中国乳腺癌HER2基因检测、临床病理特征分析及流行病学研究
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摘要
目前,分子诊断技术在乳腺癌个体化诊疗的临床实践中发挥着越来越重要的作用。依据受体状态选择乳腺癌内分泌治疗和分子靶向治疗成为个体化诊疗的典范,尤其是人表皮生长因子受体2(HER2)在乳腺癌治疗中的地位越来越受重视,不仅可以预测细胞毒性药物蒽环类或紫杉类药物的疗效,而且已经成为评价抗HER2靶向药物临床获益的重要分子标志物。针对HER2的单克隆抗体曲妥珠单抗,使HER2阳性乳腺癌患者复发风险明显降低,无论单药、与化疗联合或辅助治疗均能够持续改善患者的无病生存时间,因其在乳腺癌治疗取得的卓越疗效,成为肿瘤分子靶向治疗的代表。因此,根据HER2表达状态制定细胞毒性药物及靶向药物的合理治疗方案,并预测药物疗效和评价预后已经成为乳腺癌诊疗的主要策略。那么,如何准确检测HER2的状态,为乳腺癌患者的诊断、治疗和评价提供依据,成为目前一项意义重大的紧迫任务。
     HER2定位于17q12,是表皮生长因子受体家族(EGFR)的成员之一,HER2基因可以编码分子量为185KDa的酪氨酸激酶活性跨膜糖蛋白。HER2与配体结合形成二聚体,构象发生改变,导致细胞内受体酪氨酸激酶的磷酸化,引起信号通路上的连锁反应,促进细胞增殖分化。国内外研究报道,HER2过度表达与乳腺癌的发生、发展、侵袭和转移密切相关。然而,随着国内HER2检测的逐步开展以及曲妥珠单抗的临床应用,在HER2检测准确性及其临床实践中的指导意义方面暴露出一系列问题：
     一、HER2的检测方法多种多样,但检测技术的标准化、检测结果的准确性、不同方法的一致性以及进口检测试剂价格昂贵等问题亟待解决。
     二、中国乳腺癌患者HER2表达的流行病学情况是否与国外存在差异仍不明确。
     三、17号染色体多倍体在中国乳腺癌患者中的表达情况,对HER2状态的影响,以及与临床病理特征的关系仍不清楚。
     四、临床实践中是否可以用血清代替肿瘤组织标本检测HER2的状态仍存在争议。
     为此,我们试图从以上几个方面进行研究,研究内容分为四个部分：
     第一部分：国产GLP和进口PathVysion FISH探针试剂盒检测乳腺癌HER2基因状态的比较研究。通过收集108例乳腺浸润性导管癌肿瘤组织标本,分别采用国产试剂盒GLP和进口试剂盒Vysis PathVysion探针检测乳腺癌患者肿瘤组织HER2基因表达水平,比较2种试剂检测HER2基因状态的差异。结果表明,与Vysis探针相比,国产GLP HER2探针试剂盒在检测乳腺癌HER2基因扩增的敏感度、特异度、阳性预测值和阴性预测值均高,且具有价格优势,在国内临床评价乳腺癌HER2基因状态中具有广泛应用价值。
     第二部分：中国乳腺癌HER2表达的流行病学研究。运用免疫组织化学(IHC)和原位杂交技术(FISH)分别评价了不同地域和不同种族3,149例中国乳腺癌患者HER2的表达水平,分析了HER2的表达与地理分布及临床病理特征的相关性。结果表明,中国乳腺癌患者发病年龄较西方早,临床病理特征与美国和欧洲相比,肿瘤负荷较大(p<0.001)、组织分级较差(p<0.001)、且ER/PR多为阴性(p<0.001)。提示,中国乳腺癌患者的肿瘤侵袭性可能更强。HER2蛋白过表达率和基因扩增率分别为23.3%和27.5%,两者一致率达71.2%(Kappa=0.494,p<0.001)。HER2基因扩增与临床分期晚(Ⅲ/Ⅳ)(p=0.002)、肿瘤负荷大(>5cm)(p=0.002)、组织分级差(p<0.001)、绝经(p<0.001)、ER/PR表达阴性(p=0.002)以及淋巴结转移≥4个(p<0.001)密切相关。南方与北方乳腺癌患者的HER2扩增状态无显著差异(p>0.05)。本研究揭示了中国乳腺癌HER2蛋白过表达和基因扩增流行病学特征,以及病理特征与西方人群的差异,为乳腺癌个体化治疗和早期预防提供有价值的理论依据。
     第三部分：17号染色体多倍体与HER2表达的相关性研究。运用FISH技术检测了348例乳腺癌患者的HER2基因和17号染色体CEP17拷贝数的情况,结合HER2蛋白表达(IHC)情况和相关临床病理特征进行分组对比分析。结果表明,所有患者中CEP17平均拷贝数为2.1(1.0-12.4),17号染色体多倍体的比率(CEP17≥3)为13.8%(48/384)。HER2基因拷贝数>6的患者占26.4%(92/348),HER2/CEP17>2.2的占25.3%(88/348)。HER2拷贝数>6的患者中,17号染色体多倍体的比率占38.0%(35/92),HER2蛋白表达与HER2基因拷贝数以及比值密切相关。17号染色体多倍体与HER2蛋白表达或基因扩增相关,但相关性较差(分别为r=0.271,p<0.05和r=0.223,p<0.05)。在HER2拷贝数≤6的患者中,17号染色多倍体的比率占5.4%(5/92)。单纯17号染色多倍体组的临床病理特征更倾向于HER2阴性组的病理特征。提示,17号染色体信号的增加影响了部分HER2结果的判读,但单纯的17号染色体多倍体并不能作为HER2基因扩增的独立预测因子。
     第四部分：检测乳腺癌患者血清中HER2ECD的水平。本研究收集了我院Ⅰ-ⅢA期乳腺癌患者术前血232例,运用ELISA法检测血清HER2ECD水平,IHC法和FISH法检测配对肿瘤组织HER2的表达,分析血清HER2ECD表达与临床病理特征关系及临床意义。结果表明,血清HER2ECD的中位浓度为6.8ng/ml,HER2ECD水平升高的界值为7.4ng/ml,低于转移性乳腺癌血清HER2ECD水平的临界值(15ng/ml)。89例(38.3%)患者血清HER2ECD水平升高,而肿瘤组织77例(33.2%)HER2阳性表达,一致率达76.7%。血清HER2ECD升高与绝经(p<0.001)、高级别组织分级(p<0.001).ER-(p=0.007).PR-(p<0.001).CA153水平升高(p=0.039)和TPS水平升高(p=0.018)密切相关。与单纯检测肿瘤组织HER2表达相比,同时联合检测术前血清中HER2ECD水平能提供更多的信息。我们支持降低术前血清中HER2ECD的界值指标更有利于评价乳腺癌患者HER2的状态及预后。
     本研究通过回答上述问题,明确了HER2国产试剂盒广泛的应用价值、获得了中国乳腺癌HER2表达的流行病学数据、了解了17号染色体多倍体如何影响HER2的表达、阐述了血清代替组织标本检测HER2状态的可行性,为今后临床实践中准确判读HER2状态提供了依据,推动了HER2检测技术的标准化及乳腺癌个体化靶向治疗的临床应用。
     目的通过与进口Vysis PathVysion HER2探针试剂盒(简称“Vysis
     PathVysion探针试剂”)比较,评价国产金菩嘉GLP HER2探针试剂盒(简称"GLP探针试剂”)检测乳腺癌患者HER2基因状态的临床应用价值。方法收集108例乳腺浸润性导管癌肿瘤组织标本,分别采用GLP和Vysis PathVysion HER2探针试剂运用FISH技术检测乳腺癌患者HER2基因扩增状态。以IHC染色结果为参考,比较2种探针试剂检测乳腺癌患者HER2基因状态的差异,并评价GLP HER2探针试剂检测乳腺癌患者组织标本中HER2基因扩增的敏感度、特异度、准确度、阳性预测值和阴性预测值。比较2种试剂盒不同时间段检测同一标本的重复性和稳定性。结果GLP HER2探针和PathVysion HER2探针检测乳腺癌患者组织标本中HER2基因扩增率分别为25.0%(27/108)和26.9%(29/108)。与PathVysion HER2探针相比,GLP HER2探针检测乳腺癌患者组织标本中HER2基因扩增的敏感度、特异度和准确度分别为89.7%(26/29)、98.7%(78/79)和96.3%(104/108),阳性预测值(PPV)和阴性预测值(NPV)均为96.3%(26/27,78/81)。GLP HER2探针检出17号染色体多倍体的敏感度、特异度和准确度分别为93.3%(14/15)、100%(93/93)和99.1%(107/108)。在1个月内,均间隔5天时间,4次分别检测了同一标本的HER2基因状态,Vysis PathVysion HER2试剂盒检测结果表明,4次检测一致率为100%。GLP试剂盒的检测结果同样表明,4次检测的一致率为100%,提示2种试剂盒的稳定性和可重复性较高。结论GLP HER2探针试剂盒在检测乳腺癌患者组织标本中HER2基因扩增的敏感度和特异度高,在临床评价乳腺癌HER2基因状态中具有广泛应用价值。
     本研究运用免疫组织化学(Immunohistochemistry, IHC)和原位杂交技术(Fuorescence in situ hybridization, FISH)分别评价了中国不同地域和不同种族3,149例乳腺癌患者HER2的表达水平,分析了HER2表达的流行病学特征、与地理位置以及及临床病理特征的关系,阐述了中国乳腺癌患者的病理特征与西方国家的差异。结果表明,中国乳腺癌患者发病年龄较西方早,有2个发病高峰,临床病理特征与美国、欧洲相比,肿瘤负荷较大(p<0.001)、组织分级较差(p<0.001)、且ER/PR多为阴性(p<0.001),提示,中国乳腺癌患者的肿瘤侵袭性可能更强。HER2蛋白过表达率和基因扩增率分别为23.3%和27.5%,两者一致率达71.2%(Kappa=0.494,p<0.001)。其中,IHC检测结果为2+的患者中,FISH检测到72.9%为HER2基因无扩增。随机比对5个参与检测的实验室间的HER2结果显示,IHC和FISH检测结果不一致率分别为5%-28%、1%-16%。HER2基因扩增与肿瘤进展期(p=0.002)、肿瘤直径>5cm(p=0.002)、中度或差的组织分级(p<0.001)、绝经(P<0.001)、ER/PR阴性(p=0.002)以及淋巴结浸润>4枚(p<0.001)密切相关。满族和回族人群HER2扩增率显著高于其他少数民族(p<0.001)。南方与北方乳腺癌患者的HER2扩增状态无显著差异(p>0.05)。本研究揭示了中国乳腺癌HER2蛋白过表达和基因扩增流行病学特征,阐述了中国乳腺癌患者临床病理特征与西方人群的差异,为乳腺癌个体化治疗和早期预防提供有价值的理论依据。
     目的：本研究探讨了17号染色体多倍体在判读浸润性乳腺癌HER2检测结果中的影响。目前,美国ASCO/CAP指南将FISH检测HER2阳性定义为单个核HER2基因拷贝数>6或HER2/CEP17比值>2.2。但这一准侧存在一定的矛盾,提示17号染色体多倍体可能会影响HER2基因状态的结果判读。方法：收集了自2010年5月至2011年8月中国医学科学院肿瘤医院就诊的乳腺癌患者肿瘤石蜡组织标本348例。运用FISH技术检测肿瘤组织HER2和CEP17的拷贝数变化。IHC检测HER2蛋白表达状态。结果：所有患者中CEP17半均拷贝数为2.1(1.0-12.4),17号染色体多倍体的比率(CEP17≥3)为13.8%(48/384)。HER2基因拷贝数>6的患者占26.4%(92/348),HER2/CEP17>2.2的占25.3%(88/348)。HER2拷贝数>6的患者中,17号染色体多倍体的比率占38.0%(35/92),HER2蛋白表达与HER2基因拷贝数以及比值密切相关。17号染色体多倍体与HER2蛋白表达或基因扩增相关,但相关性较差(分别为r=0.271,p<0.05和r=0.223,p<0.05)。在HER2拷贝数≤6的患者中,17号染色多倍体的比率占5.4%(5/92)。与HER2阳性组的临床病理特征相比,单纯17号染色多倍体组的临床病理特征更倾向于HER2阴性组的病理特征。结论：17号染色体CEP17拷贝数的增加影响了部分HER2结果的判读。17号染色体多倍体与HER2蛋白/基因的表达相关,但相关性差,且17号染色多倍体组的临床病理特征更倾向于HER2.阴性组的病理特征,提示单纯的17号染色体多倍体并不能作为HER2基因扩增的独立预测因子。
     目的：目前对血清中HER2胞外区的研究多集中在复发转移晚期乳腺癌患者,对早期乳腺癌患者血清中HER2胞外区表达的研究甚少。本研究分析了乳腺癌血清HER2ECD表达与临床病理特征的关系及临床应用价值。方法：收集中国医学科学院肿瘤医院Ⅰ-ⅢA期乳腺癌患者术前血以及配对肿瘤组织标本232例,运用酶联免疫吸附法(ELISA)评价血清HER2ECD水平,IHC法和FISH法检测肿瘤组织HER2表达,分析乳腺癌血清HER2ECD表达水平与临床病理特征的关系。结果：血清HER2ECD(?)的中位浓度为6.8ng/ml(范围1.3-42.1ng/ml), HER2ECD水平升高的界值为7.4ng/ml,低于转移性乳腺癌HER2ECD水平的临界值15ng/ml。89例(38.3%)患者血清HER2ECD表达水平升高,而肿瘤组织77例(33.2%)HER2阳性表达,一致率达76.7%。血清HER2ECD升高与绝经(p<0.001)、高级别组织分级(p<0.001)、ER-(p=0.007)、PR-(p<0.001)、CA153水平升高(p=0.039)和TPS水平升高(p=0.018)密切相关。结论：与单独通过肿瘤组织检测HER2表达状态相比,联合术前血清中HER2ECD水平能提供更多信息。我们支持降低术前血清中HER2ECD (?)临界值指标更有利于评价早期乳腺癌患者肿瘤组织HER2的状态。
Molecular techniques play an increasingly important role in breast cancer detection and help in the prediction of prognosis and treatment response. According to the receptors status to choose the endocrine therapy and molecular targeted therapy for breast cancer patients is the model of the individual treatment. Especially, epidermal growth factor receptor2(HER2) is an important therapeutic target for breast cancer treatment. Trastuzumab (Herceptin(?), Roche) is a recombinant humanised monoclonal antibody directed against the extracellular domain of the HER2protein that significantly increases the survival of HER2positive patients, both as monotherapy or in combination with chemotherapy. Furthermore, HER2positive tumors are more sensi tive to anthracyclin chemotherapy and seem to respond better to aromatase inhibitors than to tamoxifen. Given its prognostic, predictive and therapeutic impli-cations, an accurate assessment of HER2status for breast cancer patients is crucial.
     HER2, a185KDa transmemb rane receptor, is a proto-oncogene located on the long arm of chromosome17that encodes a transmembrane receptor protein of the epidermal growth factor receptor family. The tyrosine kinase domains are activated by both homodimerization and heterodimerization. Transcription factors activated by the pathway regulate many genes involved in cell proliferation, survival, differentiation, angiogenesis, and invasion and metastasis. However, with the development of HER2testing and clinical application of trastuzumab in China, a number of problems have cropped up in this field as followed.
     1. There are many techniques to evaluate HER2status, but the standardization of techniques, the accuracy of detection results, the concordance of different methods, and the expensive reagent from aboard are also controversial.
     2. The epidermiology of HER2expression of breast cancer patients in China is not clear.
     3. The incidence of chromosome17polysomy and the association with HER2overexpression is also not clear.
     4. Whether the serum is a surrogate for tissues to response HER2expression.
     According to the questions above, this study focused on four parts as followed,
     Part1. Study on comparison of GLP and PathVysion FISH assays on measuring HER2gene status in breast cancer. This study detected HER2gene status from108cases with invasive ductal breast cancer using GLP and PathVysion HER2probe kits by FISH, compared HER2gene expression differentiation measured by GLP and PathVysion HER2probe, and assessed the sensitivity, the specificity and the accuracy of GLP HER2probe kit. HER2gene amplification cases were25.0%(27/108) and26.9%(29/108) detected by GLP probe kit and PathVysion probe kit, respectively. As assessed with PathVysion HER2probe as the reference, the sensitivity, the specificity and the accuracy of the GLP HER2kit were calculated to be89.7%(26/29),98.7%(78/79) and96.3%(104/108), respectively, whereas the positive predictive value (PPV) and negative predictive value (NPV). GLP probe kit can be considered to be high sensitivity and specificity, and it has the widespread clinical application value in assessing HER2gene status for breast cancer patients.
     Part2. The epidermiological characteristics of HER2expression in Chinese breast cancer. We performed a multicenter study on the HER2status in3149breast cancer specimens from different ethnic populations and areas in China by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays. The positive rates for HER2over-expression and HER2amplification were23.3%and27.5%in this population, respectively. The concordance between IHC and FISH was71.2%(Kappa=0.494, p<0.001). The HER2amplification was associated significantly with advanced tumor stage (Ⅲ or Ⅳ)(p=0.002), large tumor size (>5cm)(p=0.002), moderately and poorly histological grades (p<0.001), postmenopause (p<0.001), ER/PR-(p=0.002), and having≥4lymph nodes affected (p<0.001) in this population. The positive rates of HER2amplification in specimens from Man and Hui Chinese were significantly higher than that in other Chinese populations. There are slightly higher positive rates of HER2expression and amplification in Chinese patients with breast cancer. These findings may provide new insights into understanding the epidemiological features of HER2expression and amplification, and may be valuable for clinical practice.
     Part3. Impact of polysomy17on HER2testing of breast cancer. We collected384cases of breast cancer collected from Cancer Institute/Hospital of Chinese Academy of Medical Sciences&Peking Union Medical College. Chromosome17copies and HER2gene status were identified by fluorescent in situ hybridization, and the corresponding HER2immunohistochemistry was obtained. The average CEP17copy number for the group was2.1(range,1.0-12.4). Fourty-eight cases (13.8%,48/348) were idenfied as chromosome17polosomy with CEP17copy number≥3. Ninety-two (26.4%) cases had>6copies of HER2per nucleus, and95cases (25.3%) qualified as HER2gene amplified using the HER2/CEP17ratio (>2.2) guideline. All these cases had>6HER2signals, presented38.0%cases with>3CEP17copy number. HER2protein expression showed significant positive correlations with both HER2gene copy number and HER2/CEP17ratio (p<0.01, r=0.56and0.64, respectively). In conclusion, increased CEP17signals detected in invasive breast carcinomas may lead to discordant interpretation of HER2gene amplification in a significant proportion of the cases, depending on which criterion (ratio vs absolute number) is used for interpretation. However, increased gene dosage (>6HER2genes or HER2/CEP17ratio>2.2), regardless of the evaluation method, is positively correlated with HER2protein expression. The polysomy of chromosome17can not be a independent predictive factor for HER2gene amplification.
     Part4. Relationship of serum HER2level and tissue HER2expression in early stage of breast cancer. The measurement of the HER2protein in the serum of metastatic breast cancer patients has now been reported, but there are no consistent data to support the clinical utility of serum HER2extracellular domain (ECD) for patients with early breast cancer. We aimed to evaluate the correlation between serum HER2ECD levels and tumor HER2status, and analyze their relationship with clinicopathological parameters in patients with early stage disease. This study was conducted on232breast cancer patients with stage Ⅰ-ⅢA diseases before treatment. Preoperative serum samples were measured by enzyme-linked immunosorbent assay. Tissue HER2status was analyzed by immunohistochemistry and fluorescence in situ hybridization assays. The median serum HER2ECD concentration was6.8ng/ml. The best diagnostic cut-off value was7.4ng/ml, with62.9%sensitivity and85.3%specificity. High serum HER2ECD levels were reported in89patients (38.3%) and HER2tissue positive expression was observed in77patients (33.2%) with a moderate concordance of76.7%. Elevated serum HER2ECD correlated with postmenopausal (p<0.001), high tumor grade (p<0.001), negativity of both estrogen (p=0.007) and progesterone receptors (p<0.001),high level of CA153(p=0.039) and TPS (p=0.018). HER2ECD may provide more additional information compared with HER2tissue alone. We supported that it is necessary to decrease the cut-off value in evaluating serum HER2ECD level for early stage of breast cancer.
     Taken together, we cleared the wide application value of GLP HER2DNA probe kit, got the epidemiological data of HER2expression in Chinese breast cancer patients, found the influence of chromosome17polysomy on HER2status, and explicated the feasibility of serum instead of tissue to detect HER2expression in new diagnosis breast cancer, which may provide the basis for accurately interpreting HER2status in the future clinical practice, and promot individualized targeted therapy in clinical application.
     Objective To evaluate clinical application of Jin Pujia GLP HER2probe kit in testing HER2gene status of breast cancer through comparing with Vysis PathVysion HER2probe kit. Methods This study detected HER2gene status from108cases with invasive ductal breast cancer using GLP and PathVysion HER2probe kits by FISH, compared HER2gene expression differentiation measured by GLP and PathVysion HER2probe, and assessed the sensitivity, the specificity and the accuracy of GLP HER2probe kit. Results HER2gene amplification cases were25.0%(27/108) and26.9%(29/108) detected by GLP probe kit and PathVysion probe kit, respectively. As assessed with PathVysion HER2probe as the reference, the sensitivity, the specificity and the accuracy of the GLP HER2kit were calculated to be89.7%(26/29),98.7%(78/79) and96.3%(104/108), respectively, whereas the positive predictive value (PPV) and negative predictive value (NPV) were96.3%(26/27) and96.3%(78/81), respectively. With regard to the ability to presume polysomy17, the GLP HER2kit had a sensitivity of93.3%(14/15), a specificity of100%(93/93) and an accuracy of99.1%(107/108). Each lot was run on five non-consecutive days over one month. The GLP and PathVysion HER2probe kit all had high reproducibility with concordance rate of100%. Conclusion GLP probe kit can be considered to be high sensitivity and specificity, and it has the widespread clinical application value in assessing HER2gene status for breast cancer patients.
     We performed a multicenter study on the HER2status in3149breast cancer specimens from different ethnic populations and areas in China by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays. The potential association of HER2status with demographic and clinical characteristics was analyzed. The positive rates for HER2over-expression and HER2amplification were23.3%and27.5%in this population, respectively. The concordance between IHC and FISH was71.2%(Kappa=0.494, p<0.001). Furthermore,72.9%of specimens with IHC2+were negative to FISH. The discordance rates among laboratories were from5%to28%for IHC and1%to16%for FISH. The HER2amplification was associated significantly with advanced tumor stage (Ⅲ or Ⅳ)(p=0.002), large tumor size (>5cm)(p=0.002), moderately and poorly histological grades (p<0.001), postmenopause (p<0.001), ER-PR-(p=0.002), and having≥4lymph nodes affected (p<0.001) in this population. The positive rates of HER2amplification in specimens from Man and Hui Chinese were significantly higher than that in other Chinese populations. There are slightly higher positive rates of HER2expression and amplification in Chinese patients with breast cancer than that in Caucasian. These findings indicate the epidemiological features of HER2expression in Chinese breast cancer patients, state the difference between Chinese patients and Western Caucasian patients, which may provide new insights into understanding personalized targeted therapy for breast cancer, and may be valuable for early prevention in clinical practice.
     Backgroud:The current study was performed to determine the impact of polysomy17on the interpretation of HER2testing of invasive breast carcinomas using fluorescent in situ hybridization methods. Current American Societyof Clinical Oncology/College of American Pathologists guidelines define HER2positive tumors as those with>6HER2genes per nucleus or those with HER2/CEP17(chromosome17) ratio>2.2. These guidelines are potentially con-tradictory in tumors with polysomy of chromosome17. Methods:Chromosome17copies (≥3CEP17signals on average) and HER2gene status were identified by fluorescent in situ hybridization in the384cases of breast cancer collected from Cancer Institute/Hospital of Chinese Academy of Medical Sciences&Peking Union Medical College, and the corresponding HER2immunohistochemistry was obtained. Results:The average CEP17copy number for the group was2.1(range,1.0-12.4). Fourty-eight cases (13.8%,48/348) were idenfied as chromosome17polosomy with CEP17copy number≥3. Ninety-two (26.4%) cases had>6copies of HER2per nucleus, and95cases (25.3%) qualified as HER2gene amplified using the HER2/CEP17ratio (>2.2) guideline. All these cases had>6HER2signals, presented38.0%cases with>3CEP17copy number. HER2protein expression showed significant positive correlations with both HER2gene copy number and HER2/CEP17ratio (p<0.01, r=0.56and0.64, respectively). Conclusions:Increased CEP17signals detected in invasive breast carcinomas may lead to discordant interpretation of HER2gene amplification in a significant proportion of the cases, depending on which criterion (ratio vs absolute number) is used for interpretation. Increased gene dosage (>6HER2genes or HER2/CEP17ratio>2.2), regardless of the evaluation method, is positively correlated with HER2protein expression, but the polysomy of chromosome17can not be a independent predictive factor for HER2gene amplification.
     Background:The measurement of the human epidermal growth factor receptor2(HER2) protein in the serum of metastatic breast cancer patients has now been reported, but there are no consistent data to support the clinical utility of serum HER2extracellular domain (ECD) for patients with early breast cancer. We aimed to evaluate the correlation between serum HER2ECD levels and tumor HER2status, and analyze their relationship with clinicopathological parameters in patients with early stage disease. Methods:A prospective study was conducted on232breast cancer patients with stage Ⅰ-Ⅱ diseases before treatment. Preoperative serum samples were measured by enzyme-linked immunosorbent assay (ELISA). Tissue HER2status was analyzed by immunohistochemistry and fluorescence in situ hybridization assays. Results:The median serum HER2ECD concentration was6.8ng/ml (range1.3-42.1ng/ml). The best diagnostic cut-off value was7.4ng/ml, with72.9%sensitivity and85.3%specificity, which was lower than HER2ECD cut-off value with metastasis breast cancer. High serum HER2ECD levels were reported in89patients (38.3%) and HER2tissue positive expression was observed in77patients (33.2%) with a moderate concordance of76.7%. Elevated serum HER2ECD correlated with postmenopausal (p<0.001), high tumor grade (p<0.001), negativity of both estrogen (p=0.007) and progesterone receptors (p<0.001), high level of carbohydrate antigen153(CA153)(p=0.039) and tissue polypeptide specific antigen (TPS)(p=0.018). Conclusion: HER2ECD may provide more additional information compared with HER2tissue alone. We support that it is necessary to decrease the cut-off value in evaluating serum HER2ECD level for early stage of breast cancer.
引文
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