Predicting tissue HER2 status using serum HER2 levels in patients with metastatic breast cancer

BACKGROUND: Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) are reliable ways to identify overexpression or amplification of the HER-2/neu (HER2, symbol ERBB2) gene, but each technique requires a high-quality tissue sample, which may not be available. We investigated whether serum concentrations of the HER2 extracellular domain (ECD) can be used as an alternative to tissue HER2 status in metastatic breast cancer, and we defined an optimal decision-level concentration of serum HER2 for prediction of tissue HER2 status. METHODS: In 195 patients with metastatic breast cancer, we determined HER2 expression by IHC and performed FISH analysis on tumors for which IHC staining was graded as 2+. We measured serum HER2 by immunoassay and used ROC curve analysis to determine optimal serum HER2 ECD concentrations for differentiation between positive and negative HER2 status. RESULTS: IHC results were 0/1+ for 30 (15%) of the patients, 2+ for 89 (46%), and 3+ for 76 (39%). FISH revealed HER2 amplification in 19 (21%) of the IHC 2+ tumors. Mean (SE) serum HER2 ECD was 22.2 (5.1) microg/L in the tissue HER2-negative group, significantly lower than the concentration of 363 (96) microg/L in the tissue HER2-positive group (P<0.0001). ROC curve analysis showed 95% specificity and 62% sensitivity for tissue HER2 positivity at 37 microg/L of serum HER2. CONCLUSION: To use serum HER2 concentration as an alternative to direct determination of tissue HER2 status, we suggest 37 microg/L as a cutoff for predicting positive tissue HER2 with 95% specificity. Sensitivity, however, is low.     

Prognostic and predictive implications of HER2 status for breast cancer patients

Women diagnosed with breast cancer face many emotional and psychological challenges, which are often related to how they perceive their chances of survival. A number of factors are known to be indicators of breast cancer prognosis, including tumour type, size and grade, and lymph node status. These factors can be used alone or in combination to make management decisions based on a broad assessment of tumour aggression. However, identifying an independent marker of prognosis has proved more difficult. The human epidermal growth factor receptor-2 (HER2) is amplified/overexpressed in 25–30% of breast tumours. This event has been shown to be associated with poor prognosis in breast cancer patients. Initial observations indicated that median survival duration is reduced by at least 50% in patients who overexpress HER2 compared with those who do not overexpress the receptor. This finding has been supported by many subsequent studies and data are accumulating to indicate that the relationship holds for both node-negative and node-positive patients. This could be particularly important for identifying the 30% of node-negative patients who will progress despite therapy. HER2 status may also be able to predict the outcome of therapy. It appears likely that HER2 overexpression predicts for resistance to tamoxifen and other hormonal therapies. It is also possible that HER2-overexpressing patients may respond better to dose-intense anthracycline therapy and worse to cyclophosphamide/methotrexate/5-fluorouracil than non-overexpressing patients. Explaining these associations to patients may empower them to deal with the psychological effects of a diagnosis of breast cancer while providing hope for the future.     

Prognostic markers in breast cancer: the reliability of HER2/neu status in core needle biopsy of 325 patients with primary breast cancer

INTRODUCTION: The assessment of HER2/neu overexpression in tissue provides information about one of the most relevant prognostic and predictive markers in breast cancer: overexpression of HER2/neu is associated with worse prognosis in primary breast cancer. Since core needle biopsy is increasingly used for the diagnosis of breast cancer, the purpose of this study was to assess the reliability of HER2/neu evaluation using this technique in patients with primary breast cancer. PATIENTS AND METHODS: We investigated the accuracy of immunohistochemical assessment of HER2/neu in core needle biopsies compared with surgically obtained specimens in 325 patients with primary breast cancer. In patients strongly positive for HER2/neu, additional fluorescence in situ hybridization (FISH) analysis of needle biopsies was performed. RESULTS: Using immunohistochemistry alone, accuracy of HER2/neu assessment in core biopsies in relation to surgically removed specimens was 92% and increased to 96% with additional FISH analysis (weighted Kappa coefficient: 0.86). DISCUSSION: As proven with this large series of patients, the assessment of HER2/neu status by core needle biopsy in breast cancer is accurate. Notwithstanding, in order to minimize the number of false-positive results, strongly positive core needle biopsies identified using immunohistochemistry should be confirmed by FISH analysis.     

Treatment of brain metastases in patients with HER2+ breast cancer

Brain metastases are a frequent complication of cancer. However, effective treatments are available. This article aims to review clinical aspects of patients with brain metastases discussing the various treatment options for such patients. It will address the importance and significance of brain metastases in patients with breast cancer and, finally, review the problem of brain metastasis associated with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. With ever-improving survival rates of patients with cancer, there is a greater likelihood that many will develop brain metastases. Treatments such as whole brain or stereotactic radiotherapy and surgery have been shown to be effective against brain metastases. In HER2+ breast cancer, trastuzumab has been shown to be very effective, although it cannot cross the blood-brain barrier. If patients with breast cancer who are being treated with trastuzumab and are responding systemically, develop brain metastases, then patient prognosis does need to be taken into account; however, maintaining treatment with trastuzumab while using available therapies to treat intracranial lesions should be considered as an option.     

Treatment of brain metastases in patients with HER2+ breast cancer

Brain metastases are a frequent complication of cancer. However, effective treatments are available. This article aims to review clinical aspects of patients with brain metastases discussing the various treatment options for such patients. It will address the importance and significance of brain metastases in patients with breast cancer and, finally, review the problem of brain metastasis associated with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. With ever-improving survival rates of patients with cancer, there is a greater likelihood that many will develop brain metastases. Treatments such as whole brain or stereotactic radiotherapy and surgery have been shown to be effective against brain metastases. In HER2+ breast cancer, trastuzumab has been shown to be very effective, although it cannot cross the blood-brain barrier. If patients with breast cancer who are being treated with trastuzumab and are responding systemically, develop brain metastases, then patient prognosis does need to be taken into account; however, maintaining treatment with trastuzumab while using available therapies to treat intracranial lesions should be considered as an option.     

HER2: the neu prognostic marker for breast cancer

A fundamental mechanism of genetic alteration is amplification of entire gene sequences that results in overexpression of a gene product or protein. If the amplified gene is a member of the oncogene family and/or a regulator of DNA replication or cell cycle progression, overexpression of this oncoprotein may result in enhanced growth advantages for these cells. Amplification of one such oncogene, HER2 (neu, erbB-2), in up to 35% of human breast cancers is associated with a poor prognosis but may predict response to various therapeutic modalities. FDA-approved assays are available to detect the HER2 protein receptor or the HER2 gene sequence to determine eligibility for Herceptin treatment or adriamycin treatment in node positive patients, respectively. As testing for HER2 is becoming more common in the clinical laboratory, we provide an overview of the biology, diagnostic methods, and emerging clinical value of HER2 gene amplification.     

Adjuvant treatment of breast cancer: impact of monoclonal antibody therapy directed against the HER2 receptor

The use of chemotherapy and endocrine therapies as adjuncts to the treatment of early-stage breast cancer has yielded small but significant improvements in disease-free and overall survival. Increased understanding of the role of growth factor receptors enabled the rational development of agents that are capable of modulating their function. A humanised monoclonal antibody to the HER2 receptor, trastuzumab, has demonstrable single-agent activity in metastatic breast cancer and enhances the antitumour effects of chemotherapy. As a consequence, trastuzumab has been tested in the adjuvant setting the results of which have been presented recently. This review briefly summarises the use of trastuzumab in advanced breast cancer and describes recent studies of its use in the adjuvant setting.     

Adjuvant treatment of breast cancer: impact of monoclonal antibody therapy directed against the HER2 receptor

The use of chemotherapy and endocrine therapies as adjuncts to the treatment of early-stage breast cancer has yielded small but significant improvements in disease-free and overall survival. Increased understanding of the role of growth factor receptors enabled the rational development of agents that are capable of modulating their function. A humanised monoclonal antibody to the HER2 receptor, trastuzumab, has demonstrable single-agent activity in metastatic breast cancer and enhances the antitumour effects of chemotherapy. As a consequence, trastuzumab has been tested in the adjuvant setting the results of which have been presented recently. This review briefly summarises the use of trastuzumab in advanced breast cancer and describes recent studies of its use in the adjuvant setting.     

Shed HER2 surrogacy evaluation in primary breast cancer patients: a study assessing tumor tissue HER2 expression at both extracellular and intracellular levels

The aim of the present study was to investigate serum HER2 extracellular domain (ECD) as a putative surrogate marker of the shedding phenomenon of HER2 receptor from the tumor tissue of primary breast cancer (BC) patients. A pilot retrospective study was conducted on 100 matched serum and tissue samples from patients with node-positive primary BC, stage II/III. Analysis of association and concordance between serum HER2 ECD levels (measured by chemiluminescence immunoassay) and the expression in matched tumor tissue of HER2 ECD and intracellular receptor domain (ICD) (determined by immunohistochemistry) were performed. The median serum HER2 ECD level was 9.4?ng/ml and cutoff values were set at 15.2?ng/ml or 13.0?ng/ml. HER2 ICD and ECD were overexpressed in tumor tissue of 19.8% and 6.9% of patients, respectively. Statistically significant associations were found between serum HER2 ECD levels and tissue expression of both HER2 ICD and ECD (p?<?.001; Fisher analysis). Moreover, strong concordances were found between serum HER2 ECD levels and tissue expression of HER2 ICD or ECD (cutoff 15.2?ng/ml: 80 and 92.5%, respectively). Our findings support a role for serum HER2 ECD as a surrogate marker of tissue HER2 status in primary BC, both for HER2 ICD or ECD expression.     

HER2阳性乳腺癌患者ER表达状态与高频超声及SWE特征的相关性研究

目的:探讨人表皮生长因子受体2(human epidermal growth factor 2,HER2)表达阳性的乳腺癌患者,其雌激素受体(estrogen receptor,ER)表达状态与高频超声及剪切波弹性成像(shear wave elastography,SWE)图像特征的相关性.方法:选取2019年3月—...     

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.     

Cardiotoxicity associated with trastuzumab treatment of HER2+ breast cancer

Introduction

Although having high clinical efficacy in the treatment of human epidermal growth factor receptor-2 (HER2+) metastatic breast cancer, trastuzumab has been associated with cardiotoxicity, and the etiology and pathogenesis of this condition is currently under investigation.

Methods

This paper reviews the cardiotoxicity, associated with trastuzumab use and discusses the risk assessment and management of cardiac dysfunction.

Results

The increased risk of cardiotoxicity is lower when trastuzumab is given as monotherapy (3%–7%) compared with anthracyclines + trastuzumab therapy (27%). Type II cardiac changes occur in trastuzumab-treated patients, which do not appear to be dose-related, are not associated with histological changes, and are generally reversible. Several risk factors for cardiac events have been identified and assessing levels of troponin I and N-terminal pro-brain B-type natriuretic peptide before and after treatment with trastuzumab may allow early detection of cardiotoxicity. A symptomatic and functional evaluation scheme for patients indicated for treatment with trastuzumab has also been proposed to work alongside therapeutic options for the treatment of heart failure.

Conclusion

The risk of cardiac dysfunction associated with trastuzumab can be justified given the increase in overall survival. This risk is lower when trastuzumab is given as monotherapy. The paradigm for cardiologists remains the same: treat the cancer effectively whilst preventing cardiotoxicity.

     

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.     

GP和PathVysion HER2试剂盒检测乳腺癌患者HER2基因状态的比较

目的 通过与进口PathVysion HER2试剂盒比较,评价国产金菩嘉GP HER2试剂盒检测乳腺癌患者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(简称"乳腺癌")肿瘤组织标本,分别采用FISH技术与GP HER2试剂盒和PathVysion HER2试剂盒检测乳腺癌患者HER2基因表达水平,比较2种试剂盒检测乳腺癌患者HER2基因表达差异,并评价GP HER2试剂盒检测乳腺癌患者组织标本中HER2基因扩增的敏感度、特异度和准确性.结果 GP HER2试剂盒和PathVysion HER2试剂盒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试剂盒相比,GP HER2试剂盒检测乳腺癌患者组织标本中HER2基因扩增的敏感度、特异度和准确性分别为89.7%(26/29)、98.7%(78/79)和96.3%(104/108),PPV和NPV均为96.3%(26/27,78/81).GP HER2试剂盒检出第17号染色体多倍体的敏感度、特异度和准确性分别为93.3%(14/15)、100%(93/93)和99.1%(107/108).结论 GPHER2试剂盒在检测乳腺癌患者组织标本中HER2基因状态的敏感度和特异度及准确性高,在临床评价乳腺癌HER2基因状态中具有广泛应用价值.     

Interaction of the gp120 V1V2 loop with a neighboring gp120 unit shields the HIV envelope trimer against cross-neutralizing antibodies

The HIV-1 envelope trimer adopts a quaternary conformation that effectively shields neutralization-sensitive domains and thus represents a major obstacle for natural and vaccine-elicited antibody responses. By using a structure-function analysis based on a specifically devised mathematical model, we demonstrate in this study that protection from neutralization is enforced by intersubunit contact between the variable loops 1 and 2 (V1V2) and domains of neighboring gp120 subunits in the trimer encompassing the V3 loop. Our data are consistent with an interaction of the V1V2 and V3 loop at the spike apex as proposed by cryoelectron tomography experiments. By defining the orientation of the V1V2 loop within the trimer toward the neighboring gp120 subunit's V3 loop, our data close an important gap in the understanding of the architecture of the trimeric spike. Knowledge on how the V1V2 barrier functions in the context of the trimer to mask conserved epitopes on gp120 may aid future vaccine design.     

GP和PathVysion HER2试剂盒检测乳腺癌患者HER2基因状态的比较

目的 通过与进口PathVysion HER2试剂盒比较,评价国产金菩嘉GP HER2试剂盒检测乳腺癌患者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(简称"乳腺癌")肿瘤组织标本,分别采用FISH技术与GP HER2试剂盒和PathVysion HER2试剂盒检测乳腺癌患者HER2基因表达水平,比较2种试剂盒检测乳腺癌患者HER2基因表达差异,并评价GP HER2试剂盒检测乳腺癌患者组织标本中HER2基因扩增的敏感度、特异度和准确性.结果 GP HER2试剂盒和PathVysion HER2试剂盒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试剂盒相比,GP HER2试剂盒检测乳腺癌患者组织标本中HER2基因扩增的敏感度、特异度和准确性分别为89.7%(26/29)、98.7%(78/79)和96.3%(104/108),PPV和NPV均为96.3%(26/27,78/81).GP HER2试剂盒检出第17号染色体多倍体的敏感度、特异度和准确性分别为93.3%(14/15)、100%(93/93)和99.1%(107/108).结论 GPHER2试剂盒在检测乳腺癌患者组织标本中HER2基因状态的敏感度和特异度及准确性高,在临床评价乳腺癌HER2基因状态中具有广泛应用价值.