于癌旁组织(P<0.05);无淋巴结转移、孕激素(PR)阴性表达者PTPRO阳性率高于淋巴结转移、PR阳性表达者,临床分期Ⅲ~Ⅳ期、PR阳性表达者的HER2阳性率高于临床分期Ⅰ~Ⅱ期、PR阴性表达者,临床分期Ⅲ~Ⅳ期、有淋巴结转移者PIASy阳性率高于临床分期Ⅰ~Ⅱ期、无淋巴结转移者(P<0.05)。结论乳腺癌患者中PTPRO低表达,而HER2、PIASy呈高表达,且PTPRO、HER2、PIASy均与患者临床病理参数有一定关系,有潜在的临床诊断意义。     

ABO血型和肿瘤标记物与乳腺癌及其骨转移的关系

目的了解ABO血型分布特征、抗原表达和血清肿瘤标志物水平在乳腺癌中的临床诊断价值。方法用微柱凝胶法进行ABO血型正反定型,应用吸收放散法检测患者红细胞表面的弱抗原,用血清学实验确定其亚型特征。应用化学发光免疫检测技术检测血清肿瘤标志物CA153、CEA含量和阳性率。用SPECT行全身骨扫描检查明确骨转移发生率。结果 1)乳腺癌的患病易感性以B血型为高,血型分布从高到低依次B型>O型>A型>AB型,在497名乳腺癌患者中发现13例ABO血型抗原表达异常(9例为骨转移),其中11例正向定型出现弱凝集,2例不凝集,反向定型正常,正反定型不一致,经吸收放散实验确定ABO血型抗原性减弱或消失,血清学实验确定无明显亚型特征,在乳腺纤维瘤患者和健康献血者中各发现2例ABO血型抗原减弱,但血清学实验呈现较明显亚型特征。2)乳腺癌患者血清CA153、CEA含量分别为87.43μg/L和13.13μg/L、阳性率分别为73.84%和35.01%,均显著高于乳腺纤维瘤患者和健康献血者(P<0.05);乳腺癌骨转移者血清CA153、CEA含量分别为159.48μg/L和24.23μg/L、阳性率分别为95.51%和56.74%,显著高于未转移患者(P<0.05)。3)乳腺癌ABO血型抗原表达与CA153、CEA水平相关。结论血清肿瘤标记物CA153、CEA水平与乳腺癌发生相关,乳腺癌患者可出现ABO血型抗原减弱,其ABO血型分布特点亦与乳腺癌相关联,是乳腺癌发生的危险因子;若联合检测ABO血型抗原和肿瘤标记物CA153、CEA水平,能提高诊断乳腺癌的准确率,尤其对乳腺癌骨转移判断有一定的临床应用价值。     

HER2与乳腺癌抗肿瘤治疗策略

HER2基因的过度表达与乳腺癌的关系极为为密切,它增加肿瘤细胞的侵袭力,破坏机体组织抗侵袭屏障,通过增加血管内皮生长因子的表达,促进肿瘤新生血管形成,促进癌细胞的扩散和转移,参与化疗耐药的机制,抑制细胞凋亡,促进肿瘤细胞存活。这些特殊的分子生物功能奠定了HER2能作为乳腺癌生物治疗靶点的理论基础,现就近年来以HER2为靶点的抗肿瘤研究最新进展综述如下。     

不同分子分型乳腺癌血清肿瘤标志物的表达差异与肿瘤复发转移的影响因素

目的探讨不同分子分型乳腺癌患者血清肿瘤标志物CEA、CA125和CA15-3的表达差异,以及其与复发转移的相关性。方法回顾性分析212例乳腺癌患者的病历及随访资料,并根据激素受体表达情况分为Luminal A型、Luminal B型、Her-2过表达型和Basal-like型4个分子亚型。比较不同分子分型乳腺癌患者术前血清肿瘤标志物CEA、CA125和CA15-3的表达水平及其临床特征,并分析影响乳腺癌患者复发转移的因素。结果不同分子分型的乳腺癌患者各肿瘤标志物的表达水平存在差异,其中,Her-2过表达型患者CA15-3的表达水平较其他3组明显升高(χ~2=7.98,P=0.04)。此外,不同分子分型乳腺癌患者肿瘤细胞的分化程度不同,Her-2过表达型患者低分化的比例明显高于其他3组(χ~2=12.42,P=0.006)。4个亚组间的复发转移率也存在明显差异,Her-2过表达型患者的复发转移率最高(F=8.69,P=0.034)。多因素Cox回归分析显示,肿瘤直径、组织分化程度和有无脉管瘤栓是乳腺癌患者复发转移的独立危险因素(P均0.05)。结论 Her-2过表达型乳腺癌患者CA15-3水平高,预后差,提示临床应该结合分子分型、肿瘤标志物以及相关危险因素进行个体化治疗。     

ABP 980: promising trastuzumab biosimilar for HER2-positive breast cancer

Introduction: Approval of the HER2-targeted antibody trastuzumab dramatically improved outcomes for patients with HER2-positive breast cancer. Multiple trastuzumab biosimilars, including ABP 980, are in clinical development. Biosimilars are not identical to the reference biologic, but exhibit equivalence and safety in analytical and clinical studies.

Areas covered: A brief introduction to trastuzumab, overview of trastuzumab biosimilars, and detailed review of ABP 980 preclinical and clinical studies are included. We searched PubMed and 2016–2017 ASCO and ESMO conference proceedings for ‘ABP 980’ or ‘trastuzumab biosimilar’. ‘ABP 980 and breast cancer’ or ‘trastuzumab biosimilar and breast cancer’ were used to search clinicaltrials.gov for phase III trials. Analytical studies of ABP 980 pharmacokinetics (PK) or pharmacodynamics (PD), phase I studies of ABP 980 safety and PK/PD, and phase III studies of clinical efficacy vs trastuzumab are included.

Expert opinion: Questions remain regarding long-term impact of biosimilars on overall healthcare costs, insurance coverage of multiple approved biosimilars, and extensive clinical safety and efficacy follow-up. By producing a competitive market, trastuzumab biosimilars are anticipated to improve access to standard of care therapies, although real-world evidence remains to be obtained. Increased global access to HER2-targeted therapy may eventually alter the landscape of breast cancer and survival rates.     

Clinical perspective: Antibody-drug conjugates for the treatment of HER2-positive breast cancer

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Measurement of c-erbb-2 proteins in sera from patients with carcinomas and in breast tumor tissue cytosols: Correlation with serum tumor markers and membrane-bound oncoprotein

Using a commercial kit with antibodies against the ectodomain of c-erbB-2 protein, we detected c-erbB-2 immunoreactivity in human serum. We found that the percentages of patients with elevated serum c-erbB-2 immunoreactivities were 35, 21, and 9% in breast, prostate, and ovarian carcinoma, respectively. The majority of the elevated immunoreactivities were associated with sera containing highly elevated tumor markers with the highest in breast carcinoma (35%) and lowest in ovarian cancer (9%). Excellent correlations were also observed between the serum levels of c-erbB-2 immunoreactivity and the dominant tumor markers in serial specimens from individual cancer patients. We could also detect the c-erbB-2 immunoreactivity in the cytosols prepared from the breast tumor tissue for estrogen and progesterone receptor (ER&PgR) measurements using the same commercial kit for serum studies, and the intact c-erbB-2 oncoprotein (p 185) in the extracts of the tissue membrane fractions with a different kit designed for tissue extract. The level of c-erbB-2 immunoreactivity in the cytosol from 124 human breast tumor specimens had an excellent correlation with the cell membrane concentrations of p 185 (γ = 0.89). Most of the elevated cytosol c-erbB-2 immunoreactivities were also found to associate with breast tumor specimens containing low concentrations of ER&PgR. It appears that measuring the c-erbB-2 immunoreactivity potentially could be used as a prognostic marker without performing tissue biopsies and also as a serum tumor marker for managing cancer patients.©1995 wiley-Liss, inc.     

Trastuzumab emtansine: a novel antibody-drug conjugate for HER2-positive breast cancer

Introduction: Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) that combines intracellular delivery of the potent cytotoxic agent, DM1 (a derivative of maytansine) with the antitumor activity of trastuzumab. While there are several ADCs in Phase III development, T-DM1 is the only one in which the targeting antibody has antitumor properties. T-DM1 is also the only ADC that is directed toward the human EGFR 2 (HER2). Effective therapies are limited in HER2-positive advanced or metastatic breast cancer (MBC), particularly following progression on available HER2-targeted therapies.

Areas covered: The mechanisms of action, preclinical efficacy and clinical profile of T-DM1 are reported. The latest preclinical and clinical data for T-DM1 are examined.

Expert opinion: T-DM1 has significant antitumor potency in vitro and in vivo, which is maintained in tumors resistant to trastuzumab or lapatinib. In Phase I and II trials, T-DM1 provided objective tumor responses and was well tolerated across various lines of therapy in patients with HER2-positive MBC. In addition, it showed similar efficacy to trastuzumab plus docetaxel in first-line MBC. Ongoing trials (including two Phase III studies) are investigating T-DM1 as single-agent therapy or combined with other chemotherapeutic or biologic agents, and the results should help to define the place of T-DM1 within current treatment algorithms for HER2-positive disease.     

Clinical development of CT-P6 in HER2 positive breast cancer

ABSTRACT

Introduction: CT-P6 (trastuzumab-pkrb, Herzuma) is a trastuzumab biosimilar approved for use in HER2 positive breast cancer and HER2 positive gastric cancer. CT-P6 has been shown to exhibit similar safety and efficacy profiles to its reference product, trastuzumab. Preclinical and clinical studies have been performed to prove equivalence between CT-P6 and the trastuzumab originator.

Areas Covered: In this review, we examine the evidence comparing CT-P6 with its reference product, trastuzumab. Both monoclonal antibodies function to target cells that overexpress HER2 on the cell surface. Preclinical pharmacologic modeling of CT-P6 shows a similar mechanism of action to trastuzumab, similar pharmacologic properties and a phase I trial in healthy volunteers showed similar pharmacokinetics. A multicenter phase III randomized clinical trial in patients with early breast cancer showed equivalent safety and efficacy between CT-P6 and trastuzumab. One-year follow-up of patients showed identical rates of cardiotoxicity.

Expert Opinion: Preclinical and clinical studies showed CT-P6 pharmacologic profile, safety and efficacy are equivalent to trastuzumab. As such, it is a safe and effective alternative for use in patients with HER2 positive breast cancer and gastric cancer. Its implementation into clinical practice can potentially increase patient access and help financially alleviate overburdened health-care systems.     

HER2 as a target for breast cancer therapy

Importance of the field: Differential levels of HER2 expression in normal versus HER2-overexpressing breast carcinomas, together with the demonstration of a key role for HER2 in tumor progression, make HER2 an ideal target for specific therapeutic approaches.

Areas covered in this review: This review considers the clinical value of trastuzumab and lapatinib, the two HER2-targeted therapies approved for clinical practice. References were chosen by searching the PubMed and MEDLINE datasets using as search term: ‘HER2’, in association with ‘prognosis’, ‘response’, ‘trastuzumab’, ‘lapatinib’ and ‘resistance’.

What the reader will gain: This review deals with HER2 as a target for breast carcinoma treatment, focusing on anti-HER2 therapies used in clinical practice, their merits and shortcomings.

Take home message: The benefit of anti-HER2 therapies demonstrated in clinical trials indicates that HER2 is, to date, one of the most promising molecules for targeted therapy. Nevertheless, since tumor cells utilizing alternative growth signaling pathways through transmembrane receptors as well as intracellular signaling transduction molecules can bypass HER2 blockade, a future ambitious aim is the successful combination of anti-HER2 strategies with drugs directed to molecules that contribute to anti-HER2 resistance.     

外科治疗对晚期乳腺癌骨转移患者生活质量的影响

目的探讨乳腺癌晚期骨转移的外科治疗对患者生活质量的影响。方法1988-04/2001-03,56例有随访结果的乳腺癌骨转移患者行Guy's疼痛分级和Karnofsky评分,测量X线平片中长骨骨皮质破坏厚度(或椎体骨折塌陷的程度)作为定量计算指标。依据全身状况和骨转移灶特征将患者分为手术组与非手术组。对比两组临床缓解率、Karnofsky及生活质量评分结果并作统计学分析。结果平均随访19.5个月。56例患者中42例接受手术治疗,总有效率83%,明显高于非手术组57%。17例有病理骨折或骨折危险性的患者接受大段异体骨关节移植,依据Mankin's异体骨移植评价标准,术后总评优良率为88%。接受手术治疗与未行手术治疗的患者相比,疼痛减轻,Karnofsky评分增加,生活质量明显提高。结论根据骨转移癌分组标准进行有选择性的手术治疗可以提高患者终末期的生活质量和生命活力。