雄激素受体（AR)在HER-2过表达型乳腺癌中的作用及机制研究进展

人表皮生长因子受体-2（human epidermal growth factor receptor-2,HER-2）过表达型乳腺癌是乳腺癌中具有侵袭性的亚型之一,与其他类型乳腺癌相比,此类型疾病进展迅速,易复发转移,且预后差。近年来,研究表明雄激素受体（androgen receptor,AR）在HER-2过表达型乳腺癌中高表达。因此,本文将对AR在HER-2过表达型乳腺癌中的作用机制,对预后的影响及最新研究进展进行综述,以期为未来研究提供新的思路。     

雄激素受体在Luminal B型乳腺癌中的表达及意义

目的 探讨雄激素受体(AR)在人Luminal B型乳腺癌中的表达情况及其与临床特征间关系.方法 选取76例Luminal B型乳腺癌患者病理标本,应用免疫组织化学方法 检测AR表达情况,同时分析AR的表达与乳腺癌患者年龄、绝经与否、肿瘤大小、淋巴结转移、组织分级、临床分期及Her-2的关系.结果 76例Luminal B型乳腺癌患者中,AR表达阳性的患者54例,阳性率为71.1%.AR阳性表达率在年龄、肿瘤直径、是否绝经、组织学分级、Her-2是否阳性中差异均无统计学意义(P>0.05).不同TNM分期肿瘤患者AR表达情况不同,差异有统计学意义(P<0.05).结论 AR在Luminal B型乳腺癌中具有较高的表达率,且其与肿瘤临床分期有关,AR可能为Luminal B型乳腺癌的治疗提供新的靶点.     

cNCCN指南对Her-2过表达型乳腺癌治疗的指导意义

摘 要：［目的］ 总结在cNCCN指导下的Her-2过表达型乳腺癌的临床特征、诊疗现状及相应预后;判定cNCCN指南对于Her-2过表达型乳腺癌临床治疗的指导价值。［方法］ 回顾性分析具有明确病理学诊断的530例Her-2过表达型乳腺癌患者资料,并进行预后因素分析。［结果］ 根据2007～2011各年cNCCN乳腺癌临床实践指南,紫杉类药物规范治疗组较非规范治疗组的OS延长(49.379个月 vs 2.087个月,P=0.024);而蒽环类规范治疗组与非规范治疗组的PFS及OS无统计学差异。对于AJCC分期Ⅲ期Her-2过表达型乳腺癌患者,紫杉规范治疗组较蒽环规范治疗组PFS明显延长(49.875个月 vs 31.594个月,P=0.036),而两组之间的OS无统计学差异(P=0.369);AJCCⅠ期,Ⅱ期,Ⅳ期及淋巴结阴性的紫杉规范治疗组与蒽环规范治疗组的PFS及OS无统计学差异(P<0.05)。规范放疗组较非规范放疗组延长了OS(54.360个月vs 45.927个月,P=0.044);赫塞汀规范治疗组较非规范治疗组的延长了PFS(66.758个月vs 52.863个月,P=0.027),但OS无统计学意义(P=0.059)。［结论］ 对于Her-2过表达型乳腺癌,规范的紫杉醇类化疗方案、规范放疗可延长患者的总生存,而赫塞汀规范应用可改善其无病生存期。     

pAKT在恩度诱导Her-2过表达乳腺癌细胞凋亡中的作用

目的:检测经不同浓度的恩度处理后Her-2过表达乳腺癌细胞MDA-MB-453中pAKT的表达量,初步探讨pAKT在恩度诱导的肿瘤细胞凋亡中的作用。方法:常规体外培养MDA-MB-453细胞,分别用浓度为0 μg/ml、200 μg/ml、400 μg/ml、800 μg/ml的恩度处理细胞24 h,Western Blot法检测各浓度恩度处理后细胞的pAKT表达量。结果:随恩度浓度增加,细胞中pAKT表达量逐渐下降。与0 μg/ml恩度组相比,200 μg/ml组与之无统计学差异（P=0.306）,400 μg/ml和800 μg/ml组与之比较均有统计学差异（P<0.05）,但400 μg/ml组与800 μg/ml组之间无统计学差异（P=0.91）。结论:pAKT表达下调可能参与介导恩度诱导的Her-2过表达乳腺癌细胞凋亡。     

Her-2过表达乳腺癌复发相关因素分析(附6例报告)

目的探讨Her-2过表达乳腺癌的复发相关因素。方法选取2013年6月至2014年8月镇江市第一人民医院治疗的6例Her-2过表达乳腺癌复发转移患者,分析总结Her-2过表达乳腺癌的复发相关因素及分子生物学行为。结果 2例为胸壁局部复发,2例为锁骨上区域淋巴结转移,2例为远处器官转移;所有Her-2过表达复发患者术后病理均提示存在淋巴结转移:1~3枚淋巴结阳性2例;4~9枚淋巴结阳性2例;≥10枚淋巴结阳性2例;Ki-67表达<15%0例;15%~50%3例,>50%3例。结论腋窝淋巴结转移状态及Ki-67表达强度是Her-2过表达型乳腺癌复发的重要因素,影响其预后。     

雄激素受体在三阴性乳腺癌中的表达及其预后价值

目的:探讨雄激素受体(androgen receptor,AR)在三阴性乳腺癌(triple-negative breast cancer,TNBC)中的表达及其预后价值。方法:回顾性分析江苏省肿瘤医院2001年1月-2006年12月手术病理确诊的TNBC 256例,免疫组化检测AR的表达情况,统计学分析AR的不同表达情况与临床病理特征的相关性,并进行随访。结果:TNBC中AR的阳性率为41%。AR与肿瘤大小、组织学分级、淋巴结转移具有统计学相关性。随访显示AR阴性者的10年总生存率和无病生存率均低于AR阳性者(68%vs 86%,19%vs 31%)。结论:TNBC中AR阳性者预后好,AR可能成为TNBC新的治疗靶点。     

Herceptin治疗Her-2过度表达的转移性乳腺癌

目的 探讨抗Her-2受体单克隆抗体Herceptim联合泰素对Her-2／neu过度表达的转移性乳腺癌的疗效和毒副作用。方法 Her-2／neu过度表达的转移性乳腺癌患者60例,22例接受Hereeptin联合泰素治疗,38例接受泰素加阿霉素方案化疗,刘两组的疗效进行了比较,并观察了Hereeptin联合泰素治疗的毒副反应、Her-2／neu表达强度与Herceptin联合泰素治疗疗效之间的关系。结果 Hereeptin联合泰素治疗22例中,完全缓解(CR)3例,部分缓解(PR)12例,无变化(NC)3例,进展(PD)4例,有效率(CR PR)为68.2％,明显高于泰素加阿霉素化疗组的44.7％。Her-2／neu( )6例,PR3例,NC2例,PD1例,CR PR为50.0％;Her-2／neu( )16例,CR3例,PR9例,NC2例,PD2例,CR PR为75.0％。结论 初步分析抗Her-2受体单克隆抗体Herceptin联合泰素能提高转移性乳腺癌的疗效,近期缓解率与Her-2／neu表达状况相关,不良反应发生率较低。     

雄激素受体在不同分子亚型乳腺癌中的表达及其意义

目的探讨乳腺癌组织雄激素受体（androgen receptor,AR）的表达,分析其在各分子亚型中表达的特点及其意义。方法采用免疫组织化学方法检测AR在335例乳腺浸润性导管癌石蜡包埋组织中的表达,结合66月随访情况,分析AR在五个分子亚型中表达的特点。 结果乳腺癌组织中AR阳性率较高,达72.5%,尤其在ER阴性PR阴性乳腺癌病例,AR常常显示阳性（占53.2%）。较多 (61.0%) basal like型乳腺癌AR显示阴性,提示预后欠佳。在luminal A、luminal B、basal-like以及normal-like亚型中AR阳性组出现局部复发、远处转移或死亡比例较AR阴性组少(P=0.019,0.044,0.034和 0.032),生存曲线也显示了AR阳性患者预后较好(P=0.006,0.013,0.036和0.010)。结论检测乳腺癌AR的表达水平有助于改进和细化乳腺癌的分子分型,为指导个体化治疗提供理论依据。     

EGFR、Her-2在食管鳞癌中表达的研究进展

表皮生长因子受体（epidermal growth factor receptor,EG-FR）家族属于Ⅰ型跨膜酪氨酸激酶生长因子受体,包括EG-FR、Her-2、Her-3、Her-4四个成员,分别是原癌基因C-erbB-1-4的表达产物。该家族成员在人胃肠道肿瘤、乳腺癌、肺癌、前列腺癌等均有过度表达,而且与这些肿瘤的进展与预后密切相关。现就食管鳞癌组织EGFR、Her-2表达的研究进展综述如下。1 EGFR、Her-2基因及检测方法1.1 EGFR基因EGFR是由1186个氨基酸组成的受体酪氨酸蛋白激酶（tyrosine protein kinase,TPK）,其原癌基因定位于人7P13-7P12。当表皮生长因子（epidermal growth factor,EGF）等专一     

Her-2和Cox-2在乳腺癌组织中的表达及其相关性

目的 探讨癌基因Her-2和Cox-2在乳腺癌组织中的表达及其相关性.方法 应用免疫组化技术,检测40例人乳腺癌中Her-2和Cox-2蛋白的表达情况,分析其相互关系及与乳腺癌的临床病理特征间的联系.结果 40例乳腺癌组织中Her-2表达阳性率为35﹪(14/40),与肿瘤分期、淋巴结转移及阴性激素受体状态密切相关(P＜0.05);Cox-2表达阳性率为47.5﹪(19/40),与肿瘤分期、组织学分级、阴性激素受体状态密切相关(P＜0.05);二者表达与肿瘤大小无关,两者的表达存在显著的相关性(P＜0.01).结论 Cox-2在乳腺癌中高水平表达且与Her-2密切相关,提示乳腺癌中Her-2和Cox-2存在相互调控机制共同促进肿瘤的发生和发展.     

Prolonged Survival in Patients with Human Epidermal Growth Factor Receptor-2-Overexpressed Metastatic Breast Cancer after Targeted Therapy is Dominantly Contributed by Luminal-Human Epidermal Growth Factor Receptor-2 Population

The prognosis of patients with human epidermal growth factor receptor-2 (HER2)-overexpressed metastatic breast cancer (MBC) has improved drastically following the development of anti-HER2 therapies. We question what factors are involved in the improved outcome by the treatment. One hundred and two MBC patients who received chemotherapy were classified into groups according to breast cancer subtype: luminal/HER2-negative (n = 50), HER2 (n = 26), and triple-negative subtypes (n = 26). Clinicopathologic features and clinical outcomes of the groups were compared. Disease-free intervals in the triple-negative group were significantly shorter than those in the other two groups. Age, tumor grade, the number of disease sites, and prior chemotherapeutic regimens did not differ among the groups. As a result, median overall survival was significantly longer in the HER2 and luminal/HER2-negative groups than in the triple-negative group (114, 68, and 18 months, respectively, p < 0.001). To determine key factors underlying favorable outcomes of the HER2 group, the HER2 group was further divided into two subgroups, luminal-HER2 and non-luminal-HER2 groups, according to their hormone receptor status, and clinical outcomes were compared. Median overall survival from the time of diagnosis of MBC in the luminal-HER2 group was significantly longer than that in the non-luminal-HER2 group (not reached and 39 months, respectively, p = 0.048), and was as favorable as shown in the luminal/HER2-negative group. In conclusion, the prognosis and survival of patients with HER2-overexpression receiving anti-HER2 therapy improved considerably in the luminal-HER2, but not in the non-luminal-HER2 group.     

人表皮生长因子受体-2在雌孕激素双阴性乳腺癌中的表达及作用

目的：研究三阴性乳腺癌和人表皮生长因子受体-2过表达型乳腺癌的临床病理特征,探讨多因素对雌激素（ER）,孕激素（PR）双阴性乳腺癌预后的影响。方法：对本院2004年确诊并行手术治疗的1 250例单侧乳腺癌进行回顾性分析,并通过免疫组化和FISH检测筛选三阴性乳腺癌和HER-2过表达型乳腺癌两种亚型,对两组患者在临床病理特征、复发转移部位、以及生存期进行分析。结果：中位随访60个月（6～73个月）,两种亚型在发病年龄、月经状态、组织学分级、肿瘤大小和PCNA表达等方面组间差异均无统计学意义。三阴性乳腺癌患者中乳腺癌家族史患者比例 （8.9% vs 4.3%, P=0.010）和P53的阳性表达均较高（64.4% vs 60.7%, P=0.006）;HER-2过表达型乳腺癌更易发生腋窝淋巴结转移,且淋巴结大于4枚以上的比例较高 （36.6% vs 29.7%, P=0.004）,TNM分期Ⅲ期+Ⅳ期的患者比例比三阴性乳腺癌组高 （18.3% vs 29.3%, P=0.014）。两亚型乳腺癌在远处转移率和5年无病生存率相比较差异无统计学意义（P>0.05）。结论：三阴性乳腺癌与HER-2过表达型乳腺癌在肿瘤临床病理特征方面有显著性差异,但短期（5年）无病生存率无显著性差异,因此推测HER-2不是ER,PR双阴性乳腺癌的短期生存的独立预后因素。     

Association of Human Epidermal Growth Factor Receptor-2 Expression and Clinicopathological Findings in Patients with Colorectal Cancer

Background: To determine the frequency of HER-2 overexpression in colorectal cancer (CRC) patients,and to explore the relationship between clinicopathological prognostic factors and their effects on survival,based on immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) analysis. Materials andMethods: The study included 80 patients with a histologically proven diagnosis of CRC that received adjuvantFOLFOX-4 chemotherapy at our department between March 2006 and September 2010. Patient data wereanalyzed retrospectively. Results: The median follow-up period and age of the patients were 24 months and59 years, respectively. In immunohistochemical staining, 3+ staining was found in 2 patients (2.5%) while 2+was in 13 (16%) . FISH for HER-2 was performed for all of these 15 patients; samples which were 3+ showedpositivity but the ones with 2+ were negative. There was no significant correlation between HER-2 expressionand age, gender, tumor localization, histological subtype, grade, lymphovascular and perineural invasion, orpTN stage (P>0.05), even when the patients with HER-2 overexpression were analyzed separately. There wasalso no significant relationship between progression-free survival (PFS) and overall survival (OS), and HER-2expression, gender, tumor localization, obstruction-perforation, bleeding, histological type, grade, lymphovascularand perineural invasion, or pT staging (P>0.05); however, there was a significant relationship between lymphnode involvement, and PFS and OS (P<0.05). Conclusions: Evaluation of HER-2 overexpression in a morecomprehensive, multi-center, prospective trial with standardized methods will be an appropriate approach.     

Paraneoplastic Encephalitis Associated with Locally Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer

Paraneoplastic neurologic diseases (PND) are rare but can occur in patients with common malignancies including breast cancer. In patients with hormone receptor (HR)-negative human epidermal growth factor receptor 2 (HER2)-positive breast cancer, PND have been reported in association with anti-Yo antibodies and with clinical presentation of paraneoplastic cerebellar degeneration. We describe the case of a woman with progressively altered mental status and seizures, ultimately requiring admission. Based on her clinical presentation, imaging findings, and evidence of neural-directed antibodies in her serum and cerebrospinal fluid, she was diagnosed with paraneoplastic limbic encephalitis (LE) due to an underlying HR-negative, HER2-positive breast cancer. She showed a transient response to immunosuppression but had more significant improvement after surgical resection and initiation of chemotherapy along with HER2-directed therapy. To the best of our knowledge, this is the first documented case of paraneoplastic LE in a patient with HR-negative, HER2-positive breast cancer likely caused by the production of an unclassified anti-neuronal antibody.     

肺癌患者血清细胞生长因子及受体联合检测的临床意义

目的：探讨联合检测血管内皮生长因子（VEGF）、表皮生长因子受体（EGFR）、血小板衍生生长因子（PDGF）对肺癌的诊断价值和靶向治疗的监测作用。方法：采用双抗体夹心ABC-ELISA法测定肺癌患者及健康对照组血清血管内皮生长因子、表皮生长因子受体、肺癌患者血小板衍生生长因子。结果：肺癌组血清VEGF、EGFR、PDGF测定值均高于正常对照组（P〈0．001）。联合检测VEGF＋PDGF＋EGFR对肺癌诊断的敏感性91．4％、特异性53．3％、准确性73．8％，血清VEGF、PDGF、EGFR值与非小细胞肺癌分期有关，与肺癌病理分型无关（P〉0．05）。血清VEGF与PDGF及EGFR测定值之间呈正相关。在接受重组血管内皮抑素治疗的患者中，三项指标有下降的趋势。结论：VEGF、EGFR、PDGF的联合检测对肺癌诊断具有一定临床指导意义。对肺癌的靶向治疗可能有监测作用。     

Association of Human Epidermal Growth Factor Receptor 2 with Radiotherapy Resistance in Patients with T1N0M0 Breast Cancer

Purpose

Preclinical studies have shown that human epidermal growth factor receptor 2 (HER2) status is associated with resistance to radiotherapy (RT). In this study, we evaluated the overall survival of a T1N0M0 breast cancer cohort in Korea according to the use of RT and the HER2 status.

Methods

We analyzed data collected from 11,552 patients with invasive breast cancer who were enrolled in the Korean Breast Cancer Society Registration Program between 1999 and 2007. Data on the TNM stage, estrogen receptor status, progesterone receptor status, HER2 status, operation method, and the use of RT were analyzed.

Results

The median follow-up period was 51 months. A significant improvement in overall survival after RT was observed only in the HER2(-) group. In this group, the 10-year overall survival rate was 95.5% for patients who did not receive RT and 96.3% for patients who received RT (p=0.037). In contrast, in the HER2(+) group, RT was not associated with a survival benefit (p=0.887). Multivariate analysis showed that RT was significantly associated with a reduction in mortality in the HER2(-) group (hazard ratio, 0.738; 95% confidence interval, 0.549-0.993; p=0.045).

Conclusion

We found that postoperative RT was not associated with a survival benefit in HER2(+) breast cancer patients, suggesting that HER2(+) breast cancers could be RT resistant.     

Platelet Derived Growth Factor-B and Human Epidermal Growth Factor Receptor-2 Polymorphisms in Gall Bladder Cancer

Gall bladder cancer (GBC) is a gastro-intestinal cancer with high prevalence among north Indian women.Platelet derived growth factor-B (PDGFB) and human epidermal growth factor receptor-2 (HER2) may playroles in the etiology of GBC through the inflammation-hyperplasia-dysplasia-carcinoma pathway. To study theassociation of PDGFB and HER2 polymorphisms with risk of GBC, 200 cases and 300 controls were considered.PDGFB +286A>G and +1135A>C polymorphisms were investigated with an amplification refractory mutationsystem and the HER2 Ile655Val polymorphism by restriction fragment length polymorphism. Significant riskassociations for PDGFB +286 GG (OR=5.25) and PDGFB +1135 CC (OR=3.19) genotypes were observed forGBC. Gender wise stratification revealed susceptibility for recessive models of PDGFB +1135A>C (OR=3.00) andHER2 Ile655Val (OR=2.52) polymorphisms among female GBC cases. GBC cases with gall stones were predisposedto homozygous +286 GG and +1135 CC genotypes. Significant risk associations were found for ACIle (OR=1.48),GAVal (OR=1.70), GAIle (OR=2.00) haplotypes with GBC cases and GCIle haplotype with female GBC cases(OR=10.37, P=<0.0001). Pair-wise linkage disequilibrium revealed negative associations among variant alleles.On multi-dimensional reduction analysis, a three factor model revealed significant gene-gene interaction forPDGFB +286A>G, PDGFB +1135A>C and HER2 Ile165Val SNPs with GBC. Protein-protein interaction showedsignificant association of PDGFB and HER2 with the epidermal growth factor receptor signaling pathway.