Ki67 Index in Breast Cancer: Correlation with Other Prognostic Markers and Potential in Pakistani Patients

Introduction: Breast cancer aggressiveness can be correlated with proliferation status of tumor cells, whichcan be ascertained with tumor grade and Ki67 indexing. However due to lack of reproducibility, the ASCO donot recommend routine use of Ki67 in determining prognosis in newly diagnosed breast cancers. We thereforeaimed to determine associations of the Ki67 index with other prognostic markers like tumor size, grade, lymphnode metastasis, ER, PR and HER2neu status. Methods: A total of 194 cases of newly diagnosed breast cancerwere included in the study. Immunohistochemical staining for ER, PR, HER2neu and Ki67 was performed bythe DAKO envision method. Associations of the Ki67 index with other prognostic factors were evaluated bothas continuous and categorical variables. Results: Mean age of the patients was 51.7 years (24-90). Mean Ki67index was 26.9% (1-90). ER, PR, HER2neu positivity was noted in 90/194 cases (46.4%), 74/194 cases (38.1%)and 110/194 cases (56.70%) respectively. Significant association was found between Ki67 and tumor grade,PR, HER2neu positivity and lymph node status, but no link was apparent with ER positivity and tumor size.There wasan inverse relation between Ki67 index and PR positivity, whereas a direct correlation was seen withHER2neu positivity. However, high Ki67 (>30%) was associated with decreased HER2neu positivity as comparedto intermediate Ki67 (16-30%). The same trend was established with lymph node metastasis. Conclusion: Ourstudy indicates that with high grade tumors, clinical utility of ki67 is greater in combination with other prognosticmarkers because we found that tumors with Ki67 higher than 30% have better prognostic profile comparedto tumors with intermediate Ki67 level, as reflected by slightly lower frequency of lymph node metastasis andHER2neu expression. Therefore we suggest that Ki67 index should be categorized into high, intermediate andlow groups when considering adjuvant chemotherapy and prognostic stratification.     

Ki67在乳腺癌中的表达水平及其对新辅助化疗患者预后的评估价值

目的研究Ki67表达水平对乳腺癌新辅助化疗后患者预后的评估价值。方法调取行乳腺癌新辅助化疗的120例患者的临床资料,并对其临床病理指标、Ki67的表达及预后进行回顾性分析。结果乳腺癌患者的病理有效率与月经状态、病理组织学类型、雌激素受体状态无关,与原发肿瘤大小、淋巴结转移情况有关(P<0.01)。新辅助化疗后患者的Ki67阳性表达率与化疗前相比显著降低(P<0.01);在病理有效率方面,化疗前Ki67高表达组经新辅助化疗后有效率明显高于Ki67低表达组,差异具有统计学意义(χ~2=19.00,P<0.01);Ki67表达化疗前后明显下降组的病理有效率明显高于轻度下降组病理有效率,差异具有统计学意义(χ~2=89.68,P<0.01)。结论 Ki67呈高表达状态时提示乳腺癌患者新辅助化疗效果良好,同时其表达变化也可对患者的病情进行有效的评估。     

Higher Ki67 Expression is Associates With Unfavorable Prognostic Factors and Shorter Survival in Breast Cancer

Background: The prognostic value of the Ki67 expression level is yet unclear in breast cancer. The aim of thisstudy was to investigate the association between Ki67 expression levels and prognostic factors such as grade, Her2and hormone receptor expression status in breast cancers. Materials and Methods: Clinical and pathologicalfeatures of the patients with breast cancer were retreived from the hospital records. Results: In this study, 163patients with breast cancer were analyzed, with a mean age of 53.4±12.2 years. Median Ki67 positivity was 20%and Ki67-high tumors were significantly associated with high grade (p<0.001), lymphovascular invasion (p=0.001),estrogen receptor (ER) negativity (p=0.035), Her2 positivity (p=0.001), advanced stage (p<0.001) and lymphnode positivity (p<0.003) . Lower Ki67 levels were significantly associated with longer median relapse-free andoverall survival compared to those of higher Ki67 levels. Conclusions: High Ki67 expression is associated withER negativity, Her2 positivity, higher grade and axillary lymph node involvement in breast cancers. The levelof Ki67 expression is a prognostic factor predicting relapse-free and overall survival in breast cancer patients.     

Studies of the Potential Utility of Ki67 as a Predictive Molecular Marker of Clinical Response in Primary Breast Cancer

INTRODUCTION: Objectives were to characterise the relationship of the proliferation marker Ki67 with response to systemic treatment in early breast cancer and to assess its clinical utility, using fine needle aspirates. MATERIALS AND METHODS: Hundred and six women were treated with primary tamoxifen (n = 33), chemotherapy (n = 33) or chemotherapy and tamoxifen (n = 40). Treatment was not randomised and response was assessed clinically. Ki67 was evaluated prior to treatment and at Day 14 or 21 after commencing treatment. To assess reproducibility, Ki67 was evaluated in repeat FNAs taken from 37 untreated patients. RESULTS: The percentage change in Ki67 in first 21 days was different between responders and non-responders for patients treated with tamoxifen (p = 0.007) and chemotherapy (p = 0.005) but not for chemoendocrine treatment (p = 0.062). The reproducibility study indicated that a decrease to 36% or less of the pre-treatment Ki67 value in an individual patient was required for it to be regarded as a statistically significant change. A significant decrease in Ki67 was seen in responding patients treated with chemotherapy (p = 0.026) and chemoendocrine treatment (p = 0.041). Positive and negative predictive values for response were 85 and 59% for chemotherapy patients and 88 and 54% for chemoendocrine patients, respectively. CONCLUSION: Ki67 is unlikely to be useful as a predictive marker in individual patients. Further molecular markers that predict lack of response continue to be required.     

EGFR、Ki67在三阴性与非三阴性乳腺癌中的表达及其与TNBC病理特征的相关性

目的 探讨EGFR、Ki67在三阴性与非三阴性乳腺癌中的表达差异及两者的表达与TNBC临床病理特征的关系.方法 分析non-TNBC与TNBC患者的临床病理资料,采用非生物素二步法检测76例乳腺癌标本里EGFR、Ki67的表达,对比两者在non-TNBC与TNBC中的区别.检测EGFR与Ki67在TNBC中的阳性表达率,研究其与病理参数的相关性.结果 和non-TNBC相比,TNBC多见于绝经前妇女,组织学分级较差,较易发生淋巴结转移、复发转移、远处转移,且出现较早.EGFR与Ki67在TNBC组织中的阳性表达率均高于在non-TNBC组织中的阳性表达率.EGFR、Ki67的表达与TNBC肿块直径、淋巴结转移情况、TNM分期、组织学分级之间均具有相关性.结论 EGFR与Ki67在TNBC中表达均升高.两者的表达与肿块直径、淋巴结转移情况、TNM分期、组织学分级之间均具有相关性.     

胃癌组织中 CDX2表达及其与 KI67的关系分析

目的：探讨CDX2在胃癌组织中的表达情况及其与Ki67的相关性。方法收集新鲜胃癌组织标本50例,应用免疫组化检测CDX2和Ki67在胃癌组织中的表达情况。结果胃癌组织中的CDX2、Ki67的表达水平升高（ P＜0．05）;与分化程度、浸润深度、淋巴结转移、分期有相关性（P＜0．05）,且分化不好、浸润深度T3-4、有淋巴结转移,分期较晚的胃癌组织,CDX2表达较低,Ki67表达较高,两者可能与胃癌的增殖分化有关,但两者的表达无明显相关性（ P＞0．05）。结论 CDX2、Ki67在胃癌中高度表达,对于分析胃癌的恶性程度并判断预后有很高的临床价值。     

Pin1在宫颈癌中过表达及其与Ki67关系的研究

目的:探讨宫颈癌中肽基脯氨酰顺反异构酶Pin1表达、与Ki67的相关性及其临床意义。方法:应用RT-PCR和免疫组化技术检测宫颈癌组织中Pin1mRNA和蛋白表达水平及其与Ki67蛋白表达的相关性。结果:1)宫颈癌组织中Pin1mRNA表达明显高于正常宫颈组织(P<0.05);2)从正常宫颈到CIN再到浸润癌Pin1蛋白表达逐渐增强(P<0.05);3)Pin1蛋白过表达与临床分期、病理分级、淋巴结转移无明显相关(P>0.05);但宫颈腺癌Pin1表达明显高于宫颈鳞癌(P<0.05);4)Pin1过表达与Ki67表达呈显著正相关(P<0.05)。结论:1)Pin1过表达与宫颈癌细胞增殖有关,参与宫颈癌发生发展;2)Pin1过表达可作为宫颈癌诊断的辅助指标。     

Response of Triple Negative Breast Cancer to Neoadjuvant Chemotherapy: Correlation between Ki-67 Expression and Pathological Response

Triple-negative breast cancers constitute about 15% of all cases, but despite their higher response to neoadjuvant chemotherapy, the tumors are very aggressive and associated with a poor prognosis as well as a higher risk of early recurrence. This study was retrospectively performed on 101 patients with stage II and III invasive breast cancer who received 6–8 cycles of neo-adjuvant chemotherapy. Out of the total, 23 were in the triple negative breast cancer subgroup. Nuclear Ki-67 expression in both the large cohort group (n=101) and triple negative breast cancer subgroup (n=23) and its relation to the pathological response were evaluated. The purpose of the study was to identify the predictive value of nuclear protein Ki-67 expression among patients with invasive breast cancers, involving the triple negative breast cancer subgroup, treated with neoadjuvant chemotherapy in correlation to the rate of pathological complete response. The proliferation marker Ki-67 expression was highest in the triple negative breast cancer subgroup. No appreciable difference in the rate of Ki-67 expression in triple negative breast cancer subgroup using either a cutoff of 14% or 35%. Triple negative breast cancer subgroup showed lower rates of pathological complete response. Achievement of pathological complete response was significantly correlated with smaller tumor size and higher Ki-67 expression. The majority of triple negative breast cancer cases achieved pathological partial response. The study concluded that Ki-67 is a useful tool to predict chemosensitivity in the setting of neoadjuvant chemotherapy for invasive breast cancer but not for the triple negative breast cancer subgroup.     

Proliferative Index (Ki67) for Prediction in Breast Duct Carcinomas

Background and objectives: To date, many tumor markers have been used to predict prognosis and therapeuticresponse in patients with breast cancer. The well established and routinely applied tumor markers are the estrogen-receptor,progesterone-receptor and Her2/neu-receptor. In the current study, we aimed to highlight any association of theproliferation index (Ki67) in breast infiltrative duct carcinoma with the tumor grade, tumor size and nodal status inaddition to hormone receptor status. Tissue sections were stained immunohistochemically for Ki67 nuclear antigen,estrogen, progesterone and Her2/neu receptors using an automated Dako machine (Dako Denmark. There was asignificant inverse relationship of Ki67 levels with ER and PR, while values were directly proportional to the tumorgrade and Her2/neu status. No significant association was found between Ki67 and size of tumor or nodal status. Ki67immunoexpression may offer an independent predictive tumor marker and for routine application in cases of breast cancer.     

BRCA1、Ki67在不同分子分型乳腺癌中的表达及临床病理意义

目的 探讨BRCA1、Ki67在不同分子分型乳腺癌进展中的作用、临床病理意义.方法 应用荧光原位杂交技术(FISH),对免疫组化方法检测Her2为2+以上(包含2+)的肿瘤蜡块做进一步检测,FISH检测出阳性表达的肿瘤蜡块定义为Her2最终阳性表达,并依据《2013版中国抗癌协会乳腺癌诊治指南与规范的标准》对乳腺浸润性导管癌进行分子分型,依据分子分型将乳腺癌分为五类Luminal A型,Luminal B like型,Luminal B样型,Her2过表达型和基底细胞样型,各分型分别选取20例,总共100例乳腺浸润性导管癌病例.采用免疫组化二步法对入选病例的肿瘤组织进行BRCA1及Ki67蛋白的检测.结果 BRCA1蛋白阳性表达率在Luminal A型组,Luminal B like型组,Luminal B样型组,Her2过表达型组,基底细胞样型组中差异具有明显显著性(P＜0.05);BRCA1蛋白表达与年龄、肿瘤大小、肿瘤距乳头距离、组织学分级、腋窝淋巴结转移情况、ER/PR状态、Her2状态均无关(P均＞0.1);Ki67高指数表达率在Luminal A型组,Luminal B like型组,Luminal B样型组,Her2过表达型组,基底细胞样型组中差异具有明显显著性(P＜0.05);年龄组≤59岁的Ki67高指数表达率较年龄组≥60岁的增高,差异有统计学意义(P＜0.1);ER/PR阴性组和Her2阳性组的Ki67高指数表达率较ER/PR阳性组和Her2阴性组增高,差异具有统计学意义(P＜0.1);Ki67表达与肿瘤大小、肿瘤距乳头距离、组织学分级、腋窝淋巴结转移等临床病理指标无相关性(P均＞0.1);BRCA1与Ki67在各亚型乳腺癌中的表达呈负相关性(P＜0.05).结论 联合检测BRCA1和Ki67对不同分子分型乳腺癌有一定的预测预后价值.     

MDR1和Ki67在胃癌中的表达及临床意义

[目的]探讨MDR1和Ki67在胃癌中表达的临床意义。[方法]应用免疫组织化学方法检测100例胃癌组织中MDR1及Ki67的表达。[结果]MDR1和Ki67在胃癌组织中的表达高于癌旁组织，而与年龄、性别、组织学类型、浸润深度以及淋巴结转移均无相关性。MDR1与Ki67之间也无明显相关性。[结论]MDR1和Ki67都不能作为胃癌病人判断预后和临床化疗耐药的单一指标。方达与疗     

Relationship of Body Mass Index with Prognosis in Breast Cancer Patients Treated with Adjuvant Radiotherapy and Chemotherapy

Background: The aim of this study was to investigate the relationship of body mass index with overall andprogression-free survival as well as other prognostic factors of breast cancer in patients with non-metastaticbreast cancer. Materials and Methods: We retrospectively reviewed 456 patients diagnosed with breast cancerin the Radiation Oncology department of Kayseri Teaching Hospital between 2005 and 2013. We investigatedrelationship of body mass index with prognosis and other prognostic factors. Results: The study included 456patients (447 women and 9 men). Mean age at presentation was 55.6 years. Of the cases, 96.9% underwentmodified radical mastectomy and 95.0% received chemotherapy, while 82.4% received radiotherapy and 60.0%were given hormone therapy. Body mass index was >25 mg/kg2 in 343 cases. Five- and 10-years overall survivalrates were 77% and 58% whereas progression-free survival rates were 65% and 49%, respectively. In univariateanalyses, factors including stage (p=0.046), tumor diameter (p=0.001), lymph node metastasis (p=0.006) andbody mass index (p=0.030) were found to be significantly associated with overall survival, while perinodalinvolvement was found to be significantly associated with progression-free survival (p=0.018). In multivariateanalysis, stage (p=0.032; OR: 3.8; 95% CI: 1.1-13), tumor diameter (p<0.000; OR: 0.0; 95% CI: 0.0-0.3), lymphnode metastasis (p=0.005; OR: 0.0; 95% CI: 0.0-0.5) and BMI (p=0.027; OR: 0.02; 95% CI: 0.0-0.8) remainedas significantly associated with OS. Conclusions: In our study, it was seen that overall survival time was shorterin underweight and obese patients when compared to normal weight patients.     

Prognostic Significance of the Ki67 Scoring Categories in Breast Cancer Subgroups

BackgroundImmunohistochemical (IHC) expression of Ki67 has a prognostic and predictive value for breast cancer, and the IHC Ki67 labeling index is estimated by counting the number of positive and negative cells. It has not been clarified whether IHC Ki67 estimated using a semiquantitative scoring system has a prognostic value. We aimed to estimate the usefulness of scoring categories of IHC Ki67 as a prognostic factor for breast cancer subgroups.Patients and MethodsWe retrospectively identified patients in the Tokai University breast cancer database for whom IHC Ki67 data were available between January 1, 2000 and December 31, 2010. Survival curves were calculated using the Kaplan-Meier method and compared using the log-rank test.ResultsOf the 1331 primary breast cancer patients included in the study, In patients with estrogen receptor (ER)-positive and HER2-negative tumors (n = 971), high and intermediate Ki67 scores were associated with poorer relapse-free survival than low Ki67 scores (P < .001 and P = .002, respectively). Furthermore, in the multivariate analyses of this subgroup, progression-free survival (PFS) was significantly longer in patients with low Ki67 scores than in patients with high Ki67 scores (hazard ratio, 0.387; 95% confidence interval, 0.233-0.643; P < .001). In the multivariate analyses, the Ki67 score was not significantly associated with PFS in the ER-positive and HER2-positive, ER-negative and HER2-positive, or ER-negative and HER2-negative subgroups.ConclusionOur data demonstrated that low, intermediate, and high Ki67 scores have a prognostic value in breast cancer patients with ER-positive and HER2-negative tumors.     

Ki67在不同分子类型乳腺癌组织中的表达及意义

目的探讨Ki67在不同分子类型乳腺癌组织中的表达及临床意义。方法采用免疫组织化学法,检测368例乳腺癌组织标本中Ki67表达情况,采用Wilcoxon秩和检验分析Ki67在不同分子类型乳腺癌组织中的表达差异;采用Spearman秩相关方法,分析Ki67表达与原发肿瘤大小、腋窝淋巴结转移及病理分期等的相关性。结果 Lumina型、Her-2型及三阴型乳腺癌组织中Ki67表达强度无显著性差异(χ2=0.015,P=0.993);Ki67表达强度与Lumina型乳腺癌的原发肿瘤大小、腋窝淋巴结转移及病理分期呈正相关性(γs=0.167,P=0.013;γs=0.142,P=0.035;γs=0.165,P=0.014),而与Her-2型及三阴型乳腺癌的以上3个病理因素无显著性相关(P>0.05)。结论在Lumina型、Her-2型及三阴型乳腺癌组织中Ki67表达强度无显著性差异,Ki67表达强度与Lumina型乳腺癌的临床病理因素相关,是Lumina型乳腺癌的不良预后因素。     

Ki67在三阴性乳腺癌中的表达及与C-erbB-2的关系

目的:对比研究Ki67基因在三阴性及非三阴性乳腺癌中的表达,并探讨Ki67与C-erbB-2基因表达间的相关性。方法:免疫组织化学法检测320例乳腺癌标本(273例为非三阴性乳腺癌,47例为三阴性乳腺癌)中Ki67及C-erbB-2的表达。结果:较之于非三阴性乳腺癌,三阴性乳腺癌中Ki67为过表达(P<0.01)。同时Ki67与C-erbB-2的表达强度间呈正相关(P<0.01)。结论:Ki67在三阴性乳腺癌中表达升高。     

Association of Immunohistochemically Defined Molecular Subtypes with Clinical Response to Presurgical Chemotherapy in Patients with Advanced Breast Cancer

Gene expression profiling (GEP) has identified several molecular subtypes of breast cancer, with differentclinico-pathologic features and exhibiting different responses to chemotherapy. However, GEP is expensive andnot available in the developing countries where the majority of patients present at advanced stage. The St GallenConsensus in 2011 proposed use of a simplified, four immunohistochemical (IHC) biomarker panel (ER, PR,HER2, Ki67/Tumor Grade) for molecular classification. The present study was conducted in 75 newly diagnosedpatients of breast cancer with large (>5cm) tumors to evaluate the association of IHC surrogate molecular subtypewith the clinical response to presurgical chemotherapy, evaluated by the WHO criteria, 3 weeks after the thirdcycle of 5 flourouracil, adriamycin, cyclophosphamide (FAC regimen). The subtypes of luminal, basal-like andHER2 enriched were found to account for 36.0 % (27/75), 34.7 % (26/75) and 29.3% (22/75) of patients respectively.Ten were luminal A and 14 luminal B (8 HER2 negative and 6HER2 positive). The triple negative breast cancer(TNBC) was most sensitive to chemotherapy with 19% achieving clinical-complete-response (cCR) followed byHER2 enriched (2/22 (9%) cCR), luminal B (1/6 (7%) cCR) and luminal A (0/10 (0%) cCR). Heterogeneity wasobserved within each subgroup, being most marked in the TNBC although the most responding tumors, 8%developing clinical-progressive-disease. The study supports association of molecular subtypes with response tochemotherapy in patients with advanced breast cancer and the existence of further heterogeneity within subtypes.     

Smac 和Ki67 在胃癌组织中的表达及其临床意义

 目的 观察Smac和Ki67在胃癌中的表达，并探讨Smac表达与Ki67的关系及其临床意义。方法 应用免疫组织化学法检测71例胃癌组织中Smac和Ki67的表达，分析Smac表达与临床病理因素、预后及Ki67的关系。结果 Smac在胃癌组织中的表达率为71．8％（51／71），在所有的癌旁组织中均见表达（20／20）。Ki67在胃癌组织中表达阳性率为66．2％（47／71）。Smac表达和Ki67表达与胃癌分化程度、浸润深度、淋巴结转移、TNM分期明显相关（Pd0．05）。Ki67在Smac表达阴性的胃癌组织的阳性率（17／20）明显高于Smac表达阳性组（30／51，Pd0．05）。Smac表达阳性患者的生存时间明显长于Smac表达阴性患者（Pd0．05）。结论 Smac和Ki67可作为判断胃癌组织恶性程度和预后的指标之一，其中Smac的表达与Ki67的表达呈负相关。     

乳腺癌淋巴结转移与Ki67、VEGF表达的相关性及其临床意义

目的探讨乳腺癌淋巴结转移与VEGF（血管内皮生长因子）、K167表达的相关关系及其临床意义。方法采用免疫组化法检测125例乳腺癌组织中VEGF、Ki67的表达以及淋巴结转移的情况。结果腋窝淋巴结转移阳性率为72．8％．VEGF、Ki67表达阳性率分别为：56．8％和74．4％,VEGF与Ki67表达呈正相关（P〈0．01）,淋巴结转移与Ki67表达无显著相关（P〉0．05）,而与VEGF表达呈正相关（P〈0．01）：结论VEGF和Ki67在肿瘤的发生和发展过程中协同作用;Ki67及VEGF的表达与乳腺淋巴结转移是影响乳腺癌预后的重要因素。