HER-2/neu-gene engineered dendritic cell vaccine stimulates stronger HER-2/neu-specific immune responses compared to DNA vaccination

HER-2/neu is a candidate for developing breast cancer-targeted immunotherapeutics. Although DNA-based and HER-2/neu transgene-modified dendritic cell (DC)-based vaccines are potent at eliciting HER-2/neu-specific antitumor immunity, there has been no side-by-side study comparing them directly. The present study utilizes an in vivo murine tumor model expressing HER-2/neu antigen to compare the efficacy between adenovirus (AdVneu)-transfected dendritic cells (DC(neu)) and plasmid DNA (pcDNAneu) vaccine. Our data showed that DC(neu) upregulated the expression of immunologically important molecules and inflammatory cytokines and partially converted regulatory T (Tr)-cell suppression through interleukin-6 (IL-6) secretion. Vaccination of DC(neu) induced stronger HER-2/neu-specific humoral and cellular immune responses than DNA vaccination, which downregulated HER-2/neu expression and lysed HER-2/neu-positive tumor cells in vitro, respectively. In two HER-2/neu-expressing tumor models, DC(neu) completely protected mice from tumor cell challenge compared to partial or no protection observed in DNA-immunized mice. In addition, DC(neu) significantly delayed breast cancer development in transgenic mice in comparison to DNA vaccine (P<0.05). Taken together, we have demonstrated that HER-2/neu-gene-modified DC vaccine is more potent than DNA vaccine in both protective and preventive animal tumor models. Therefore, DCs genetically engineered to express tumor antigens such as HER-2/neu represent a new direction in DC vaccine of breast cancer.     

Serum HER-2/neu in the management of breast cancer patients

The clinical role of HER-2/neu, a 185 kD epithelial transmembranous protein, has evolved after the approval of the anti-HER-2/neu targeted monoclonal antibody trastuzumab (Herceptin) for the therapy of metastatic breast cancer. The extracellular domain of HER-2/neu undergoes proteolytic cleavage from the full-length protein by metalloproteases, and is shed into the blood as a circulating antigen. While HER-2/neu gene amplification and/or protein overexpression are detected in approximately 25% of primary breast cancers, serum HER-2/neu levels are elevated beyond the upper limit of normal in 50 to 60% of stage IV breast cancer patients. HER-2/neu in serum can be detected by enzyme immunoassays (manual and automated versions). It has been shown to have prognostic and predictive information in breast cancer patients. Monitoring for recurrence by serum HER-2/neu reaches a high sensitivity for HER-2/neu positive tumors. Longitudinal follow-up of patients during any kind of systemic therapy allows for monitoring of the therapeutic success. When utilized in these applications, serum HER-2/neu testing is complementary to HER-2/neu tissue results and to the determination of classical tumor markers such as CA 15-3, CA 27.29 and CEA, which are not targeted by specific forms of systemic therapy.     

Circulating levels of HER-2/neu oncoprotein in breast cancer

HER-2/neu, also known as c-erbB-2/neu, is an oncogene located in chromosome 17 which encodes HER-2/neu, a transmembrane protein belonging to the EGFR family. The external domain of this protein is released by the cell and can be studied in serum by immunoassay. HER-2/neu in serum is a specific tumor marker and only slight elevations may be found in the absence of malignancy, mainly in association with liver diseases. Likewise, the highest concentrations of this oncoprotein are found in patients with breast cancer, but lower concentrations may be found in other malignancies, particularly ovarian, prostate and lung cancer (mainly adenocarcinomas). HER-2/neu assay sensitivity in patients with untreated primary loco-regional breast cancer is <10% and seems to be related to overexpression in tissue as well as to the most important prognostic factors: tumor size and nodal involvement. Serial HER-2/neu determinations after surgery seem to be useful in the early diagnosis of recurrence, mainly in patients with HER-2/neu overexpression in tissue, but additional studies are necessary to confirm these results. HER-2/neu sensitivity (proportion of patients with abnormal values) in patients with metastasis is around 40%-45%, with a clear relationship to tissue overexpression and to site (higher in visceral metastases) and number of metastases. The clinical utility of HER-2/neu in patients with advanced disease is mainly for therapeutic monitoring. Likewise, in most of the studies published, a relationship has been found between serum HER-2/neu levels (either pretreatment or at follow-up) with tumor response.     

应用FISH和IHC技术检测中国乳腺癌患者HER-2基因状态及蛋白表达的前瞻性多中心研究

目的 对比研究乳腺癌患者IHC检测c-erbB2蛋白表达和FISH检测HER-2/neu基因扩增情况,并探讨HER-2基因状态与各临床病理特征的相关性.方法 本研究为全国73家中心参与的前瞻性研究.收集2007年10月至2009年9月乳腺癌患者标本3 249份,应用IHC和FISH两种方法分别检测3 249份乳腺癌患者手术的石蜡标本c-erbB2蛋白表达和HER-2基因扩增情况,并分析HER-2基因状态与患者各临床病理特征的关系.结果 全组患者IHC检测c-erbB2蛋白表达阳性率为46.9%(1477/3149),FISH检测HER-2基因扩增率为42.6%(1342/3149),其中IHC评分为3+和0分时,与FISH检测的一致性较高,分别为94.1%(892/948)和89.9%(660/734),而IHC 1+和2+组与FISH的一致性较低,分别为71.0%(514/725)和55.9%(415/742).同时,HER-2基因扩增与激素状态中雌激素与孕激素均阴性(r=0.45,P<0.01)、组织分级Ⅲ级(r=0.51,P<0.01)、淋巴结转移数目多于4枚(r=0.35,P<0.01)、临床分期Ⅲ/Ⅳ期(r=0.33,P<0.01)、肿瘤直径>2 cm(r=0.38,P<0.01)、绝经后(r=0.24,P<0.01)有相关性,与年龄(r=0.36,P=0.068)、CA125(r=0.11,P=0.722)、CA153(r=0.23,P=0.45)和CEA(r=0.22,P=0.074)表达情况、淋巴结转移(r=0.15,P=0.18)、肿瘤个数(r=0.21,P=0.056)及脉管瘤栓(r=0.12,P=0.133)无相关性.结论 FISH和IHC两种方法检测HER-2表达状态具有较高的一致性.结合实际情况包括费用仪器等限制,在IHC作为初筛的基础上,仍然推荐FISH作为检测HER-2基因扩增的标准方法.FISH技术检测乳腺癌患者HER-2基因表达状态可为临床指导用药和预后评价提供更可靠的依据.     

HER-2/neu gene copy number quantified by real-time PCR: comparison of gene amplification,heterozygosity, and immunohistochemical status in breast cancer tissue

BACKGROUND: Amplification of the oncogene HER-2/neu influences breast cancer pathogenesis, and therapy and prognosis may be affected by the degree of amplification. The extent of amplification or protein overexpression typically is analyzed by fluorescence in situ hybridization or immunohistochemistry (IHC), but quantitative PCR techniques have been described that may provide alternatives to these methods. METHODS: We developed a rapid-cycle, real-time PCR assay for quantification of HER-2/neu gene status. We compared results obtained with this assay with short tandem repeat findings by capillary electrophoresis (CE) and with protein overexpression assessments by IHC. Accuracy and linearity were tested on cell lines and with simulation experiments. We analyzed the amplification of HER-2/neu in 51 clinical tissue samples from patients with suspected breast cancer. RESULTS: The intra- and interrun CVs for HER-2/neu quantification by real-time PCR were 12% and 18%, and the CV for different simulated amplification and deletion experiments was <7%. The results for HER-2/neu gene status in cell lines matched the values reported in literature. We detected HER-2/neu amplification by real-time PCR in 11 samples, all from patients with invasive ductal carcinoma. Allelic imbalances were found by CE analyses in three samples and by protein overexpression in six samples; five of these were also detected by real-time PCR. Comparison of the quantification results with known prognostic indices yielded results similar to those reported in several other published studies. CONCLUSIONS: The assay is suitable for accurate and precise quantification of HER-2/neu copy numbers in tumor tissue samples obtained in routine clinical practice.     

Relationship of serum HER-2/neu and serum CA 15-3 in patients with metastatic breast cancer

BACKGROUND: Serum HER-2/neu antigen concentrations have been reported to correlate with increased tumor volume in patients with breast cancer. We measured serum CA 15-3, a surrogate marker of disease burden, and correlated serum CA 15-3 with serum HER-2/neu and analyzed the association of both markers with clinical outcomes. METHODS: Pretreatment serum samples from 566 patients were retrospectively analyzed from 2 phase III clinical trials of estrogen receptor-positive (ER(+)), ER(-)/progesterone receptor-positive, or ER status unknown metastatic breast cancer patients randomized in two similar studies to receive second-line hormone therapy with either megestrol acetate or an aromatase inhibitor (fadrozole). The extracellular domain of the HER-2/neu (c-erbB-2) oncogene and serum CA 15-3 were measured by ELISA on the Bayer Immuno 1. RESULTS: Serum HER-2/neu protein was increased in 168 patients (30%), and CA 15-3 was increased in 337 (60%) patients. Serum CA 15-3 and HER-2/neu were weakly correlated (r = 0.39; P <0.0001). The clinical benefit (complete responses plus partial responses plus stable disease) of endocrine therapy was significantly lower in patients with increased serum HER-2/neu. When adjusted for serum HER-2/neu, serum CA 15-3 was not predictive of response rates. The median time to progression was shorter in patients with increased serum HER-2/neu (89 days) compared with patients with normal serum HER-2/neu (176 days). Survival was significantly shorter in patients with increased serum HER-2/neu (513 vs 869 days; P <0.0001) or increased serum CA 15-3 (689 vs 939 days; P <0.0001). This observation was confirmed by multivariate analysis. CONCLUSIONS: Serum HER-2/neu is a significant independent predictive and prognostic factor in hormone receptor-positive metastatic breast cancer, even when adjusted for tumor burden as measured by CA 15-3. The combination of increased serum HER-2/neu and increased serum CA 15-3 predicts a worse prognosis than does increased CA 15-3 alone.     

Antitumor efficacy of trastuzumab in nude mice orthotopically xenografted with human pancreatic tumor cells expressing low levels of HER-2/neu

The monoclonal antibody trastuzumab binds to the extracellular domain of HER-2/neu and induces clinical responses in breast tumors with HER-2 gene amplification and/or protein overexpression. Its role in other tumor types remains to be investigated. We evaluated the antitumor efficacy of trastuzumab in vitro and in nude mice implanted orthotopically with cells of 3 human pancreatic tumor lines expressing only low levels of HER-2/neu, as determined by flow cytometry. Although none of the 3 cell lines showed growth inhibition when cultured directly with trastuzumab, 2 of them, GER and PaCa3, were sensitive to lysis in antibody-dependent cellular cytotoxicity assay. This pattern of response was recapitulated in tumor-bearing mice repeatedly treated with trastuzumab, in which survival was significantly prolonged as compared with controls (P=0.03 for GER and 0.0008 for PaCa3). Incidence of metastases was also reduced, especially in liver. These preclinical results indicate that trastuzumab can exert an antitumor effect against orthotopic human pancreatic cancer xenografts with low-level HER-2/neu expression and that this effect correlates with the in vitro antibody-dependent cellular cytotoxicity susceptibility, suggesting a different role for HER-2/neu in the therapy of tumor types other than breast cancer.     

HER-2/neu在上皮性卵巢癌中的表达及其临床意义

目的：研究HER-2／neu在上皮性卵巢癌患者中的表达情况及其临床意义。方法：应用免疫组织化学SP法检测52例上皮性卵巢癌、10例卵巢交界性肿瘤、10例卵巢良性上皮性肿瘤中HER-2蛋白的表达情况。结果：上皮性卵巢癌中的HER-2阳性表达率显著高于卵巢良性上皮性肿瘤及卵巢交界性肿瘤，差异有显著性（P=0．045）。HER-2／neu蛋白在不同组织学类型、病理分级及临床分期上皮性卵巢癌中的表达差异无显著性（P〉0．05）。HER-2／neu蛋白阳性组平均生存时间短于阴性组（16．9个月vs40．7个月），经Log Rank检验，差异有显著性（P=0．005）。结论：HER-2／neu蛋白的过表达可能在上皮性卵巢癌的发生和发展中起一定作用，且与上皮性卵巢癌患者的不良预后相关．显著缩短患者术后生存时间。是上皮性卵巢癌患者的不良预后因素。[     

抑制素和激活素在上皮性卵巢癌中的表达及其与卵巢癌发病机制的关系

目的：研究人表皮生长因子受体2（human epidermal growth factor receptor 2，HER-2/neu）在上皮性卵巢癌患者中的表达情况及其临床意义。方法：应用免疫组织化学SP法检测52例卵巢癌、10例交界性卵巢肿瘤、10例良性上皮性卵巢肿瘤中HER-2蛋白的表达情况。结果：（1）卵巢癌中的HER-2阳性表达率显著高于卵巢良性上皮性肿瘤及卵巢交界性肿瘤，差异有显著性(P=0.045)。（2）HER-2/neu蛋白在不同组织学类型、病理分级及临床分期卵巢癌中的表达差异无显著性(P>0.05)。（3）生存时间比较：HER-2/neu蛋白阳性组平均生存时间短于阴性组（16.9月与40.7月），经Log Rank检验，差异有显著性（P=0.005）。结论：HER-2/neu蛋白的过表达可能在卵巢癌的发生和发展中起一定作用，且与卵巢癌患者的不良预后相关，显著缩短患者术后生存时间，是卵巢上皮性癌患者的不良预后因素。     

Immunization with a HER-2/neu helper peptide vaccine generates HER-2/neu CD8 T-cell immunity in cancer patients

CD4 T-cell help is required during the generation and maintenance of effective antitumor CD8 T cell-mediated immunity. The goal of this study was to determine whether HER-2/neu-specific CD8 T-cell immunity could be elicited using HER-2/neu-derived MHC class II "helper" peptides, which contain encompassed HLA-A2-binding motifs. Nineteen HLA-A2 patients with HER-2/neu-overexpressing cancers received a vaccine preparation consisting of putative HER-2/neu helper peptides p369-384, p688-703, and p971-984. Contained within these sequences are the HLA-A2-binding motifs p369-377, p689-697, and p971-979. After vaccination, the mean peptide-specific T-cell precursor frequency to the HLA-A2 peptides increased in the majority of patients. In addition, the peptide-specific T cells were able to lyse tumors. The responses were long-lived and detectable for more than 1 year after the final vaccination in select patients. These results demonstrate that HER-2/neu MHC class II epitopes containing encompassed MHC class I epitopes are able to induce long-lasting HER-2-specific IFN-gamma-producing CD8 T cells.     

The clinical significance between activation of nuclear factor kappa B transcription factor and overexpression of HER-2/neu oncoprotein in Taiwanese patients with breast cancer

BACKGROUND: This study investigated the role of nuclear factor-kappa B (NF-kappaB) activity in human breast cancer with overexpression of HER-2/neu oncoprotein, as well as its role on expression of different histological grades of cancer cells taken from Taiwanese breast cancer patients. MATERIALS AND METHODS: Specimens were collected from 82 female breast cancer patients. The HER-2/neu oncoprotein was measured by immunohistochemistry. NF-kappaB activity expression was assessed by the electrophoretic mobility shift assay, and confirmed by the supershift technique using anti-P65 antibody in both breast cancer tissue and the adjacent normal tissue. The histological grades were measured by Modified Bloom-Richardson Grading Scheme. RESULTS: Of the 82 cancer specimens, 81 (98.7%) showed higher or equal expressions of NF-kappaB activity when compared to the adjacent normal tissue. Fifty-five cases (67.1%) had higher levels of NF-kappaB activity in the cancerous tissue than in the adjacent normal tissue (p<0.005). With regard to tumor size, steroid receptors, stages, histological types, and node status, there were no statistically significant differences in NF-kappaB activity between cancerous tissues and adjacent normal tissues. However, significantly higher expressions of NF-kappaB activity were seen in those cases with positive HER2/neu oncoprotein, poorly differentiated histological grades, high nuclear pleomorphisms, and high mitotic counts (p<0.05). Positive HER-2/neu overexpression of oncoprotein had higher NF-kappaB activity (86%) than negative overexpression (60%) (p<0.05). It has been shown that the NF-kappaB activity increases in the HER-2/neu oncoprotein overexpression in human breast cancer. CONCLUSION: Overexpression of HER-2/neu gene could induce NF-kappaB activity in human breast cancer cells, as has been confirmed in other research on cell lines.     

阿那曲唑联合依维莫司治疗乳腺癌的效果及对血清HER-2/neu、p185水平的影响

目的探究阿那曲唑联合依维莫司用于治疗乳腺癌的临床疗效及其对患者血清中人类表皮生长因子受体2蛋白(HER-2/neu)、p185水平的影响。方法选取2013年1月至2018年12月广元市第一人民医院治疗的符合纳入标准的患者1000例,按照随机数字表法分为对照组(n=500)和观察组(n=500)。对照组给予口服阿那曲唑片,观察组在对照组的基础上给予口服依维莫司片。治疗3个月后,观察比较2组患者的临床疗效及不良反应发生率,比较2组患者雌激素、HER-2/neu、p185水平。结果观察组的临床缓解率为60.60%,要明显高于对照组(54.20%),差异有统计学意义(χ^2=4.190,P=0.041)。治疗前,2组患者的雌二醇(E2)、黄体生成素(LH)、HER-2/neu、p185水平比较,差异无统计学意义(P>0.05)。经过3个月的治疗,观察组的E2、LH、HER-2/neu、p185水平均明显低于对照组(t=8.148,P=0.000;t=85.170,P=0.000;t=20.209,P=0.000;t=16.109,P=0.000)。治疗过程中,对照组和观察组患者不良反应发生率分别为8.60%和7.60%,差异无统计学意义(χ^2=0.340,P=0.562)。结论阿那曲唑联合依维莫司治疗乳腺癌具有良好的临床疗效,可抑制肿瘤细胞的生长发育,降低患者体内雌激素水平,且安全性高。     

HER-2/neu assessment in breast cancer by immunohistochemistry and fluorescence in situ hybridization: comparison of results and correlation with survival.

BACKGROUND: HER-2/neu immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) results guide breast cancer therapy; however, few studies compared the results and no published studies have correlated them with patient outcome. METHODS AND RESULTS: We compared results, cost, and turnaround time in 117 archival, invasive breast carcinomas and compared 50-month survival in 65 of these cases using commercial HER-2/neu IHC and FISH assays. Twenty-one of 112 FISH (19%) and 33 of 117 IHC cases (28%) were positive. Concordance was high overall (88%; 98 of 112 cases) and in IHC 3+ cases (88%; 14 of 16 cases) but low in IHC 2+ cases (35%; six of 17 cases). Survival correlated with IHC results in 3+ cases (P =.02) and FISH cases with signal ratio greater than 4.0 (P =.03), but not in IHC 2+ cases (P=.7). Cost and turnaround time were greater for FISH. CONCLUSION: IHC is appropriate for initial HER-2/neu assessment; however, patients with tumors scored less than 3+, particularly those interpreted as 2+, would benefit from FISH to more accurately assess HER-2/neu status and avoid inaccurate prognostication and inappropriate treatment.     

COX-2、HER-2和VEGF在乳腺癌中的表达及其临床意义

【目的】研究环氧化酶-2（cOx-2）在乳腺癌组织中的表达情况与,临床病理指标及预后之间的相关性及与VEGF和HER-2表达的关系。【方法】检测120例乳腺癌石蜡包埋组织中COX-2、HER-2和VEGF的表达。【结果】120例中cox-2的高表达率为38．3％（46／120）。淋巴结转移阳性组和阴性组以及不同临床分期的病人之间COX-2的表达差异有显著意义（P〈0．05）,而与病人年龄、肿瘤大小、病理类型、ER、PR等差异无显著意义（P〉0．05）。COX-2在乳腺癌组织中的表达与HER-2／neu、VEGF的表达密切相关（P〈0．01）。COX-2和HER-2共同表达的患者与两者单独表达的患者相比,前者的TNM分期较晚,有显著差异（P=0．027）。COx_2和VEGF共同表达与单独表达的TNM分期无显著差异（P=0．479）。COX-2低表达的患者总生存期较长,与高表达患者的总生存期有显著差异（P〈0．005）。【结论】乳腺癌组织中COX-2的高表达可提示恶性程度高和预后不良。乳腺癌组织中COX-2与HER-2、VEGF的表达相关,且COX-2和HER-2／neu同时高表达时预后更差。     

HER-2/neu基因表达与卵巢上皮性癌的预后

【目的】探讨HER-2／neu基因在卵巢上皮性癌中的表达水平及其与预后的关系。【方法】利用免疫组化检测93例卵巢上皮性癌组织中HER-2／neu基因表达水平,并结合临床病理及随访资料进行分析。【结果】HER-2／neu基因主要为细胞膜及胞浆表达,阳性率为44．1％。其表达与临床分期、病理类型、组织学分级及残余灶直径等无相关性;但与预后相关。HER-2／neu表达阴性组的1,3,5年生存率分别为90．4％、74．0％、54．6％,弱阳性组分别为81．1％、45．4％、27．9％,强阳性组分别为80．0％、20．0％、10．0％。差异有显著性(P=0．0028)。COX模型多因素分析提示：HER-2／neu表达水平是影响卵巢癌预后的独立因素(P=0．005)。【结论】HER-2／neu基因表达水平可作为预测卵巢上皮性癌预后的可靠指标。     

三羟异黄酮对HER-2/neu过度表达乳腺癌裸鼠移植瘤血管生成的抑制作用

背景血管生成是判断肿瘤预后的一个重要标志.原癌基因HER-2/neu高表达乳腺癌患者预后不良,大量研究资料表明三羟异黄酮对乳腺癌有抗癌作用.目的探讨乳腺癌HER-2/neu表达状态与血管生成的关系,以及三羟异黄酮对HER-2/neu过度表达乳腺癌血管生成的影响.设计以实验动物为研究对象,随机对照观察研究.单位一所军医大学营养与食品卫生学教研室.材料20只健康雌性BALB/c裸小鼠,SPF级,体质量(10±2)g,鼠龄3～4周,购自第三军医大学实验动物中心.方法实验于2001-06/2002-03在第三军医大学营养与食品卫生学教研室完成.HER-2/neu表达阴性的乳腺癌MCF-7细胞通过转染HER-2/neu基因建立HER-2/neu过度表达的MCF-7细胞(命名为MCF-7/HER-2细胞),建立MCF-7和MCF-7/HER-2细胞BALB/c裸鼠移植瘤模型.4周后,MCF-7/HER-2细胞移植瘤裸鼠随机分为3组对照组,三羟异黄酮处理组和抗HER-2/neu抗体处理组.3周后处死动物,切下移植瘤,检测肿瘤体积、微血管密度和血管内皮生长因子表达.主要观察指标主要结局裸鼠移植瘤微血管密度(microvessel density,MVD)及血管内皮生长因子(vasular endothelial growthfactor,VEGF).次要结局①MCF-7细胞转染HER-2/neu的鉴定.②裸鼠移植瘤体积.结果MCF-7细胞移植瘤组、MCF-7/HER-2细胞移植瘤对照组、三羟异黄酮处理组、HER-2/neu抗体处理组微血管密度分别为(16±6),(98±21),(56±18),(52±19)个/视野.MCF-7/HER-2细胞移植瘤的微血管密度和血管内皮生长因子水平显著高于MCF-7细胞移植瘤,而三羟异黄酮和抗HER-2/neu抗体处理明显降低MCF-7/HER-2细胞移植瘤的微血管密度和血管内皮生长因子水平,移植瘤体积变化特点与微血管密度和血管内皮生长因子水平变化类似.结论乳腺癌过度表达HER-2/neu促进血管生成,而三羟异黄酮能抑制HER-2/neu过度表达乳腺癌的血管生成,这有助于改善乳腺癌的预后.     

Potential clinical utility of serum HER-2/neu oncoprotein concentrations in patients with breast cancer

BACKGROUND: The HER-2/neu oncogene and its p185 receptor protein are indicators of a more aggressive form of breast cancer. HER-2/neu status guides Herceptin therapy, specifically directed to the extracellular domain (ECD) of the HER-2/neu oncoprotein. The HER-2/neu ECD is shed from cancer cells into the circulation and is measurable by immunoassay. METHODS: We performed a systematic review of the peer-reviewed literature on circulating ECD with respect to prevalence, prognosis, prediction of response to therapy, and monitoring of breast cancer. RESULTS: The prevalence of increased ECD in patients with primary breast cancer varied between 0% and 38% (mean, 18.5%), whereas in metastatic disease the range was from 23% to 80% (mean, 43%). Some women with HER-2/neu-negative tumors by tissue testing develop increased ECD concentrations in metastatic disease. Increased ECD has been correlated with indicators of poor prognosis, e.g., overall survival and disease-free survival. Increased ECD predicts a poor response to hormone therapy and some chemotherapy regimens but can predict improved response to combinations of Herceptin and chemotherapy. Many studies support the value of monitoring ECD during breast cancer progression because serial increases precede the appearance of metastases and longitudinal ECD changes parallel the clinical course of disease. CONCLUSIONS: The monitoring of circulating HER-2/neu ECD provides a tool for assessing prognosis, for predicting response to therapy, and for earlier detection of disease progression and timely intervention with appropriate therapy.     

乳腺癌患者血清HER-2／neu浓度及临床意义的分析

目的分析乳腺癌患者血清人表皮生长因子受体．2（HER-2／neu）的水平与组织HER-2表达水平的差异,分析血清HER-2／neul的影响因素以及与化疗疗效的相关性。方法采用酶联免疫吸附（ELISA）方法检测37例可手术的早期乳腺癌患者及74例晚期转移性乳腺癌患者血清HER-2／neu的水平,分析血清HER-2／neu与组织中HER-2的表达、临床参数的相关性。结果晚期乳腺癌患者血清HER-2／neu的水平与组织HER-2的状态一致性较好（P〈0．05）,早期乳腺癌患者中两者则无明显关系。乳腺癌血清HER-2的水平与血清CA153、CEA均无明显相关性。晚期乳腺癌血清HER-2的水平与肿瘤大小、远处转移数目、脉管瘤栓具有明显关系,而与月经状况、ER、PR均无明显关系（P〉0．05）。血清HER-2水平的变化与化疔疗效有关（P〈0．05）。结论晚期乳腺癌患者血清HER-2／neu水平与肿瘤组织中HER-2表达是一致的且与肿瘤负荷密切相关,可作为组织学检测的重要补充方法。     

Adenovirus-mediated ribozyme targeting of HER-2/neu inhibits in vivo growth of breast cancer cells

HER-2/neu is overexpressed in 25-30% of human breast cancers. We prepared an anti-HER-2/neu hammerhead ribozyme expressed by a recombinant adenovirus (rAdHER-Rz). Human breast cancer cell lines were transduced with high efficiency, resulting in decreased HER-2/neu expression. In vivo injections of rAdHER-Rz into BT-474 tumors established in nude mice inhibited tumor growth to 20% of mock-treated controls. Similar in vivo effects were shown in MCF-7 cells, which do not overexpress HER-2/neu. The growth inhibitory effects of rAdHER-Rz were greater than those of an antisense-expressing vector. These results suggest the utility of anti-HER-2/neu ribozymes as a rational strategy for gene therapy of breast cancer. Gene Therapy (2000) 7, 241-248.     

Antibody association with HER-2/neu-targeted vaccine enhances CD8 T cell responses in mice through Fc-mediated activation of DCs

The pathogenic nature of cancer is attributed, at least in part, to the ability of tumors cells to induce systemic and local mechanisms of immune tolerance. However, we previously reported that tumor-free survival in up to 100% of tolerized HER-2/neu transgenic mice can be achieved by administration of neu-specific mAb concurrently with a HER-2/neu-expressing, GM-CSF-secreting whole cell vaccine. In this report, we show that one mechanism of improved antitumor activity induced by the combination of these 2 neu-targeted interventions was enhanced Fc-mediated activation of APCs. Specifically, in vivo studies demonstrated localization of radiolabeled neu-specific mAb at the vaccine site. Subsequently, increased accumulation of neu-specific mAb at the vaccine-draining lymph node correlated with increased vaccine cell uptake by DCs in vivo. This led to enhancement of CD8(+) neu-specific T cell function in terms of proliferation, cytokine production, and central memory development. Thus, the administration of a neu-specific mAb with a neu-targeted GM-CSF-secreting tumor vaccine enhanced induction of neu-specific CD8(+) T cells through Fc-mediated activation of DCs. This multimodality attack on the same tumor antigen may have the potential to overcome tolerance to self antigens and weaken the immunosuppressive networks within the tumor microenvironment.