Evaluation of prognostic and predictive value of microtubule associated protein tau in two independent cohorts

Introduction  

Microtubule associated proteins (MAPs) endogenously regulate microtubule stabilization and have been reported as prognostic and predictive markers for taxane response. The microtubule stabilizer, MAP-tau, has shown conflicting results. We quantitatively assessed MAP-tau expression in two independent breast cancer cohorts to determine prognostic and predictive value of this biomarker.     

Stathmin and phospho-stathmin protein signature is associated with survival outcomes of breast cancer patients

Currently, Stathmin1 (STMN1) and phospho-STMN1 levels in breast cancers and their clinical implications are unknown. We examined the expression of STMN1 and its serine phospho-site (Ser16, Ser25, Ser38, and Ser63) status by immunohistochemistry. Using Cox regression analysis, a STMN1 expression signature and phosphorylation profile plus clinicopathological characteristics (STMN1-E/P/C) was developed in the training set (n = 204) and applied to the validation set (n = 106). This tool enabled us to separate breast cancer patients into high- and low-risk groups with significantly different disease-free survival (DFS) rates (P < 0.001). Importantly, this STMN1-E/P/C model had a greater prognostic value than the traditional TNM classifier, especially in luminal subtype breast cancer (P = 0.002). Further analysis showed that patients in the low-risk group would benefit more from adjuvant paclitaxel-based chemotherapy (P = 0.002). In conclusion, the STMN1-E/P/C signature is a reliable prognostic indicator for luminal subtype breast cancer and may predict the therapeutic response to paclitaxel-based treatments, potentially facilitating individualized management.     

A novel approach for targeted elimination of CSPG4‐positive triple‐negative breast cancer cells using a MAP tau‐based fusion protein

Chondroitin sulfate proteoglycan 4 (CSPG4) has been identified as a highly promising target antigen for immunotherapy of triple‐negative breast cancer (TNBC). TNBC represents a highly aggressive heterogeneous group of tumors lacking expression of estrogen, progesterone and human epidermal growth factor receptor 2. TNBC is particularly prevalent among young premenopausal women. No suitable targeted therapies are currently available and therefore, novel agents for the targeted elimination of TNBC are urgently needed. Here, we present a novel cytolytic fusion protein (CFP), designated αCSPG4(scFv)‐MAP, that consists of a high affinity CSPG4‐specific single‐chain antibody fragment (scFv) genetically fused to a functionally enhanced form of the human microtubule‐associated protein (MAP) tau. Our data indicate that αCSPG4(scFv)‐MAP efficiently targets CSPG4⁺ TNBC‐derived cell lines MDA‐MB‐231 and Hs 578T and potently inhibits their growth with IC₅₀ values of ～200 nM. Treatment with αCSPG(scFv)‐MAP resulted in induction of the mitochondrial stress pathway by activation of caspase‐9 as well as endonuclease G translocation to the nucleus, while induction of the caspase‐3 apoptosis pathway was not detectable. Importantly, in vivo studies in mice bearing human breast cancer xenografts revealed efficient targeting to and accumulation of αCSPG4(scFv)‐MAP at tumor sites resulting in prominent tumor regression. Taken together, this preclinical proof of concept study confirms the potential clinical value of αCSPG4(scFv)‐MAP as a novel targeted approach for the elimination of CSPG4‐positive TNBC.     

Reduced tau expression in gastric cancer can identify candidates for successful Paclitaxel treatment

A recent study disclosed that breast cancer cases with low 'tau' expression can predict susceptibility to Paclitaxel administration. In the current study, the clinical significance of tau expression in gastric cancer cases was established by identifying candidates with Paclitaxel administration. Tissue specimens from 20 cases of in-operable or noncuratively resected gastric cancer were examined. Subsequent to the administration of 80 mg m(-2) of Paclitaxel in six 3-h intravenous infusions, the clinical effectiveness of Paclitaxel was evaluated by the size of metastatic lesions with computed tomography. The status of the tau expression was determined by immunohistochemistry. Based on a previously reported classification scheme, six were classified as tau-negative expression (0, 1+) cases and 14 were classified as tau-positive expression (2+, 3+) cases. All six (100%) cases of tau-negative expression showed a favourable response (partial response or minor response) to Paclitaxel administration. However, 12 (86%) of the 14 cases of tau-positive expression showed progressive disease (n = 11) or no change (n = 1) after Paclitaxel administration. The serum carcinoembryonic antigen values of the six cases of tau-negative expression were markedly decreased in comparison to the 14 tau-positive cases. These data indicate that tau-negative expression can be used to select gastric cancer patients, which will favourably respond to Paclitaxel treatment.     

Predictive and prognostic value of PDL1 protein expression in breast cancer patients in neoadjuvant setting

Objective: Programmed death-ligand-1 (PDL1) is a molecule involved in immune evasion in various kinds of tumors. Here, we aim to determine whether the expression of PDL1 protein is related to the response of patients to neoadjuvant therapy and survival outcome.

Methods: Immunohistochemistry (IHC) was performed on paraffin-embedded tumor samples from core needle biopsy before neoadjuvant therapy (NAT). Univariate and multivariate logistic regression were used to analyze the associations between PDL1 protein expression and pathological complete response (pCR) outcome. Kaplan-Meier plot and log-rank test were used to compare disease-free survival (DFS) between groups. A cox proportional hazards model was used to calculate the adjusted hazard ratio (HR) with 95% confidential interval (95%CI).

Results: A total of 94 patients were included for IHC testing. PDL1 protein expression on tumor cells was associated with better pCR rate in both univariate (OR = 2.621, p = 0.043) and multivariate (OR = 3.595, p = 0.029) logistic regression analysis. It was also associated with shorter DFS both by log-rank test (p = 0.015) and cox hazard model (HR = 22.824, 95%CI 1.621–321.284, p = 0.020). In hormone receptor (HR)-positive patients, PDL1 protein expression was also associated with better pCR (OR = 2.362, p = 0.022). It was also associated with poor DFS (HR = 18.821, 95%CI 1.645–215.330, p = 0.018).

Conclusions: Our results show that PDL1 protein expression is a predictive biomarker of pCR and a prognostic factor of DFS in breast cancer patients and HR-positive subgroups.     

Bcl-2 protein expression in breast cancer and its relationship to prognosis

The expression of bcl-2 protein was studied in invasive breast cancer by immunohistochemistry. Fourty-six (56.8%) bcl-2 protein-positive tumors were found in 81 breast cancers. There was no significant correlation between the bcl-2 protein immunoreactivity and histologic type, primary tumor status, or lymph node metastasis. However, a strong positive relationship was demonstrated between bcl-2 immunoreactivity and estrogen receptor status. The 5-year survival rate and disease-free survival rates were 73.7% and 71.1% of patients with bcl-2-positive tumors, and 62.5% and 58.0% of those with bcl-2-negative tumors; these differences between the two groups of patients wete significant (p<0.05). In multivariate analysis using Cox regression model, bcl-2 immunoreactivity emerged as an independent prognostic indicator in breast cancer patients.     

蛋白酪氨酸磷酸酶受体J在乳腺癌组织中的表达及其与临床预后的相关性

目的：探讨蛋白酪氨酸磷酸酶受体J（PTPRJ）在乳腺癌中的表达,并分析其与临床病理指标和预后的关系。方法：应用免疫组化SP法检测198例乳腺癌组织及其配对癌旁正常组织中PTPRJ的表达情况,并分析PTPRJ表达与乳腺癌临床病理指标及预后的关系。结果：免疫组化染色结果显示PTPRJ在癌旁正常组织中的表达显著高于乳腺癌组织（P=0.003）,PTPRJ表达水平与淋巴结转移（P=0.014）、TNM分期（P=0.003）,ER状态相关（P=0.048）。Kaplan-Meier生存分析显示PTPRJ低表达组患者的总生存率明显低于PTPRJ高表达组（P=0.002）。多因素COX比例风险模型分析显示TNM分期和PTPRJ表达是影响患者总生存的独立预后因素。结论：PTPRJ在乳腺癌中低表达,与肿瘤进展密切相关,可作为评价乳腺癌患者预后的有效指标之一。     

Robo1蛋白在乳腺癌中的表达及其与乳腺癌脑转移的关系

目的 检测Robo1蛋白在不同乳腺肿瘤组织中的表达情况,并探讨Robo1蛋白的表达与乳腺癌脑转移的关系.方法 采用链霉素抗生物素蛋白-生物素(LSAB)法,对24例发生脑转移的乳腺浸润性导管癌、71例未发生脑转移的乳腺浸润性导管癌、22例乳腺导管内癌和23例乳腺纤维腺瘤组织中Robo1蛋白的表达情况进行检测.结果 Robo1蛋白在导管内癌和浸润性导管癌组织中的阳性表达率分别为59.1%和45.3%,均明显低于其在纤维腺瘤组织中的阳性表达率(87.0%,P＜0.05).Robo1蛋白在有脑转移的浸润性导管癌组织中的阳性表达率为12.5%,明显低于其在无脑转移的浸润性导管癌中的阳性表达率(56.3%,P＜0.05).Robo1蛋白在＞50岁乳腺浸润性导管癌患者中的阳性表达率为57.8%,明显高于其在≤50岁乳腺浸润性导管癌患者中的阳性表达率(34.0%,P＜0.05).Robo1蛋白阴性表达患者的5年生存率为57.7%,明显低于阳性表达的患者(83.7%,P<0.05).Robo1蛋白在乳腺浸润性导管癌中的表达与肿瘤大小、淋巴结转移状态、病理学分期、组织学分级以及临床分期均无关(均P＞0.05).结论 Robo1蛋白在乳腺浸润性导管癌中的表达与脑转移呈负相关,与患者的发病年龄及预后呈正相关,可成为判断乳腺癌预后和脑转移的分子标志物.

Abstract：

Objective To detect the expression of Robo1 in different breast tumors and its association with the breast cancer brain metastasis. Methods Labelled streptavidin-biotin (LSAB) staining was used to examine the Robo1 expression in specimens from 24 cases of invasive ductal carcinoma(IDC)with brain metastasis, 71 cases of IDC without brain metastasis, 22 cases of ductal carcinoma in situ (DCIS) and 23 cases of fibroadenoma. Results The expression pattern of Robo1 in DCIS (59.1%) and IDC (45.3%) was significantly lower than that in adenofibroma (87.0%, P<0.05). The expression of Robo1 in IDC with brain metastasis (12.5%) was significantly lower than that in IDC without brain metastasis (56.3%, P<0.05). The expression of Robo1 was much higher in more than 50 year-old-group (57.8%) than that in less than 50 year-old-group (34.0%) of IDC patients. The overall survival time in patients with the Robo1 negative expression was significantly shorter than those with positive expression (P<0.05). No correlation was found between the Robo1 expression and the tumor size, lymph node metastasis, pathologic stage, histological grade and clinical stage (P>0.05). Conclusions The Robo1 expression correlates negatively with IDC brain metastasis, and correlates positively with the age and prognosis of IDC patients. Robo1 may be applied as a marker in evaluation of the IDC prognosis and brain metastasis.     

乳腺癌组织人端粒酶逆转录酶表达及其临床病理意义

目的：分析乳腺浸润性导管癌中人端粒酶逆转录酶（hTERT）的蛋白表达与肿瘤的临床分期、组织学分级、转移及患者预后的关系.方法：采用免疫组化SLAB法,检测67例乳腺浸润性导管癌石蜡包埋组织中hTERT的蛋白表达.结果：67例乳腺浸润性导管癌中强阳性者44例,弱阳性者23例.hTERT蛋白主要定位于癌细胞胞质,少部分细胞核也有表达.本组乳腺癌分期和分级越高,hTERT蛋白表达的强阳性率越高,P值分别为0.002 8和0.010 2.hTERT强阳性组转移率为63.6%（28/44）,弱阳性组转移率为30.4%（7/23）,两者差异有统计学意义,P=0.0000.hTERT强阳性组3年生存率为69.2%（27/39）,hTERT弱阳性组3年生存率为95.7%（22/23）,两者差异有统计学意义,P=0.0000.结论：hTERT的蛋白表达可能与乳腺浸润性导管癌的分化和转移有关,可以作为判断乳腺癌患者预后的指标之一.     

乳腺癌组织人端粒酶逆转录酶表达及其临床病理意义

目的:分析乳腺浸润性导管癌中人端粒酶逆转录酶(hTERT)的蛋白表达与肿瘤的临床分期、组织学分级、转移及患者预后的关系。方法:采用免疫组化SLAB法,检测67例乳腺浸润性导管癌石蜡包埋组织中hTERT的蛋白表达。结果:67例乳腺浸润性导管癌中强阳性者44例,弱阳性者23例。hTERT蛋白主要定位于癌细胞胞质,少部分细胞核也有表达。本组乳腺癌分期和分级越高,hTERT蛋白表达的强阳性率越高,P值分别为0.002 8和0.010 2。hTERT强阳性组转移率为63.6%(28/44),弱阳性组转移率为30.4%(7/23),两者差异有统计学意义,P=0.000 0。hTERT强阳性组3年生存率为69.2%(27/39),hTERT弱阳性组3年生存率为95.7%(22/23),两者差异有统计学意义,P=0.000 0。结论:hTERT的蛋白表达可能与乳腺浸润性导管癌的分化和转移有关,可以作为判断乳腺癌患者预后的指标之一。     

S100蛋白在乳腺癌中的表达及意义

目的　探讨钙结合蛋白S10 0在乳腺癌组织中的表达及其临床意义 ,研究S10 0蛋白表达与乳腺癌已知预后相关因子C -erbB - 2、ER、PR的关系。方法　采用Elivision二步免疫组织化学法检测 4 6例乳腺癌组织中S10 0蛋白、C -erbB - 2、ER、PR的表达。结果　S10 0蛋白的表达与乳腺癌淋巴结转移及预后有密切关系。S10 0蛋白阳性乳腺癌患者 5年无病生存率显著低于阴性者 (P <0 0 1)。S10 0蛋白在乳腺癌组织中的表达与C -erbB - 2、ER、PR无相关性。结论　S10 0蛋白可以作为预测乳腺癌预后的独立分子指标     

Skp2蛋白在非小细胞肺癌中的表达及其与p27kip1蛋白表达的关系

目的探讨Skp2蛋白表达在非小细胞肺癌(NSCLC)发生、发展中的作用及其与p27k ip1蛋白表达的关系。方法应用免疫组化S-P法检测60例NSCLC和20例正常支气管黏膜上皮组织中Skp2、p27k ip1蛋白的表达。结果NSCLC组织中Skp2蛋白表达的阳性率为48.33%(29/60),显著高于正常支气管黏膜组织中的表达(P<0.01);Skp2的表达与肿瘤的组织学类型、分化程度、淋巴结转移和患者吸烟与否显著相关,但与年龄、性别无关;NSCLC组织中Skp2表达与p27k ip1表达呈显著负相关(P<0.01)。结论NSCLC中Skp2蛋白表达与靶蛋白p27k ip1蛋白降解有关,提示Skp2蛋白过表达可能在NSCLC的发生和发展中起重要作用。     

Association between RCAS1 expression and clinical outcome in uterine endometrial cancer

RCAS1, which acts as a ligand for a putative receptor on immune cells such as peripheral lymphocytes and natural killer cells, is strongly expressed in human cancers. RCAS1 can induce these cells to undergo apoptotic cell death, which suggests that RCAS1 expression may prohibit the stromal reaction occurring in a tumour. To clarify the clinical significance of RCAS1 expression in uterine endometrial cancer, we analysed the association between RCAS1 expression and clinicopathologic variables by statistical methods. With the use of immunohistochemical techniques, we performed a retrospective study of RCAS1 expression in resected tumour tissue from 147 patients with uterine endometrial cancer. We evaluated the statistical correlation between RCAS1 expression and clinicopathologic variables. RCAS1 was expressed in 106 of 147 patients with uterine endometrial cancer; 30 of these 147 patients showed RCAS1 overexpression. Overexpression of RCAS1 was significantly correlated with age at surgery, stage, extent of myometrial invasion, and positive peritoneal cytologic results. Multivariate analysis revealed that RCAS1 expression and metastasis were clinically significant prognostic factors for the overall survival. These findings indicated that analysis for RCAS1 expression can provide crucial information about the clinical behaviour of uterine endometrial cancer, which may be valuable for the management of patients with this disease.     

The relationship between prognostic and predictive factors in the management of breast cancer

The discovery of new prognostic factors proceeds at a much more rapid pace than our knowledge of how to properly utilize this information in the management of patients with breast cancer, especially those with early breast cancer that has not metastasized to regional lymph nodes. Prognostic factors provide information on how the patient is likely to do regardless of treatment. Predictive factors provide information on whether a patient is likely to benefit from therapy. Most factors identified to date provide prognostic information, but relatively few provide information that is truly helpful in making a therapeutic decision in the management of individual patients. In large part this is because there has been insufficient study of the factor, especially prospective evaluations of the factor. Unfortunately this has resulted in the premature use of this information under the general rubric that patients with a poor prognosis deserve more treatment in spite of the fact that there may be no benefit from that therapy in the poor prognostic group.     

Cytosol protein content and prognosis in operable breast cancer

Summary Several biochemical parameters quantitated in tumor cytosols from malignant breast tumors have been evaluated as possible prognostic factors. Cytosol protein content has always been regarded as a reference parameter, to correct for cellularity and representativity of tumor samples. But recent studies have suggested an altered protein distribution in malignant tissues. The present study on 382 women with histologically proven breast cancer, Stage I and Stage II, therefore evaluates whether cytosol protein content by itself may add information as a prognostic factor in the clinical management of breast cancer.Cytosol protein content was found to be significantly correlated (p<0.001) to tumor size, and inversely correlated to progesterone receptor (PgR) content (p=0.015) and age at operation (p=0.021). Using the median value of protein (4.15 mg/ml) as a cut-off value, two groups could be constructed. The number of node-positive patients in the protein-poor group was significantly decreased (p=0.018) compared to the protein-rich group, which also contained a significantly (p<0.001) lower number of patients with estrogen receptor (ER) positive tumors (i.e. ER10 pmol/g). An increased number of events was observed in the protein-rich group (p<0.001), with a great contribution to the number of deaths due to breast cancer. In a multivariate analysis of the likelihood to predict axillary nodal involvement, protein category was found to be a significant (p<0.031) independent predictive factor. As to relapse free survival (RFS), protein category did not reveal any prognostic power. A subgroup containing Stage II patients with ER+ tumors was included in a prospective, randomized study on the role of tamoxifen as an adjuvant endocrine therapy. In a multivariate analysis, treatment option (tamoxifen vs. control) (p=0.0008) and axillary nodal tumor burden (p=0.009) were significant independent prognostic factors for RFS in protein-rich patients. In protein-poor patients, only tumor size showed a positive association with RFS, but without reaching statistical significance (p=0.062).The present observations make cytosol protein content interesting in the context of tumor biology and breast cancer prognosis. Further studies are needed to evaluate cytosol protein content as a possible prognostic factor useful in the clinical management of breast cancer.     

TIP30蛋白在乳腺癌中的表达及与bax蛋白相关性研究

目的研究肿瘤转移抑制基因TIP30和促凋亡基因bax在乳腺癌中的表达,探讨它们之间的关系及其临床意义。方法应用免疫组织化学S-P法,检测88例乳腺癌病人TIP30蛋白和bax蛋白的表达,并与32例乳腺良性病变组织进行对照。结果①乳腺癌中TIP30蛋白的表达阳性率42％,明显低于在乳腺良性病变中的表达率75％（P〈0．05）,在Ⅲ级癌组织中TIP30蛋白的表达率比Ⅰ、Ⅱ级低（P〈0．05）,而与病人年龄、组织学分型、腋淋巴结转移无关。②bax蛋白在乳腺癌中的表达明显低于乳腺良性病变（P〈0．05）,Ⅲ级癌组织中bax蛋白的表达率比Ⅰ、Ⅱ级低（P〈0．05）,与乳腺癌腋淋巴结转移有关（P〈0．05）,而与病人年龄、组织学分型无关。结论TIP30蛋白的缺失表达与乳腺癌的发生发展有关,TIP30蛋白与bax蛋白成正相关,TIP30基因可能通过上调bax基因的表达促进细胞的凋亡。     

乳腺癌组织FAP表达病理生物学意义的研究

目的:探讨乳腺癌成纤维细胞活化蛋白(FAP)的表达与乳腺癌临床病理因素和生物学预后因子(ER、PR、p53、c-erbB-2、Ki-67)的相关性,评价FAP在乳腺癌的表达意义。方法:选取经病理确诊的乳腺癌患者82例,免疫组织化学法检测乳腺癌组织FAP的表达。收集乳腺癌患者的临床病理信息,分析FAP与乳腺癌临床病理因素和生物学预后因子的表达水平的关系。结果:FAP表达与患者年龄、肿瘤部位、肿瘤大小与FAP的表达无相关性(P>0.05),临床分期与FAP表达呈正相关(r=0.922,P=0.000),病理分级与FAP表达呈弱正相关,r=0.360,P=0.001。FAP表达在有无淋巴结转移组间差异统计学意义,t=11.003,P=0.00。FAP表达与p53(r=0.498,P=0.000)、c-erbB-2(r=0.326,P=0.004)、Ki-67(r=0.449,P=0.000)的表达呈正相关,FAP表达与ER、PR的表达无相关性,P>0.05。结论:FAP在女性乳腺癌发生、发展、侵袭转移方面起到了重要的作用。FAP可作为预测乳腺癌预后的重要因子。     

乳腺癌耐药蛋白在乳腺癌组织中的表达及其与预后的关系

目的:研究乳腺癌耐药蛋白(BCRP)在乳腺癌组织中的表达,评估其在乳腺癌预后中的作用。方法:采用免疫组织化学方法(IHC)检测60例手术切除的乳腺癌组织中BCRP的表达,并分析其与临床病理特征的关系及对预后的影响。结果:①BCRP在乳腺癌组织中的阳性表达率为35%(21/60例);②腋淋巴结或激素受体阳性者BCRP表达水平显著高于腋淋巴结阴性者和激素受体阴性者(P<0.05),BCRP表达与年龄、月经状况、肿瘤大小和组织学分级均无关(P>0.05);③Kaplan-Meier生存分析结果表明BCRP表达与无病生存期显著相关(P<0.05),但和总生存期无关(P>0.05);④Cox单因素和多因素分析都显示肿瘤大小、淋巴结转移和雌激素受体(ER)与无病生存期和总生存期显著相关(P<0.05),另外孕激素受体与总生存期(P<0.05)显著相关。结论:BCRP在乳腺癌组织中具有一定的表达水平,与乳腺癌患者的无病生存期有关,而与总生存期无关。     

mTOR蛋白和Beclin 1蛋白在三阴性乳腺癌组织中的表达及临床意义

目的:探讨三阴性乳腺癌组织中mTOR蛋白、Beclin 1蛋白的表达,以及二者与三阴性乳腺癌各临床病理参数之间的关系。方法:检测mTOR蛋白和Beclin 1蛋白在80例三阴性乳腺癌组织及62例癌旁组织中的表达情况,并分析其表达与患者临床病理参数之间的关系,以及两种蛋白之间的相关性。结果:mTOR和Beclin 1蛋白在三阴性乳腺癌组织中阳性率分别为67.5%（54/80）及30%（24/80）,在癌旁组织中阳性率为35.5%（22/62）及93.5%（58/62）,差异具有统计学意义;mTOR蛋白的阳性表达与淋巴结转移呈正相关（P＜0.05）;Beclin 1蛋白阳性表达与组织学分级呈负相关,与Ki67的表达及TNM分期呈正相关,mTOR蛋白和Beclin 1蛋白表达呈负相关（P＜0.05）。结论:mTOR蛋白和Beclin 1蛋白的异常表达可能参与三阴性乳腺癌的发生发展。