Expression of growth factor and chemokine receptors: new insights in the biology of inflammatory breast cancer.

PURPOSE: Recent studies have indicated that expression of chemokine receptors CXCR4 and CCR7 could be an indicator of the metastatic potential of breast cancer. Expression of CXCR4 and CCR7 along with the biomarkers HER2-neu and epidermal growth factor receptor (EGFR) was investigated in inflammatory breast cancer (IBC) to evaluate their prognostic implications. EXPERIMENTAL DESIGN: CXCR4, CCR7, and EGFR were evaluated by immunohistochemical staining (IHC) of paraffin-embedded tissue sections. HER2-neu amplification was assessed by FISH and/or IHC. All patients received chemotherapy, surgery, and radiation. RESULTS: Forty-four cases diagnosed with IBC from 1994 to 2002 were included in the study. In all, 18 (40.9%) patients had positive CXCR4, 10 (22.7%) had positive CCR7, 21 (47.7%) had positive HER2-neu, and EGFR was positive in 12 of 40 patients (30%). The 5-year overall survival (OS) was 24.8% for CXCR4-positive disease versus 42.3% for CXCR4-negative patients (P = 0.53) and 20.0% for CCR7-positive disease versus 41.9% for CCR7-negative patients (P = 0.24). EGFR-positive disease had significantly worse OS compared with EGFR-negative disease (P = 0.01). CONCLUSIONS: These data demonstrate the expression of growth factor and chemokine receptors in IBC. The expression of these receptors is associated with increased risk of recurrence and death, and thus, they may represent potential therapeutic targets in IBC.     

Clinical significance of Akt and HER2/neu overexpression in African-American and Latina women with breast cancer

Introduction

Breast cancer patients with HER2/neu overexpression have poor outcomes with a decrease in disease-free survival (DFS) and overall survival. The biology of HER2/neu overexpression in breast tumors in African-American and Latina women is poorly understood. The purpose of this study is to understand the clinical significance of activated Akt (phospho-Akt or pAkt) expression in breast tumors from African-American and Latina patients with corresponding tissue HER2/neu overexpression. Cellular and molecular studies have shown that activation of the cell signaling phosphatidylinositol-3-kinase/Akt cascade via the HER2/neu and other receptor tyrosine kinases induces cell proliferation.

Methods

A total of 234 African-American and Latina patients were selected retrospectively. From this group, 141 tumor tissue samples were analyzed for tissue pAkt by immunohistochemistry (IHC). This cohort consisted of 46 HER2/neu-positive (3+ by IHC) and 95 HER2/neu-negative tumors. The prognostic value of activated tissue Akt in relation to HER2/neu overexpression for DFS was determined.

Results

Patients with low pAkt and HER2-negative tumors had the best DFS. As expected, HER2/neu-overexpressing tumors with low pAkt had a decrease in DFS. Similarly, those with high pAkt and HER2-negative tumors also had poor DFS. However, those with an increase in both HER2 and pAkt had the worst DFS. An increase in pAkt was significantly associated with HER2/neu-positive and lymph node-positive breast tumors. Tumors with high HER2 and high pAkt were metastatic. Multivariate analysis demonstrated that, in addition to the common risk factors such as larger tumor size, lymph node involvement, estrogen receptor/progesterone receptor-negative tumors, and HER2/neu-positive tumors, overexpression of pAkt significantly was associated with a decrease in 5-year DFS. A decrease in DFS with an increase in pAkt was observed in both HER2/neu-positive and -negative groups. However, the DFS was similar between HER2/neu-positive/pAkt-negative and HER2/neu-negative/pAkt-positive groups.

Conclusion

Our data suggest that there may be differences in tumor phenotypes within the HER2/neu-overexpressing breast cancer patients. The overexpression of pAkt may be a powerful prognostic marker for predicting DFS and overall survival of breast cancer patients.     

ER和PR阴性乳腺癌雄激素受体与HER2表达相关性及其临床意义

目的 激素受体阴性(ER-/PR-)乳腺癌具有明显的肿瘤异质性,临床治疗手段相对有限.本研究探讨激素受体阴性乳腺癌组织中,雄激素受体(androgen receptor,AR)和HER2表达的相关性,及其与临床病理参数和预后的相关性.方法 收集中国人民解放军福州总医院经手术治疗并病理确诊的乳腺癌120例,中位年龄52岁.采用FISH法检测收集的激素受体阴性乳腺癌组织HER2/neu基因状态,分为HER2阳性(HER2过表达组)和HER2阴性(三阴组)两组,每组60例.并采用EliVisionTM plus免疫组化法检测AR、Ki-67、EGFR表达,分析HER2和AR表达与临床病理参数、3年无病生存期(disease free survival,DFS)的相关性.结果 AR在激素受体阴性乳腺癌组织阳性率为61.67％(74/120),HER2过表达组和三阴组分别为73.33％(44/60)和50.00％(30/60).激素受体阴性乳腺癌组织中,AR表达与月经状态、肿瘤大小、组织学分级、EGFR表达及HER2状态相关,均P值＜0.05;在HER2过表达组中,AR表达与月经状态、淋巴结受累、EGFR表达相关,均P值＜0.05;三阴组中,AR表达与肿瘤大小和组织学分级相关,均P值＜0.05.Kaplan-Meier法分析显示,HER2过表达组中AR表达与患者的3年DFS呈正相关,P＜0.05;Cox回归法分析结果示,肿瘤大小、淋巴结受累、EGFR表达、AR表达均与患者的3年DFS有关,P＜0.05.结论 AR可能成为筛选激素受体阴性乳腺癌高危人群和预测其预后的辅助指标之一,可作为激素受体阴性乳腺癌的新治疗靶点,为不同HER2状态乳腺癌治疗提供新思路.     

AIB1在乳腺良、恶性病变组织中的表达及临床意义

目的 探讨乳腺良、恶性组织中乳腺癌扩增性抗原1 (amplified in breast cancer 1,AIB1)蛋白的表达与临床意义.方法 采用免疫组织化学方法检测120例乳腺癌组织、40例良性乳腺病变、20例癌旁正常乳腺组织中AIB1的表达,并探讨该蛋白与乳腺癌患者的肿瘤大小、组织学分级、淋巴结有无转移及基因分型等的关系.结果 乳腺癌组织中AIB1过表达(40.0％)显著高于正常乳腺组织(10.0％)和乳腺良性病变组织(15.0％)(P＜0.05).在乳腺癌组织中,组织分级Ⅲ级组的过表达率(62.0％)显著高于Ⅰ级组(10.5％)和Ⅱ级组(29.4％)(P＜0.05)).腋淋巴结转移组中的过表达率(53.8％)显著高于淋巴结无转移组(14.3％)(P＜0.05).乳腺癌组织中,AIB1蛋白表达率在ER阳性组(45.2％)、阴性组(27.8％)间的差异无统计学意义(P =0.0741),PR阳性组(42.9％)、阴性组(34.9％)间的差异无统计学意义(P=0.393),而HER2阳性组的AIB1过表达率(51.5％)显著高于阴性组(25.0％)(P＜0.05).乳腺癌组AIB1蛋白的阳性表达率与乳腺癌不同基因分型亚型明显相关(P＜0.05).结论 乳腺癌中AIB1过表达与乳腺癌的发生、发展及肿瘤的恶性程度密切相关,AIB1蛋白高表达可能提示临床预后不良.     

TopoⅡα蛋白在不同分子亚型乳腺癌中的表达及其预后价值

  目的  探讨拓扑异构酶Ⅱ(TopoisomeraseⅡ, TopoⅡα)蛋白在三阴性乳腺癌和HER2高表达型乳腺癌中的表达及其与预后的关系。  方法  选取2004年1月至7月天津医科大学附属肿瘤医院乳腺癌患者202例为研究对象, 其中三阴性乳腺癌101例, HER2高表达型乳腺癌101例, 采用免疫组化方法检测TopoⅡα蛋白在两型乳腺癌中的表达及其与预后的关系。  结果  TopoⅡα蛋白在三阴性乳腺癌中的表达率为51.9%, 在HER2过表达型乳腺癌中的表达率为48.9%, 二者差异无统计学意义(P>0.05)。TopoⅡα蛋白表达水平与两型乳腺癌患者月经状况、肿瘤大小、临床分期、腋下淋巴结转移状况、组织学分级、病理学类型等临床病理指标均无相关性(P>0.05)。HER2高表达型乳腺癌中, TopoⅡα蛋白阳性和阴性组5年无瘤生存率为81.0%和60.5%, 5年总生存率分别为92.1%和76.3%, 两组差异均具有统计学意义(P=O.037, P=0.047)。多因素分析结果显示TopoⅡα蛋白表达可以作为HER2过表达型乳腺癌的独立预后因子。三阴性乳腺癌中, TopoⅡα蛋白阳性和阴性组5年无瘤生存率分别为69.7%和82.4%, 差异具有统计学意义(P=0.044), 5年总生存率分别为75.0%和84.5%, 二者差异无统计学意义(P=0.927)。  结论  HER2过表达型乳腺癌, TopoⅡα蛋白阳性的患者预后较好, 提示此型乳腺癌患者可从蒽环类化疗药物中获益, 为临床用药提供一定的理论依据在三阴性乳腺癌患者中, TopoⅡα蛋白阳性表达患者较TopoⅡα蛋白阴性预后差, 对于临床判断预后具有指导意义。      

Automated quantitative analysis of E-cadherin expression in lymph node metastases is predictive of survival in invasive ductal breast cancer.

PURPOSE: The tumor suppressor adhesion molecule E-cadherin is believed to have an anti-invasive role in breast cancer. Lymph node involvement is the best prognostic marker known, yet there is variability in outcome among node-positive patients. We investigated the relationship between E-cadherin expression in primary invasive ductal tumors and corresponding nodal metastases, and determined the prognostic value of E-cadherin expression in node-positive breast cancer. EXPERIMENTAL DESIGN: Membrane E-cadherin expression was studied by immunohistochemical staining of tissue microarrays with fluorescent-labeled antibodies. An objective method of automated quantitative analysis (AQUA) was used. AQUA uses cytokeratin to define pixels as breast cancer (tumor mask) within the array spot, and measures E-cadherin expression using a Cy5-conjugated antibody within the mask. RESULTS: We employed a tissue microarray containing 207 primary and matched nodal metastases suitable for AQUA analysis. There was no significant difference in mean staining intensity between the primary and nodal specimens (P = 0.8). A scattergram was generated which identified a subset of patients (25%) with high E-cadherin expression in nodal metastases, and this top quartile had improved survival (P = 0.028). On univariate analysis, increased E-cadherin expression in nodal metastases was strongly associated with improved survival (P = 0.007), whereas expression in primary tumors was not (P = 0.13). On multivariate analysis, nodal E-cadherin expression retained its independent association with survival, as did tumor size and HER2/neu status. CONCLUSIONS: Strong E-cadherin expression in lymph node metastases was highly predictive of improved survival. This suggests that expression of adhesion molecules at metastatic sites portends less aggressive tumor behavior.     

Conflicting roles of EGFR expression by subtypes in breast cancer

Epidermal growth factor receptor (EGFR) is one of the receptors that belong to the epidermal growth factor family of receptor tyrosine kinases (ErbBs). Several malignancies including breast cancer that express EGFR have poor prognosis. Our study examined the EGFR expression among 5176 breast cancer patients from {"type":"entrez-geo","attrs":{"text":"GSE96058","term_id":"96058"}}GSE96058 and METABRIC cohorts and the contribution of tumor immune microenvironment in different subtypes. We found that among different breast cancer subtypes, EGFR expression in TNBC was the highest compared to other subtypes. EGFR high ER-positive/HER2-negative breast cancer had significantly higher survival compared to EGFR low ER-positive/HER2-negative breast cancer. It was also associated with high level of intratumor heterogeneity and homologous recombination defects (HRD). This group was also enriched in immune-related gene sets. On the other hand, low EGFR tumor was enriched in cell proliferation-related gene sets. However, these findings were not observed in TNBC. Interestingly, there was a greater infiltration of anti-cancer immune cells in high EGFR ER-positive/HER2-negative breast cancers, while, TNBC with higher EGFR expression had lower fraction of immune cells along with low level of cytolytic activity. Tumor cells have significantly higher EGFR expression compared to immune cells in single cell sequencing data. There was higher expression of immune checkpoint molecules in high EGFR ER-positive/HER2-negative breast cancer but lower expression in TNBC. High EGFR metastatic tumor was significantly associated with worse survival, but no association with infiltrating immune cells was observed. Our study shows that higher EGFR expression in ER-positive/HER2-negative breast cancer is associated with improved outcomes and an anti-cancer immune microenvironment.     

Systemic therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative early stage and metastatic breast cancer

Hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer is defined by the presence of the estrogen receptor and/or the progesterone receptor and the absence of HER2 gene amplification. HR-positive/HER2-negative breast cancer accounts for 65%–70% of all breast cancers, and incidence increases with increasing age. Treatment varies by stage, and endocrine therapy is the mainstay of treatment in both early stage and late-stage disease. Combinations with cyclin-dependent kinase 4/6 inhibitors have reduced distant recurrence in the early stage setting and improved overall survival in the metastatic setting. Chemotherapy is used based on stage and tumor biology in the early stage setting and after endocrine resistance for advanced disease. New therapies, including novel endocrine agents and antibody-drug conjugates, are now changing the treatment landscape. With the availability of new treatment options, it is important to define the optimal sequence of treatment to maximize clinical benefit while minimizing toxicity. In this review, the authors first discuss the pathologic and molecular features of HR-positive/HER2-negative breast cancer and mechanisms of endocrine resistance. Then, they discuss current and emerging therapies for both early stage and metastatic HR-positive/HER2-negative breast cancer, including treatment algorithms based on current data.     

Trastuzumab as first-line therapy in HER2-positive metastatic breast cancer patients

Trastuzumab is a humanized monoclonal antibody against the extracellular domain of hEGF receptor-2 (HER2). Trastuzumab in combination with chemotherapy has proven efficacy in treating both early and metastatic HER2-positive breast cancer. In the metastatic setting, the addition of trastuzumab to chemotherapy is associated with a statistically significant longer time to disease progression, higher rate of objective response and improvement in overall survival. Trastuzumab efficacy is not influenced by hormone receptor status, but differences in median overall survival exist between HER2-positive and HER2-negative states. Reassessment of the benefit of re-exposing patients with metastatic breast cancer to trastuzumab following relapse in the adjuvant setting is necessary. Ongoing research into new HER2-targeted therapies and trials involving combination anti-HER2 drug therapy without chemotherapy show promise. This review is focused on the available results obtained with the use of trastuzumab in the subset of HER2-positive breast cancer patients with metastatic disease.     

Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer

Trastuzumab (T) is effective in metastatic breast cancer (MBC) with HER2 overexpression and/or amplification, but resistance to T develops in a significant number of HER2-positive patients. Understanding the mechanisms of resistance is critical to the care of these patients. Formalin-fixed paraffin-embedded tumor tissue samples were collected from 256 patients with T-treated MBC. Clinical information was collected retrospectively from the patients' medical records. Central review of HER2 status by fluorescent in situ hybridization (FISH) and/or immunohistochemistry (IHC) revealed that of the 227 eligible patients only 139 (61%) were truly HER2-positive. PTEN, ER, PgR, and Ki67 were evaluated by IHC, while PTEN status was evaluated by FISH as well. PIK3CA mutations were identified with single nucleotide polymorphism (SNP) genotyping. Median time to progression (TTP) was 14.4?months for the HER2-positive and 10.3 for the HER2-negative patients (log-rank, P?=?0.22). Survival from the initiation of T (survivalT) was 50.4?months for the HER2-positive and 35.3 for the HER2-negative subgroups (P?=?0.006). Higher risk of progression was associated with HER2-positive status and the presence of PIK3CA mutations (P?=?0.014). PTEN loss, as determined by IHC, was associated with lower survivalT in the whole population (P?=?0.029) and in the HER2-positive population (P?=?0.017). PIK3CA mutations and/or PTEN loss status were evaluated together as a single parameter, to estimate the impact of activation of the PI3K/AKT molecular pathway, and it was significantly associated with both decreased TTP (P?=?0.003 in the total population, P?=?0.004 in HER2-positive patients) and survival (survivalT, P?=?0.011 in total, P?=?0.006 in HER2-positive). In this trastuzumab-treated breast cancer population, PIK3CA activating mutations were associated with shorter TTP and PTEN loss with decreased survival. The activation of the PI3K/AKT pathway from either defect was associated with both TTP and survival, indicating the adverse effect of this pathway's status on trastuzumab efficacy.     

雌激素受体阴性乳腺癌 HER －2过表达及与影像学和临床病理特征的关系

目的：探讨人类表皮生长因子受体 HER －2过表达在雌激素受体阴性（ER －）乳腺癌诊断中的价值及其与钼靶、超声影像学特征及临床病理特征的关系,并与 ER －／HER －2－乳腺癌进行比较。方法：收集临床资料完整的 ER －乳腺癌患者190例,其中 HER －2过表达（HER －2＋）乳腺癌患者78例,HER －2无过表达（HER －2－）型乳腺癌患者112例。比较两组患者的钼靶及超声影像学表现和临床病理特征。结果：在这190例 ER －乳腺癌患者中,HER －2＋乳腺癌组与 HER －2－组比较,年龄差异具有统计学意义（P ＝0．0049）;均具有较高的病理组织学分级,组间差异无统计学意义（P ＝0．296）。HER －2＋乳腺癌组更多表现为淋巴结阳性（P ＝0．003）。钼靶 X 线检查 HER －2＋与 HER －2－两组间比较,差异具有统计学意义（P ＜0．001）。单纯钙化 HER －2＋组（46．2％）较 HER －2－组（13．4％）,差异具有统计学意义（P ＜0．001）;单纯肿物 HER －2－组（58．0％）较 HER －2＋组（34．6％）,差异具有统计学意义（P ＝0．0038）;肿物特征 HER －2＋组与 HER －2－组比较,差异具有统计学意义（P ＝0．017）;HER －2＋组（42．5％）多表现为分叶状肿物,较 HER－2－组（14．9％）,差异具统计学意义（P ＝0．0030）;HER －2－组（33．3％）多为圆形肿物,较 HER －2＋组（12．5％）,差异具有统计学意义（P ＝0．013）;HER －2＋组与 HER －2－组肿物边缘组间比较,差异具有统计学意义（P ＜0．001）;HER －2＋组（57．5％）较多变现为毛刺,较 HER －2－组（14．9％）,差异具有统计学意义（P ＜0．001）;HER －2－组较 HER －2＋组光滑程度,差异具有统计学意义（P ＜0．001）;HER －2＋组（89．8％）更多表现为恶性钙化,较 HER －2－组（29．7％）,差异具有统计学意义。超声检查 HER －2＋组与 HER －2－组,差异具有统计学意义（P ＜0．005）;肿块边缘差异具有统计学意义（P ＜0．001）;内部回声差异具有统计学意义（P ＝0．014）。结论：不同类型的乳腺癌有不同的生物学特征,其钼靶影像学表现也不尽相同,了解 ER －HER －2＋型乳腺癌的钼靶及超声影像学特征,可帮助临床医师预测乳腺癌这一亚型及相关类型和患者的预后,以及评估患者对各种治疗方法的敏感性,有利于制定最优的治疗方案。     

Glucosylceramide synthase, a factor in modulating drug resistance, is overexpressed in metastatic breast carcinoma

Drug resistance causes treatment failure in approximately 50% of breast cancer patients with chemotherapy. Overexpression of glucosylceramide synthase (GCS) confers drug resistance in cancer cells, and suppression of GCS sensitizes cancers to chemotherapy in preclinical studies. Thus, GCS becomes a potential target to reverse drug resistance; however, little is known about GCS expression levels in normal tissues and whether GCS overexpression is associated with metastatic cancers. Herewith, we report our studies in GCS expression levels and breast cancer from patients. GCS levels were analyzed using cancer profiling arrays, breast cancer histo-arrays and quantitative RT-PCR in tumor tissues. We found that breast (18 exp. index) and other hormone-dependent organs (testis, cervix, ovary, prostate) displayed the lowest levels of GCS mRNA, whereas liver (52 exp. index) and other organs (kidney, bladder, stomach) displayed the highest levels of GCS. GCS mRNA levels were significantly elevated in tumors of breast, cervix, rectum and small intestine, as compared to each paired normal tissue. In mammary tissue, GCS overexpression was detected in breast cancers with metastasis, but not in benign fibroadenoma or primary tumors. GCS overexpression was coincident with HER2 expression (γ2=0.84) in ER-negative breast adenocarcinoma. In tumor specimens, GCS mRNA was elevated by 4-fold and significantly associated with stage III (5/7), lymph node-positive (7/8) and estrogen receptor-positive breast cancers (7/9). GCS expression was significantly and selectively elevated in breast cancer, in particular in metastatic disease. GCS overexpression was highly associated with ER-positive and HER2-positive breast cancer with metastasis. Although a small study, these data suggest that GCS may be a prognostic indicator and potential target for the treatment of chemotherapy-refractory breast cancer.     

Coexisting ductal carcinoma in situ independently predicts lower tumor aggressiveness in node-positive luminal breast cancer

Primary breast invasive ductal carcinoma coexisting with ductal carcinoma in situ (IDC-DCIS) is characterized by lower proliferation rate and metastatic propensity than size-matched pure IDC. IDC-DCIS is also more often ER-positive, PR-positive and/or HER2-positive. This analysis aims to clarify whether the presence of coexisting DCIS in IDC affects tumor aggressiveness in various biological subtypes of breast cancer, respectively. Tumor data obtained from 1,355 consecutive female patients undergoing upfront surgery for primary breast cancer were analyzed retrospectively; 196 patients with pure DCIS were excluded. Based on evidence that immunohistochemistry (IHC) provides a reasonable approximation of molecular phenotypes, the tumor samples were divided into 4 groups: (1) luminal A (ER and/or PR-positive, HER2-negative, Ki67 ≤ 12), (2) luminal B (ER and/or PR-positive, HER2-negative, Ki67 > 12), (3) HER2 (HER2-positive) and (4) basal-like (triple-negative) disease. Ki67 expression and nodal involvement of IDC with or without DCIS in these groups were compared. The number of patients with luminal A, luminal B, HER2 and basal-like breast cancer were 396, 265, 258 and 117, respectively. Ki-67 was lower in IDC-DCIS than in size-adjusted pure IDC of both luminal A and luminal B subtypes (P = 0.15 and <0.005, respectively). In HER2 or basal-like tumors, there were no significant difference between pure IDC and IDC-DCIS. The presence of coexisting DCIS in IDC predicts lower biological aggressiveness in luminal cancers but not in the conventionally more aggressive HER2-positive and triple-negative subtypes.     

radixin在乳腺癌组织中的表达及其与预后的相关性

目的:观察radixin蛋白表达与乳腺癌临床病理参数的相关性及临床意义。方法:收集散发性乳腺癌标本278例,乳腺纤维腺瘤组织46例,应用SP免疫组化法检测radixin蛋白的表达情况,并分析与乳腺癌患者临床病理参数的相关性。结果:乳腺癌中radixin蛋白表达阳性率为73.7%（205/278）,乳腺纤维腺瘤中radixin蛋白表达阳性率为32.6%（15/46）,与乳腺纤维腺瘤组织比较,radixin蛋白阳性表达率显著高于乳腺纤维腺瘤组织（P＜0.000 1）。在乳腺癌组织中,radixin蛋白表达与患者TNM分期、HER-2表达正相关,在临床分期高、HER-2表达阳性的组织中,radixin蛋白表达阳性率明显增加（P=0.023,P=0.007）。radixin蛋白表达与患者年龄、绝经状态、淋巴结转移、肿瘤大小、p53蛋白表达均未见相关性。生存分析发现,radixin蛋白表达与乳腺癌患者总体生存期无关,radixin阳性表达的乳腺癌患者,RFS时间明显缩短（P＜0.05）。结论:乳腺癌组织中radixin蛋白高表达与患者临床分期、HER-2表达和临床预后相关。     

Long-Term Complete Remission with nab-Paclitaxel,Bevacizumab, and Gemcitabine Combination Therapy in a Patient with Triple-Negative Metastatic Breast Cancer

This is a case study of a 52-year-old female patient diagnosed in June 2007 with primary metastatic invasive ductal carcinoma of the left breast and synchronous metastases in the bone, lymph nodes, and lung. Biopsy results of the tumor tissue were negative for the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2). In November 2007, she participated in a phase II study of metastatic HER2-negative breast cancer. Treatment consisted of systemic chemotherapy with gemcitabine 1,500 mg/m², nab-paclitaxel 150 mg/m², and bevacizumab 10 mg/kg once every other week. The patient experienced pain relief in her sternum after 5 weeks of chemotherapy, and her analgesic therapy was discontinued. After 7 months, the patient achieved a complete radiographic response, which was maintained for nearly 2 additional years. She continued receiving treatment throughout this period, requiring 1 dose reduction due to fatigue. The patient experienced no other adverse events, including neuropathy, and continued working uninterrupted throughout her treatment. The patient was discontinued from the study in May 2010 after disease progression, almost a full 3 years after diagnosis. The patient showed minimal response to subsequent therapies but had disease stabilization and died from her disease in April 2012. Median overall survival for patients with metastatic triple-negative breast cancer is between 12 and 13.3 months. This patient survived nearly 5 years following diagnosis. This case exemplifies how therapy with nab-paclitaxel, bevacizumab, and gemcitabine may prolong survival, with minimal toxicity, in select patients with triple-negative metastatic breast cancer.Key words: Triple-negative breast cancer, Metastatic breast cancer, HER2 negative, nab-paclitaxel, Long-term response     

High circulating HER2 extracellular domain levels correlate with reduced efficacy of an aromatase inhibitor in hormone receptor-positive metastatic breast cancer: a confirmatory prospective study

BACKGROUND: In this specifically designed, prospective study, the authors addressed the predictive value of circulating levels of the extracellular domain (ECD) of HER2 in patients with metastatic breast cancer who were treated with letrozole. METHODS: Two hundred twenty-six patients with hormone receptor-positive, metastatic breast cancer received letrozole (2.5 mg daily) until they developed either disease progression or unacceptable toxicity. Efficacy was measured primarily as the time to progression (TTP) and, secondarily, as the objective response rate (ORR) and overall survival. HER2 ECD levels were determined by using a sandwich enzyme HER2/neu immunoassay before letrozole treatment was initiated. Positive HER2 ECD status was correlated with treatment efficacy. RESULTS: Forty-two patients (19%) had elevated HER2 ECD levels, which were associated with primary tumor HER2 expression (P < .001) but not with age, performance status, location, or number of metastatic sites. The median TTP was significantly shorter among patients who had elevated HER2 ECD compared with the median TTP among patients who had normal levels (4 months vs 14 months; P = .0004), and the ORR was lower in the group with elevated HER2 ECD levels (14% vs 30%; P < .036). Overall survival was significantly shorter among patients with elevated serum HER-2 ECD (P < .0005). CONCLUSIONS: Elevated HER2 ECD concentrations predicted poorer outcomes in postmenopausal women with metastatic hormone receptor-positive breast cancer who were treated with aromatase inhibitors like letrozole.     

乳腺癌合并糖尿病患者肿瘤组织中Th17细胞含量测定

目的：分析乳腺癌及乳腺癌合并糖尿病患者肿瘤组织中Th17细胞含量,探讨Th17及糖尿病在乳腺癌发生发展中的意义。方法：收集2011年12月至2012年10月间18例乳腺癌非糖尿病和14例乳腺癌合并糖尿病患者乳腺癌改良根治术的手术切除组织标本,分为癌组织与癌旁组织2组,制成单细胞悬液;流式细胞术检测其中Th17细胞（ROR-γt淋巴细胞）比例。免疫组化法检测同一肿瘤组织中雌激素受体（ER）、孕激素受体（PR）、人类表皮生长因子受体2（HER-2）的表达。分析Th17细胞比例与被研究患者临床病理特征的关系。结果：乳腺癌非糖尿病患者肿瘤组织中Th17细胞表达与癌旁组织无明显差异（Z=-0．957,P=0．339〉0．05）;乳腺癌合并糖尿病患者肿瘤组织Th17细胞表达与癌旁组织存在差异（Z=-2．100,P=0．036〈0．05）;而乳腺癌非糖尿病与乳腺癌合并糖尿病患者肿瘤组织的Th17细胞表达无明显差异（Z=-0．912,P=0．337〉0．05）。结论：乳腺癌组织中有Th17细胞表达。有糖尿病的乳腺癌患者癌组织中Th17细晌含量高干痛軎绢织．     

Co-expressed type of ER and HER2 protein as a predictive factor in determining resistance to antiestrogen therapy in patients with ER-positive and HER2-positive breast cancer

The purpose of this study was to analyze whether inter-site variation types on estrogen receptor (ER) and HER2 expression may be a predictive factor for evaluating the effectiveness of endocrine therapy in patients with ER-positive and HER2-positive breast cancer. A total of 366 consecutive women with invasive breast cancer who had undergone curative surgical treatment between 1996 and 2001 were included in this study. ER status was evaluated using the Allred score and HER-2 status was evaluated according to the HercepTest. In ER-positive and HER2-positive tumors, the expression of ER and HER2 was described as the co-expressed type or the differently expressed type using double staining with ER and HER2. Of the 366 patients, 249 (68.1%) were positive for ER and 74 (20.2%) were positive for HER2. ER-positive and HER2-negative tumors were found in 221 patients (60.4%), ER-negative and HER2-negative in 71 (19.4%), ER-negative and HER-2-positive in 46 (12.6%), and ER-positive and HER2-positive in 28 (7.7%). HER2 status was inversely correlated (p<0.01) with ER status. In ER-positive tumors, an inverse correlation between ER and HER2 was also observed. The co-expressed type was found in 10 patients, and the differently expressed type was found in 18. There was no difference in tumor size and nodal involvement between the two types. There was no significant difference in disease-free survival between patients with the co-expressed type tumor and the differently expressed type tumor. In patients with the differently expressed type tumor, those who received antiestrogen therapy showed a significantly better disease-free survival rate than those who did not receive antiestrogen therapy. As for patients with the co-expressed type of tumor, no significant difference in disease-free survival was observed between patients with and without antiestrogen treatment. The present study suggests that the co-expressed type of tumour might be a resistant factor to antiestrogen therapy in ER-positive and HER2-positive breast cancer.     

HER2-positive circulating tumor cells indicate poor clinical outcome in stage I to III breast cancer patients.

PURPOSE: Early metastasis in node-negative breast cancer indicates that breast cancer cells obviously can bypass the lymph nodes and disseminate directly hematogenous to distant organs. For this purpose, we evaluated the prognostic value of blood-borne, HER2-positive circulating tumor cells (CTC) in the peripheral blood from 42 breast cancer patients with a median follow-up of 95 months. EXPERIMENTAL DESIGN: Cells were isolated by the patented combined buoyant density gradient and immunomagnetic separation procedure and analyzed by immunocytochemistry. RESULTS: We detected one to eight CTCs in the peripheral blood of 17 of 35 patients (48.6%) presenting no overt metastasis. As a positive control, 7 of 7 (100%) patients with metastatic disease presented positive. Healthy persons and patients (n = 32) operated for nonmalignant diseases presented negative for CTCs. The presence and frequency of HER2-positive CTCs correlated with a significantly decreased disease-free survival (P < 0.005) and overall survival (P < 0.05). Interestingly, in 12 patients with HER2-positive CTCs, the primary tumor was negative for HER2 as assessed by immunohistochemical score and fluorescence in situ hybridization. CONCLUSIONS: This study provides some evidence of a prognostic effect of HER2-positive CTCs in stage I to III breast cancer. Future studies have to determine the outcome of patients treated with HER2-targeting therapies with respect to HER2-positive CTC levels because it is not unlikely that high levels of HER2-positive CTCs reflect the activity of the tumor and may predict response to trastuzumab.     

Upregulation of CXCR4 is essential for HER2-mediated tumor metastasis

The receptor tyrosine kinase HER2 enhances tumor metastasis; however, its role in homing to metastatic organs is poorly understood. The chemokine receptor CXCR4 has recently been shown to mediate the movement of malignant cancer cells to specific organs. Here, we show that HER2 enhances the expression of CXCR4, which is required for HER2-mediated invasion in vitro and lung metastasis in vivo. HER2 also inhibits ligand-induced CXCR4 degradation. Finally, a significant correlation between HER2 and CXCR4 expression was observed in human breast tumor tissues, and CXCR4 expression correlated with a poor overall survival rate in patients with breast cancer. These results provide a plausible mechanism for HER2-mediated breast tumor metastasis and establish a functional link between HER2 and CXCR4 signaling pathways.