非小细胞肺癌中ERCC1的表达与新辅助化疗疗效之间的关系

背景与目的已有研究表明:肿瘤组织中核苷酸切除修复交叉互补组1(ERCC1)的阳性表达与铂类耐药密切相关,本研究探讨ERCC1在NSCLC中的表达及其与新辅助化疗疗效之间的关系。方法采用免疫组化法检测手术切除的73例NSCLC患者肿瘤组织中ERCC1的表达水平,其中33例接受含铂方案的新辅助化疗。采用χ2检验、Logrank分析和COX风险模型等分析ERCC1在NSCLC中的表达及其对新辅助化疗疗效的影响。结果ERCC1在NSCLC中的阳性表达率为34.25%。ERCC1的阳性率在新辅助化疗组(48.48%,16/33)要高于对照组(20.45%,9/40)(χ2=6.008,P=0.025)。ERCC1阳性组新辅助化疗客观缓解率31.3%,阴性组为58.8%(χ2=2.528,P=0.112);MST分别为36月和54月(P=0.118);3年生存率分别为43.8%和47.1%(χ2=0.029,P=0.866);5年生存率分别为18.8%和23.5%(χ2=0.414,P=0.520)。COX多因素回归分析结果显示:肿瘤组织中ERCC1表达水平、TNM分期和新辅助化疗与否是影响患者的预后因素。结论新辅助化疗可诱导NSCLC表达ERCC1,ERCC1高表达患者新辅助化疗客观缓解率低,ERCC1是影响该组患者预后的独立因素。     

乳腺癌组织p53表达与新辅助化疗疗效相关性Meta分析

目的评价乳腺癌组织p53的表达与新辅助化疗疗效的相关性,为乳腺癌的规范化和个体化治疗提供依据。方法计算机检索Cochrane、PubMed、Embase、中国知网、万方和维普等数据库2000-04-2013-11乳腺癌组织p53表达与新辅助化疗的临床研究,按照一定的入排标准将研究方法相似的文献归类整理,原始数据汇总后进行Meta分析和统计处理。结果共纳入22篇相关临床研究,p53表达阳性762例,其中有效478例;p53表达阴性1 094例,其中有效762例。Meta分析结果显示,乳腺癌组织p53表达阳性组与阴性组新辅助化疗的有效率差异无统计学意义,OR=0.69,95%CI:0.44~1.09,P=0.11。亚组分析显示,在蒽环类基础化疗(OR=0.65,95%CI:0.24~1.76,P=0.40)和紫杉类联合化疗(OR=0.70,95%CI:0.40~1.25,P=0.23)中,p53表达的阳性与阴性组间乳腺癌新辅助化疗疗效的差异均无统计学意义;但统一免疫组化阳性标准p53≥10%,则发现p53表达的阳性与阴性组间乳腺癌新辅助化疗有效率差异有统计学意义,OR=0.49,95%CI:0.29~0.82,P=0.006。结论 p53作为乳腺癌新辅助化疗疗效敏感性的指标,只有统一免疫组化阳性标准p53≥10%后,对乳腺癌新辅助化疗疗效才可能有预测作用。     

ERCC1对胃癌患者手术及化疗后生存预测的意义

Objective  

The aim of this study was to evaluate the effect of the excision repair cross-complementing (ERCC1) expression on survival in advanced gastric cancer patients who underwent surgical resection and treated with oxaliplatinbased adjuvant chemotherapy.     

Polymorphisms of ERCC1, XPD, XRCC1 and XPG predict clinical outcome in advanced gastric cancer patients receiving oxaliplatin-based chemotherapy in Chinese population

OBJECTIVE To investigate whether polymorphisms in ERCC1, XPD, XPG, XRCC1 genes are associated with clinical outcomes in advanced gastric cancer （AGC） patients treated with oxaliplatinbased chemotherapy. METHODS The genetic polymorphisms in ERCCI, XPD, XPG, XRCC1 were determined in 94 advanced gastric cancer patients treated with oxaliplatin-based chemotherapy, using TaqMan-MGB probes. The clinical response of 60 patients with stage IV disease, time to progression （TTP） and overall survival （OS） of 94 patients were evaluated. RESULTS The overall disease control rate （CR ＋ PR ＋ SD） of the 60 patients in stage IV was 70% （42/60）. Patients with XRCC1 399 G/G, XPG 46 C/C genotypes showed enhanced response to the oxaliplatin-based chemotherapy compared to those with other genotypes （P 〈 0.05）. The median OS and TTP of the patients were 5.5 months and 9.0 months, respectively. Among the 4 types of polymorphisms in the study, XRCC1 399 G/A ＋ A/A, XPG 46 C/T ＋ T/T genotypes were regarded to be associated with chemoresistance and poor survival （P 〈 0.05）. Combination analysis of the 2 polymorphisms using the Kaplan-Meier method revealed that the TTP and OS of the patients with a number of risk genotypes were significantly shortened （P 〈 0.05）. No significant association was found between the genotypes of the XPD codon 751, the ERCC1 codon 118 and the clinical outcome （P 〉 0.05）. CONCLUSION Testing for XRCC1 399, XPG 46 polymorphisms may allow identification of the gastric cancer patients who will benefit from oxaliplatin-based chemotherapy. Specific polymorphisms may influence clinical outcomes of AGC patients. Selecting specific chemotherapy based on pretreatment genotyping represents an innovative strategy that warrants prospective studies.     

结肠癌中p53和ERCC1的表达及其与临床病理因素的关系

目的：研究p53和ERCC1在人结肠癌中的表达情况,并分析其与临床病理因素的关系。方法选取124例经外科手术的原发性结肠癌标本组织进行研究,采用免疫组织化学SP法染色,计算阳性表达率并分析其与临床病理因素的关系。结果 p53在人结肠癌中的阳性表达率为66.1%（82/124）,明显高于癌旁正常组织（P﹤0.01）,其中与TNM分期、浸润程度关联性大（P﹤0.05）,而与其他临床病理因素如年龄、性别、淋巴结转移无关（P﹥0.05）;ERCC1在人结肠癌中的阳性表达率为46.8%（58/124）,明显高于癌旁正常组织（P﹤0.01）,其中与浸润程度关联性大（P﹤0.05）,而与其他病理因素如年龄、性别、TNM分期、淋巴结转移无关（P﹥0.05）。结论 p53和ER-CC1在结肠癌中的表达促进其发生、发展过程。结肠癌中p53和ERCC1的表达较癌旁正常组织明显升高,可能用于结肠癌的诊断、治疗及判断预后。     

Locally advanced/inflammatory breast cancers treated with intensive epirubicin-based neoadjuvant chemotherapy: are there molecular markers in the primary tumour that predict for 5-year clinical outcome?

BACKGROUND: Locally advanced and/or inflammatory breast cancer (LABC) is a heterogeneous disease. Molecular markers may help to understand this heterogeneity. This paper reports the results of a study assessing the potential prognostic or predictive value of HER-2, p53, cyclinD1, MIB1, ER and PgR expression by immunohistochemistry from patients included in an EORTC-NCIC-SAKK trial. PATIENTS AND METHODS: A total of 448 patients with a cytological or histological diagnosis of LABC were randomised into a trial comparing two anthracycline-based neoadjuvant regimens. Chemotherapy was followed by standard locoregional therapy. Survival was comparable in both arms. We collected and analysed centrally paraffin-embedded tumour specimens from 187 (72.5%) of 258 patients that had a histological diagnosis. RESULTS: Of the patients included in this molecular marker study 114 relapsed and 91 died. In the multivariate analysis p53 positivity was associated with a shorter progression-free survival [hazard ratio (HR) = 1.96; 95% CI 1.33-2.91; P = 0.0008) and a shorter overall survival (HR = 1.98; 95% CI 1.28-3.06; P = 0.002). PgR positivity predicted for a longer overall survival (HR = 0.54; 95% CI 0.35-0.83; P = 0.0045). CONCLUSIONS: p53 was an independent factor predicting for survival. In order to clarify whether p53 is a pure prognostic and/or a predictive factor, a phase III trial is being conducted (EORTC 10994/BIG 00-01 study) using functional assay in yeast from frozen tumour samples.     

ERCC1 mRNA表达与结直肠癌标准方案化疗临床预后的相关性研究

目的:探讨结直肠癌石蜡组织中切除修复交叉互补基因 (excision repair cross-complementing group 1,ERCC1) mRNA表达水平与接受标准方案化疗的结直肠癌患者临床病理的关系以及其预后意义。方法:采用实时荧光定量 RT-PCR检测福尔马林固定－石蜡包埋的结直肠癌组织中DNA修复基因ERCC1 mRNA的表达水平,并比较其表达水平与接受标准方案化疗的结直肠癌患者的临床病理及生存期之间的关系。结果:ERCC1 mRNA表达与结直肠癌临床病理特征无相关性(P＞0.05)。将ERCC1 mRNA在96例大肠癌患者中的表达量（相对于β-actin）分为低表达组与中高表达组（≤5.21为低表达组,＞5.21为中高表达组）,样本总生存期呈正态分布,中高表达组平均总生存期为68.52月（95%CI:63.06-76.06）,低表达组平均总生存期为56.63月（95%CI:44.45-68.80）,从生存曲线上看中高表达组患者总生存时间明显长于低表达组,两者有统计学差异(P=0.049)。样本无进展生存期呈偏态分布,中高表达组的中位生存时间30.98月（95%CI:0-18.65）,低表达组的中位生存时间8.48月（95%CI:6.37-10.60）,两者之间差别无统计学意义（P=0.575）。Cox多因素回归分析发现性别（P=0.023）、分期（P＜0.001）、以肠梗阻或肠穿孔起病（P=0.046）是患者总生存期的独立影响因素,年龄（P=0.043）、分期（P＜0.001）、脉管侵犯（P=0.002）是患者无进展生存期的独立影响因素。结论:ERCC1 mRNA的表达水平可能是使用标准方案化疗的结直肠癌患者预后的影响因素,性别、分期、以肠梗阻或肠穿孔起病、年龄、脉管侵犯是影响结直肠患者预后的独立影响因素。     

Tubulin, BRCA1, ERCC1, Abraxas, RAP80 mRNA expression, p53/p21 immunohistochemistry and clinical outcome in patients with advanced non small-cell lung cancer receiving first-line platinum-gemcitabine chemotherapy

Background

The aim of this study was to assess the predictive value of tumor expression of nine genes on clinical outcome in patients with advanced NSCLC receiving platinum-gemcitabine chemotherapy.

Methods

Quantitative PCR or immunohistochemistry were used to analyze the expression of β-tubuline IIA (TUBB2A), β-tubuline III (TUBB3), BRCA1, ERCC1, Abraxas (ABRX) and RAP80 in mRNA isolated from paraffin-embedded tumor biopsies of 45 NSCLC patients treated as part of a larger observational trial. All patients received first-line platinum-gemcitabine chemotherapy for stage IIIB or IV NSCLC.

Results

Median progression-free survival (PFS) was 7 months, overall survival (OS) 12 months. A partial treatment response was found in 14 patients (33%). Patients with low ERCC1 or ABRX expression had a significantly better response to chemotherapy (R = −0.45, p < 0.01 for ERCC1; R = −0.40, p = 0.016 for ABRX). A significant correlation was found between the individual time for PFS and the expression of both ERCC1 (R = −0.36, p = 0.015) and ABRX (R = −0.46, p = 0.001). Patients with low ERCC1 expression had a longer OS as compared to patients with high ERCC1 expression (HR = 0.26, log-rank p = 0.02).

Conclusions

The study confirms tumor expression of ERCC1 as a predictor for clinical outcome in patients with advanced NSCLC receiving platinum-based chemotherapy, and found ABRX expression to be similarly predictive of clinical outcome. Prospective validation is warranted and - if confirmed - non platinum-containing chemotherapy should be explored as the preferred treatment in patients with high ERCC1 or ABRX expression and no activating mutations of EGFR.     

乳腺癌新辅助化疗对凋亡相关基因p53、bc1-2的影响(英文)

目的探讨乳腺癌新辅助化疗对凋亡相关基因p53、bcl-2表达的影响及其意义。方法用免疫组织化学ABC法检测97例新辅助化疗(研究组)和同期76例未行新辅助化疗(对照组)的乳腺癌组织p53、bcl-2蛋白的表达,并结合5年无病生存率(DFS)进行分析。结果研究组p53阳性率为28.9%(28/97),对照组为38.2%(29/76);研究组bcl-2阳性率为40.2%(39/97),对照组为56.7%(43/76);研究组5年DFS为74.2%(72/97),对照组为60.5%(46/76),两者比较均有显著差异。结论新辅助化疗通过凋亡相关基因p53、bcl-2的表达影响预后。     

乳腺癌新辅助化疗对凋亡相关基因p53、bcl-2的影响

目的 探讨乳腺癌新辅助化疗对凋亡相关基因p53、bcl-2表达的影响及其意义。方法 用免疫组织化学ABC法检测97例新辅助化疗（研究组）和同期76例未行新辅助化疗（对照组）的乳腺癌组织p53、bcl-2蛋白的表达，并结合5年无病生存率（DFS）进行分析。结果 研究组p53阳性率为28．9％（28／97），对照组为38．2％（29／76）；研究组bcl-2阳性率为40．2％（39／97），对照组为56．7％（43／76）；研究组5年DFS为74．2％（72／97），对照组为60．5％（46／76），两者比较均有显著差异。结论 新辅助化疗通过凋亡相关基因p53、bcl-2的表达影响预后。     

核苷酸切除修复交叉互补基因1 mRNA表达与非小细胞肺癌铂类化疗患者预后的相关性

目的 探讨核苷酸切除修复交叉互补基因1(ERCC1)mRNA表达与非小细胞肺癌(NSCLC)铂类化疗患者临床病理特征的关系及其预后意义.方法 采用实时荧光定量逆转录聚合酶链反应(RT-PCR)方法,检测NSCLC石蜡包埋组织中ERCC1 mRNA的表达水平,并比较其表达水平与NSCLC铂类化疗患者临床病理特征和生存时间之间的关系.结果 61例NSCLC患者中,ERCC1 mRNA的中位表达量为0.48.ERCC1 mRNA表达与NSCLC患者临床病理特征无关.ERCC1mRNA低表达(<0.35)患者经铂类药物化疗后的无进展生存时间为14.3个月,而高表达者为8.0个月,差异有统计学意义(P=0.028).ERCC1 mRNA低表达(<0.28)患者的总生存时间为28.4个月,而高表达者为12.9个月,差异有统计学意义(P=0.0064).Cox多因素回归分析显示,ERCC1 mRNA表达水平是影响NSCLC患者预后的独立因素.结论 ERCC1 mRNA的表达水平可以作为以铂类为基础药物化疗的NSCLC患者预后的独立预测因素,ERCC1 mRNA低表达的NSCLC患者经铂类化疗后,总生存时间明显延长,为制定NSCLC个体化的化疗方案提供了重要信息.     

Breast cancer response to neoadjuvant chemotherapy: predictive markers and relation with outcome

The aim of this study was to provide a better insight into breast cancer response to chemotherapy. Chemotherapy improves outcome in breast cancer patients. The effect of cytotoxic treatment cannot be predicted for individual patients. Therefore, the identification of tumour characteristics associated with tumour response and outcome is of great clinical interest. We studied 97 patients, who received anthracycline-based neoadjuvant chemotherapy. Tumour samples were taken prior to and after chemotherapy. We quantified the response to chemotherapy clinically and pathologically and determined histological and molecular tumour characteristics. We assessed changes in the expression of Bcl-2, ER, P53 HER2 and Ki-67. Association with response and outcome was tested for all parameters. The experimental results showed 15 clinical (17%) and three (3%) pathological complete remissions. There were 18 (20%) clinical vs 29 (33%) pathological nonresponders. The expression of most markers was similar before and after chemotherapy. Only Ki-67 was significantly decreased after chemotherapy. Factors correlated with response were: large tumour size, ER negativity, high Ki-67 count and positive P53 status. Tumour response and marker expression did not predict disease-free or overall survival. In conclusion, clinical and pathological response assessments are poorly associated. Proliferation decreases significantly after chemotherapy. ER negativity and a high proliferation index are associated with better response. HER2 status does not predict response, and outcome is not related to tumour response.     

Time-varying effect and long-term survival analysis in breast cancer patients treated with neoadjuvant chemotherapy

Background:

Recent studies have indicated the prognostic value of tumour subtype and pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). However these results were reported after a short follow-up and using a standard Cox model which could be unsatisfactory for time-dependent factors. In the present study, we identified the prognostic factors for long-term outcome after NAC, considering that they could have an inconstant impact over time.

Methods:

Prognostic factors from 956 consecutive breast cancer patients treated with NAC were identified and associated with long-term outcomes. We estimated survival by a time function multivariate Cox model regression and stratified by follow-up length.

Results:

The prognostic value of tumour histological grade and hormone receptors status varied as distant recurrence-free interval (DRFI) increased. The multivariate analysis identified the following significant prognostic factors: tumour size, N stage, clinical and pathological response to NAC, hormone receptors (HR) status and histological tumour grade. The ‘prognostic benefit'' of low-grade and positive-HR status decreased over the years. Thus, in the early years after cancer diagnosis, the hazard ratio of distant recurrences in patients with positive-HR status increased from 0.26 (95% CI 0.1–0.4) at 6 months to 2.2 (95% CI 1.3–3.7) at 120 months. The histological tumour grade followed a similar trend. The hazard ratio of grade III patients compared with grade I was 1.83 (95% CI 1.1–2.8) at 36 months and diminished over time to 0.70 (95% CI 0.4–1.3) at 120 months. This indicates that the risk of recurrence for positive-HR patients was 74% lower at 6 months compared with the negative-hormone receptor group, but 30% higher at 5 years and more than double at 10 years. High-grade tumours presented a risk of 83% in the earlier years decreasing to 30% at 10 years versus the low-grade group.

Conclusion:

From the present study, we conclude the importance of identifying time-dependent prognostic factors. Distant recurrence-free interval within women who receive NAC are influenced by achieving pCR and breast cancer subtype. Tumours with more aggressive biology have poorer survival during the first 5 years, but if they exceed this point their prognostic impact is no longer significant. Conversely, positive-HR patients remain at risk for distant recurrence for many years.     

联合检测 ERCC1、BRCA1、RRM1表达在非小细胞肺癌选择化疗方案中的意义

目的：探讨检测非小细胞肺癌组织中 ERCC1、BRCA1、RRM1的蛋白表达在化疗方案选择中的临床意义。方法：选取确诊非小细胞肺癌患者120例,随机分为两组。常规化疗组（60例）给予吉西他滨／紫杉醇＋顺铂化疗;实验组（60例）：化疗前检测 ERCC1、RRM1、BRCA1蛋白的表达,选用敏感的化疗药物治疗。比较两组的疗效、无疾病进展时间和生存期。结果：实验组中 ERCC 1蛋 白 和 BRCA 1蛋 白 表 达 阳 性 率 为28．33％,RRM1蛋白表达阳性率为51．67％。治疗两周期后评价常规化疗组和实验组的化疗客观缓解率分别是35．00％（21／60）,43．33％（26／60）,无统计学差异（P ＞0．05）。两组无疾病进展平均时间、中位时间分别为实验组6．653个月、4．8个月;常规化疗组4．35个月、3．5个月,有统计学意义（P ＜0．05）。生存分析两组比较差异无统计学意义（P ＞0．05）。结论：检测 ERCC1蛋白、BRCA1蛋白、RRM1蛋白的表达选择化疗方案使非小细胞肺癌患者在临床化疗中获益,可以延长无疾病进展时间。     

乳腺癌分子分型在新辅助化疗疗效及预后预测中的作用

目的:探讨乳腺癌分子分型在新辅助化疗疗效及预后预测中的作用.方法:收集漯河市中心医院收治的236例接受新辅助化疗患者的临床病理资料,分为Luminal A、Luminal B、Her-2阳性和三阴乳腺癌4种分子分型,分析分子分型与临床病理因素、新辅助化疗疗效及 5 年生存率的相关性.结果:236例患者中,107例(45.3%)为Luminal A亚型,47例(19.9%)为Luminal B亚型,27例(11.4%)为Her-2阳性亚型,55例(23.3%)为三阴乳腺癌亚型.Her-2阳性(25.9%)及三阴乳腺癌亚型(30.9%)的病理完全缓解(pCR)率明显高于Luminal亚型(Luminal A亚型 4.7%及Luminal B亚型 8.5%),差异有统计学意义(P<0.05).与Luminal亚型相比,Her-2阳性及三阴乳腺癌亚型具有更差的5年无病生存和总生存(P<0.01);获得pCR的乳腺癌患者的5年无病生存和总生存明显高于化疗后仍有癌残留的患者(P<0.05).结论:相对于Luminal亚型,Her-2 阳性和三阴乳腺癌亚型对新辅助化疗更为敏感,更易达到pCR;但是Her-2阳性和三阴乳腺癌亚型预后反而更差.     

Low ERCC1 mRNA and protein expression are associated with worse survival in cervical cancer patients treated with radiation alone

Purpose

To evaluate the association of excision repair cross-complementation group 1 (ERCC1) expression, using both mRNA and protein expression analysis, with clinical outcome in cervical cancer patients treated with radical radiation therapy (RT).

Experimental design

Patients (n = 186) with locally advanced cervical cancer, treated with radical RT alone from a single institution were evaluated. Pre-treatment FFPE biopsy specimens were retrieved from 112 patients. ERCC1 mRNA level was determined by real-time PCR, and ERCC1 protein expression (FL297, 8F1) was measured using quantitative immunohistochemistry (AQUA®). The association of ERCC1 status with local response, 10-year disease-free (DFS) and overall survival (OS) was analyzed.

Results

ERCC1 protein expression levels using both FL297 and 8F1 antibodies were determined for 112 patients; mRNA analysis was additionally performed in 32 patients. Clinical and outcome factors were comparable between the training and validation sets. Low ERCC1 mRNA expression status was associated with worse OS (17.9% vs 50.1%, p = 0.046). ERCC1 protein expression using the FL297 antibody, but not the 8F1 antibody, was significantly associated with both OS (p = 0.002) and DFS (p = 0.010). After adjusting for pre-treatment hemoglobin in a multivariate analysis, ERCC1 FL297 expression status remained statistically significant for OS [HR 1.9 (1.1-3.3), p = 0.031].

Conclusions

Pre-treatment tumoral ERCC1 mRNA and protein expression, using the FL297 antibody, are predictive factors for survival in cervical cancer patients treated with RT, with ERCC1 FL297 expression independently associated with survival. These results identify a subset of patients who may derive the greatest benefit from the addition of cisplatin chemotherapy.     

ABCB1 polymorphism as prognostic factor in breast cancer patients treated with docetaxel and doxorubicin neoadjuvant chemotherapy

Expression of the adenosine triphosphate‐binding cassette B1 (ABCB1) transporter and P‐glycoprotein are associated with resistance to anticancer drugs. The purpose of this study was to investigate the role of single nucleotide polymorphism in the ABCB1 and CYP3A genes in breast cancer patients who were treated with neoadjuvant chemotherapy. Stage II/III breast cancer patients were treated with three cycles of neoadjuvant, after which the patients received curative surgery and adjuvant chemotherapy. The polymorphisms of ABCB1 and CYP3A were genotyped. The correlation of polymorphism of ABCB1, CYP3A, and clinical outcomes was analyzed. Among the 216 patients, ABCB1 3435TT genotype had a longer overall survival (OS). than CC/CT. Multivariate analyses demonstrated that good PS, invasive ductal carcinoma, non‐triple negative phenotype and initial operable stage were significantly associated with a lower death risk. ABCB1 3435TT genotype had a higher AUC than CC/CT for docetaxel. These higher AUCs in the C3435TT was associated with increased toxicities of neutropenia and diarrhea. This study showed that the genetic polymorphism of ABCB1 C3435T might be associated with a longer OS. Our results also suggest that the prediction of docetaxel toxicity might be possible for C3435T polymorphism. This study results provides valuable information on individualized therapy according to genotypes.