乳腺癌患者人表皮生长因子受体2基因扩增状态与临床病理特征的关系

目的探讨乳腺癌患者人表皮生长因子受体2(HER2)基因的扩增状态与患者临床病理特征相关性,并分析乳腺癌患者腋窝淋巴结转移的影响因素。方法收集2016年1月至2019年3月在滕州市中心人民医院病理科做常规病理检查且HER2免疫组织化学(IHC)结果为++的262例乳腺癌患者病理资料,包括年龄、肿瘤长径、组织学分级、病理类型、是否有淋巴结转移、肿瘤数量、肿瘤部位;用IHC法检测石蜡标本p53、Ki-67、雌激素受体(ER)、孕激素受体(PR)的表达结果;用荧光原位杂交(FISH)法检测HER2基因的扩增状态;分析HER2基因扩增是否与上述临床病理特征相关,以及腋窝淋巴结转移是否与上述特征相关。结果262例乳腺癌患者有69例HER2扩增阳性,阳性扩增率为26.3%;HER2基因扩增与Ki-67增殖指数和ER、PR的表达状态相关,差异有统计学意义(χ^2=13.27,P<0.01;χ^2=34.97,P<0.01;χ^2=38.31,P<0.01);与年龄、肿瘤长径等其余临床病理特征均无关(均P>0.05)。262例乳腺癌患者中发生腋窝淋巴结转移106例(40.5%);淋巴结转移与肿瘤长径显著相关(χ^2=29.10,P<0.01),与其余临床病理特征均无相关(均P>0.05)。结论乳腺癌HER2基因扩增状态与Ki-67增殖指数和ER、PR的表达相关,肿瘤大小为影响乳腺癌患者腋窝淋巴结转移的因素,准确判断上述指标能更好地指导乳腺癌患者的治疗和评估预后。     

乳腺癌原发灶与转移灶分子分型指标表达差异的研究

目的 乳腺癌患者激素受体(hormone receptor,HR)、人类表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)和增殖细胞核抗原Ki-67的表达状态直接影响治疗方案的制订.本研究通过比较可手术乳腺癌原发灶与腋窝淋巴结转移灶及治疗后远处转移灶之间HR、HER2和Ki-67表达状况,探讨其表达的一致性,以期为乳腺癌患者综合治疗方案的制订提供参考.方法 选取2015-03-01-2016-04-30就诊于山东大学附属山东省肿瘤医院(162例)和梁山县人民医院(23例)的185例乳腺癌患者作为研究对象.患者均为女性,年龄24～79岁,中位年龄49岁.浸润性导管癌171例,浸润性小叶癌14例.初治直接接受手术治疗患者110例,其中有腋窝淋巴结转移77例;复发转移患者接受转移灶穿刺患者75例,其中肝脏转移43例,肺脏转移32例.所有标本均检测ER、PR、HER2和Ki-67表达,比较原发灶与腋窝淋巴结及远处转移灶的表达情况.结果 原发灶与腋窝淋巴结转移灶ER、PR、HER2和Ki-67表达差异均无统计学意义(均P＞0.05),ER变化率为3.9％,PR为7.8％,HER2为11.7％,Ki-67为20.8％.原发灶与远处转移灶比较,PR和Ki-67表达差异有统计学意义(均P值＜0.05),而ER和HER2表达差异无统计学意义(均P＞0.05),ER变化率为21.3％,PR为29.3％,HER2为18.7％,Ki-67为29.3％.结论 乳腺癌原发灶与转移腋窝淋巴结ER、PR、HER2和Ki-67表达状况一致性较高;原发灶与远处转移灶PR和Ki-67的表达存在差异,ER和HER2的表达无差异,这可能受多种因素的影响,建议对原发灶及转移灶同时进行生物学信息的检测,为患者制订治疗方案提供可靠的生物学信息.     

Correlations between HER2 Expression and Other Prognostic Factors in Breast Cancer: Inverse Relations with the Ki-67 Index and P53 Status

Background: Overexpression or amplification of human epidermal growth factor receptor-2 (HER2) is associated with grade of malignancy and a poor prognosis in breast cancer (BC). The aim of this study was to evaluate of value of HER2 as a prognostic marker, and to analyze associations with common histopathological parameters in BC cases. Materials and Methods: Between of 2007 to 2014, 260 patients with BC referred to Oncology Clinic provided cancer tissue samples which underwent immunohistochemistry (IHC) for markers. ER and PR positivity was defined as 10% positive tumor cells with nuclear staining. HER2-positive was defined as either HER2 gene amplification by fluorescent in situ hybridization (FISH) or scored as 3 by IHC. For HER2 (2), FISH was performed to determine HER2 positivity. Results: The mean age at diagnosis for the patients with HER2-negative was significantly higher than in HER2-positive cases. Also, there were significant correlations between histological grade, nuclear grade, lymph node metastasis, tumor size, ER status, PR status, p53 overexpression and Ki-67 index with HER2 expression. HER2-negative lesions were of higher grade and more likely to be ER-negative, PR-negative, p53-positive, lymph node metastasis, with a tumor sizealso Ki-6720% as compared to the HER2-positive group. Conclusions: Contrary to the results of other studies, HER2-positive tumors in our study had a lower Ki-67 index and were p53-positive. Also, Ki-67 proliferation index 20% in more studies was associated with p53-positive.Therefore, tumors which are HER2-positive and have a Ki-6720% had a more aggressive behavior compared to HER2-positive and Ki-67<20% lesions.     

乳腺癌穿刺活检对HR和HER-2及Ki-67评价可靠性以及化疗对其影响研究

目的：研究乳腺癌空芯针穿刺活检（coreneedle biopsy,CNB）对激素受体（hormone receptor,HR）、HER-2及Ki-67表达状况评价的可靠性,探讨新辅助化疗（neoadjuvantchemotherapy,NAC）对乳腺癌分子生物学信息表达的影响,分析上述生物学指标对NAC疗效的预测价值。方法：选择2012-03-01-2013-01～31山东省肿瘤医院外科收治的乳腺癌患者177例,其中行NAc者95例作为NAC组,未行NAC者82例作为对照组。免疫组织化学SP法检测两组患者CNB和治疗性手术切除标本中ER、PR、HER-2及Kb67的表达状况,依据Miller-Payne分级系统评价化疗后病理反应,依据实体瘤反应评价标准（response evaluation criteria in solid tumors,RECIST）进行新辅助化疗的疗效评价。结果：对照组患者cNB和手术切除标本ER表达一致率为97．6％（80／82）,PR为95．1％（78／82）,HER-2为97．6％（80／82）,Ki-67为92．7％（76／82）,Spearman等级相关系数均〉0．8,P均〈0．05。NAC组和对照组CNB和手术切除标本比较,ER表达状况改变率分别为12．4％（10／79）和3．9％（2／82）,差异有统计学意义,P=0．014;PR表达状况改变率分别为24．0％（19／79）和2．4％（4／82）,差异有统计学意义,P=0．001;HER-2表达状况改变率分别为5．1％（4／79）和2．4％（2／82）,差异无统计学意义,P=0．379;Ki=67表达状况改变率分别为38．0％（30／79）和7．3％（6／82）,差异有统计学意义,Pd0．001。NAC前后ER阳性率分别为64。6％和53．2％,差异无统计学意义,P=0．146;PR阳性率分别为63．3％和45．6o／,差异有统计学意义,P=0．025;Ki-67高表达率分别为45．6％和15．2％,差异有统计学意义,P=0．017。化疗反应分级与ER、PR、HER-2表达变化无相关性,P均〉0．05;与Ki-67表达变化明显相关,P=0．008。ER和PR表达状况与NAC疗效无相关性,P均〉0．05;HER-2阳性的乳腺癌患者NAC有效率为81．8％,阴性者有效率为50．7％,差异有统计学意义,P=0．010;Ki-67高表达乳腺癌患者NAC有效率为70．2％,低表达者有效率为45．5％,差异有统计学意义,P=0．029。结论：cNB与手术切除标本在判断HR、HER-2和Ki-67表达状况上有很好的一致性;NAC能改变乳腺癌患者HR和Ki-67的表达状况,NAc使PR的阳性率降低,Ki-67的表达下降,ER阳性率有降低趋势,NAc对HER-2的表达无显著影响;HER-2阳性和Ki-67高表达的患者对化疗更敏感。     

新辅助化疗对乳腺癌疗效和雌激素受体孕激素受体Ki-67和人表皮生长因子受体2表达的影响分析

目的了解新辅助化疗（NAC）在局部进展期乳腺癌治疗前后ER、PR、Ki-67及HER-2的变化,探讨其与新辅助化疗疗效之间的相关关系。方法 46例接受新辅助化疗的乳腺癌患者纳入研究,分析患者术前弹射式空芯针穿刺活检标本和术后大标本癌组织ER、PR、Ki-67和HER-2表达的变化。患者化疗前行乳腺肿瘤粗针穿刺活检并免疫组化方法检测肿瘤组织ER、PR、Ki-67和HER-2的表达。化疗后评估疗效并对接受手术的患者的手术标本通过同法检测各指标的表达。结果新辅助化疗前后ER、PR、Ki-67和HER-2的表达均发生了改变,新辅助化疗前ER、PR、Ki-67和HER-2阳性表达的肿瘤组织新辅助化疗后下调（ER：82.6%和80.4%;PR：78.3%和71.7%;Ki-67：39.1%和30.4%;HER-2：28.3%和26.1%）,但没有统计学意义（P〉0.05）。ER、PR、Ki-67和HER-2阳性表达疗效有效率与阴性表达有效率分别为ER：68.4%和50.0%;PR：66.7%和60.0%;Ki-67：77.8%和57.1%;HER-2：53.8%和69.7%。ER、PR、Ki-67、HER-2表达状态与化疗效果均无明显的关系（均P〉0.05）。结论新辅助化疗可以改变ER、PR、Ki-67和HER-2的表达,本临床研究未发现ER、PR、Ki-67和HER-2的变化与局部进展期乳腺癌的新辅助化疗疗效有相关关系。     

Expression of Immunohistochemical Markers before and after Neoadjuvant Chemotherapy in Breast Carcinoma,and Their Use as Predictors of Response

Purpose

For patients with breast carcinoma, immunohistochemical markers are important factors in determining the breast cancer subtype and for establishing a therapeutic plan, including the use of neoadjuvant chemotherapy (NACT). However, it is not clear whether the expression of certain markers changes after NACT.

Methods

We assessed estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), Ki-67, p53, and Bcl-2 expression in specimens from 345 breast cancer cases before and after NACT. We analyzed the association between response to NACT and the expression of the markers in pre-NACT specimens. We also compared the expression between pre- and post-NACT specimens.

Results

ER and PR expression was negatively associated with pathological complete response (pCR). HER2 was associated with pCR in all cases, but the association was lost when the cases were subdivided according to hormone receptor status. The pre-NACT tumor size of cases with pCR after NACT was smaller than that of cases with residual disease. HER2-enriched and triple-negative breast cancers were more likely to achieve pCR than luminal A type cancers. PR expression and the Ki-67 index decreased after NACT. A decrease in the Ki-67 index was also demonstrated in hormone receptor positive and HER2-enriched subtypes, but no similar tendency was observed in the triple-negative subtype.

Conclusion

A patient with breast cancer scheduled for NACT should be assessed for the breast cancer subtype, as this will influence the treatment plans for the patient. The expression of PR and Ki-67 after NACT should be interpreted carefully because NACT tends to reduce the expression of these molecules.     

乳腺浸润性癌MRI表现与生物因子表达的相关性研究

目的 探讨乳腺浸润性癌MRI表现与生物因子雌激素受体(ER)、孕激素受体(PR)、人表皮生长因子受体2(HER2)、肿瘤增殖抗原Ki-67、肿瘤抑制蛋白p53表达的相关性及临床意义.方法 回顾性分析69例乳腺浸润性癌患者的MRI表现及生物因子ER、PR、HER2、Ki-67、p53的表达情况,采用Spearman相关分析和分类回归树(CART)算法分析MRI表现与各生物因子表达的相关性.结果 HER2表达与淋巴结转移呈正相关(r=0.299,P﹤0.05),p53表达与病变表现为肿块呈负相关(r=-0.261,P﹤0.05);肿块分叶征象与Ki-67(r=0.472,P﹤0.01)、p53(r=0.25,P﹤0.05)阳性表达呈正相关.根据MRI表现分析各生物因子表达的CART决策树,分类准确度依次为:Ki-67(0.797)﹥ER(0.754)﹥PR(0.725)﹥HER2(0.478)﹥p53(0.464).结论 乳腺浸润性癌的MRI表现与生物因子ER、PR、HER2、Ki-67、p53的表达有一定的相关性,可作为乳腺癌的重要诊断指标.     

A prognostic model based on combining estrogen receptor expression and Ki-67 value after neoadjuvant chemotherapy predicts clinical outcome in locally advanced breast cancer: Extension and analysis of a previously reported cohort of patients

Background

Ki-67 expression has gained attention as a breast cancer prognostic factor, however its significance in the remaining malignant cells after neoadjuvant chemotherapy (NAC) has been rarely examined. This investigation, extension and analysis of a previously reported cohort of patients, evaluates the significance of Ki-67 and estrogen receptor (ER) expression after NAC in LABC (locally advanced breast cancer).

Patients and methods

clinical stage, tumor size, clinical and pathological lymph node involvement, Ki-67, ER, progesterone receptor (PgR), HER2 expression, grading and clinical response were evaluated before and after NAC in 110 patients with LABC. Ki-67 expression was assessed both in pre and post-therapy histological samples, using >15% positive cells as cut-off value to distinguish high from low Ki-67 expressing tumors.

Results

six patients (5.45%) attained pCR after NAC. A significant relationship between elevated post-CT Ki-67 and ER expression was showed at Cox multivariate analysis of disease free survival (DFS).On univariate analysis high post-chemotherapy Ki-67 and ER status were associated with worse survival; at multivariate model included these results were confirmed.Based on these two parameters, a prognostic model identified two different groups: low risk (low postchemotherapy Ki-67 and ER positive, or either high post-chemotherapy Ki-67 or ER negative), and high risk (high post-chemotherapy Ki-67 and ER negative).The low risk group showed a good prognosis (median OS still not reached), while the high risk group had a worse OS (median 41 months).

Conclusions

Ki-67 value after NAC and ER status could predict a worse prognosis among LABC patients treated with NAC.     

Correlation between HER2 Expression and Clinicopathological Features of Breast Cancer: A Cross- Sectional Study in Vietnam

Background: HER2 is the target of the therapeutic agents which are used to treat HER2-positive breast cancer. Reports have shown that the HER2 oncogene expression and its association with clinicopathological factors remain unclear in breast cancer (BC) patients.  This study aimed to determine the correlation between HER2 expression and clinicalpathological characteristics of breast cancer in Vietnamese women. Methods: Between June 2016 and August 2018, paraffin-embedded specimens from 237 patients with primary invasive breast carcinoma in Hue University Hospital and Hue Center Hospital, Hue city, Vietnam were examined for pathological features. The gene expression of HER2, ER, PR and Ki-67 were determined by immunohistochemistry (IHC). The gene amplification of Her2 was assessed by using Dual color in situ hybridization (DISH). Results: The most frequent histological type was invasive carcinoma of no special type (NST) with 77.35%, the highest percentage of patients with Grade II was detected (59.36%), tumor size > 2 cm accounted for 71.31% of cases, Lymph node metastases were available in 57.86% cases. Most patients were diagnosed at stage II (59.18%). The majority of patients were classified as moderate Nottingham prognostic index (54.9%). Estrogen receptor and Progesterone receptor were positive in 53.16% and 50.63%, respectively. 76.37% of cases were in high expression group of Ki-67 (≥14%). HER2 IHC 2+, 3+ were accounted for 28.69% and HER2 gene amplification was detected in 31% cases. HER2 gene amplification and/or overexpression was significantly associated with cell proliferation index Ki67. Furthermore, HER2 gene expression tended to be more frequently found in tumors with large tumor size, high grade, high stage and high Nottingham prognostic index and confirmed their prognostic independent role. Conclusions: Our data indicated that HER2 gene expression was significantly correlated with cell proliferation index Ki67, but not significantly associated with another clinicopathological factors in breast cancer of Vietnamese women.     

Tumor Mutation Burden Prediction Model in Egyptian Breast Cancer patients based on Next Generation Sequencing

Objectives: This study aimed to identify the tumor mutation burden (TMB) value in Egyptian breast cancer (BC) patients. Moreover, to find the best TMB prediction model based on the expression of estrogen (ER), progesterone (PR), human epidermal growth factor receptor 2 (HER-2), and proliferation index Ki-67. Methods: The Ion AmpliSeq Comprehensive Cancer Panel was used to determine TMB value of 58 Egyptian BC tumor tissues. Different machine learning models were used to select the optimal classification model for prediction of TMB level according to patient’s receptor status. Results: The measured TMB value was between 0 and 8.12/Mb. Positive expression of ER and PR was significantly associated with TMB ≤ 1.25 [(OR =0.35, 95% CI: 0.04–2.98), (OR = 0.17, 95% CI= 0.02-0.44)] respectively. Ki-67 expression positive was significantly associated with TMB >1.25 than those who were Ki-67 expression negative (OR = 9.33, 95% CI= 2.07-42.18). However, no significant differences were observed between HER2 positive and HER2 negative groups. The optimized logistic regression model was TMB = -27.5 -1.82 ER – 0.73 PR + 0.826 HER2 + 2.08 Ki-67. Conclusion: Our findings revealed that TMB value can be predicted based on the expression level of ER, PR, HER-2, and Ki-67.     

Overexpression of the p16 cell cycle inhibitor in breast cancer is associated with a more malignant phenotype

In order to study the role of the p16^INK4A(MTS1/CDKN2a) tumor suppressor in breast cancer, we analyzed p16 protein expression in 60 breast cancer samples which were also analyzed for expression of Rb, Ki67, HER2/neu, and estrogen and progesterone receptors (ER, PR). P16 expression was investigated by two methods: western blotting (WB) followed by densitometry, and immunohistochemistry (IHC). The Rb status was studied by western blotting, and expression of Ki67, HER2/neu, ER, and PR was analyzed immunohistochemically. P16-negative results were found in 18% of the carcinomas by WB, but in only one case by IHC and were not associated with established prognostic parameters. In contrast, p16 overexpression which was detected by WB and IHC in 15% and 25% of the tumors, respectively, was significantly associated with unfavorable prognostic indicators. High p16 expression as detected by both methods correlated significantly with high grading and a negative estrogen receptor status. In addition, a significant association of p16 staining with inverse progesterone receptor status and high Ki67 expression was found with IHC. No correlation of p16 expression with clinical stage, HER2/neu immunostaining, Rb expression or Rb phosphorylation was found. Comparison of western blot results and immunohistochemistry suggests that both nuclear and cytoplasmic immunoreactivity in tumor cells is specific and due to p16 expression. We conclude that high p16 reactivity (both nuclear and cytoplasmic) is indicative of a more undifferentiated, malignant phenotype in mammary carcinomas.     

Prognostic utility of fluorescence in situ hybridization for determining HER2 gene amplification in breast cancer

An accurate investigation of the HER2 proto-oncogene is extremely important for the therapy and prognostication of breast cancer. Currently, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) are standard methods for this purpose. The aim of this study was to detect the expression and amplification of HER2 in paraffin-embedded samples of breast cancer tissue and to investigate the relationship between HER2 amplification and various clinicopathological parameters in advanced breast cancers. We used FISH to examine the HER2 gene amplification and IHC to examine the expression of HER2 protein, estrogen receptor (ER) and progesterone receptor (PR) in 62 advanced breast cancers. HER2 gene amplification was detected by FISH in 12 breast cancers (19%) and HER2 protein expression with a score of 3+ was detected by IHC in 11 (17%). There was a significant correlation between the HER2 gene amplification and HER2 protein overexpression in breast cancers (P<0.0001). However, some mismatching was evident: 3 cases, negative for the HER2 gene, showed a HER2 protein expression score of 3+ and 2 cases, positive for HER2 gene amplification, had HER2 protein expression scores of 0 and 1+ (negative), respectively. ER and PR were expressed in 41 (66%) and 46 (74%) cancers, respectively. No correlation was observed between the HER2 gene amplification and any of the clinicopathological parameters examined, including age, histopathological type, TNM stage, tumor size, lymph node status, relapse and expression of PR. We observed three patterns among the 6 deceased cases: i) triple negativity for HER2, ER and PR, ii) positivity for HER2 gene amplification with a mismatching HER2 protein expression, and iii) positivity for the HER2 gene amplification with a matching HER2 protein expression score of 2+ or 3+. The triple negative cases and HER2 gene amplification positive cases with a mismatching HER2 protein expression had a poor outcome. These results suggest that in breast cancer, the detection of HER2 gene amplification by FISH is desirable compared with the HER2 protein expression determined by IHC. Moreover, triple negativity for HER2, ER and PR is a potentially very important prognostic marker.     

Influence of Neoadjuvant Chemotherapy on HER2/neu Status in Invasive Breast Cancer

IntroductionReliably estimating HER2/neu expression in breast cancer is important for predicting patient prognosis and optimizing adjuvant therapeutic strategies. In this retrospective cohort study, effects of NAC on HER2/neu status in invasive breast cancer were evaluated, and the related factors were analyzed.Patients and MethodsOne hundred thirty-one patients with primary breast cancer were treated with anthracycline- and/or taxane-based NAC. HER2/neu status was evaluated by IHC on core needle biopsies of primary tumors before NAC and surgical resection specimens of post-NAC residual breast cancers or tumor-positive axillary lymph nodes. Thirty-two pairs of specimens with discordant HER2/neu IHC scores were analyzed by fluorescence in situ hybridization (FISH).ResultsA significant difference in HER2/neu status by IHC between core needle biopsies and surgical resection specimens in patients receiving NAC was observed. After NAC, 23.4% (29 of 124) of tumors showed downregulated HER2/neu expression by IHC. Alterations of HER2/neu IHC scores did not significantly correlate with tumor subtype, pathologic response to NAC, adjuvant regimen, or time interval from the last chemotherapy to surgery. HER2/neu protein overexpression level was associated with favorable pathologic response to anthracycline and taxane-based chemotherapy. However, tumors with altered HER2/neu IHC scores after NAC revealed stable HER2/neu gene amplification/nonamplification by FISH analysis.ConclusionNeoadjuvant chemotherapy for breast carcinoma resulted in the HER2/neu status alteration by IHC, but they have stable gene amplification status by FISH. HER2/neu protein overexpression indicated greater sensitivity to neoadjuvant anthracycline- and taxane-based chemotherapy. Thus, retesting HER2/neu IHC status in residual tumors after NAC should be considered in order to optimize adjuvant systemic therapy.     

The Case to Case Comparison of Hormone Receptors and HER2 Status between Primary Breast Cancer and Synchronous Axillary Lymph Node Metastasis

Background: Nowadays, the adjuvant treatment for breast cancer patients chosen depends on immunohistochemical pattern of Estrogen receptor(ER), Progesterone receptor(PR) and HER2 status of primary breast tumor. Several retrospective studies showed significant discordance in receptor expression between primary and metastatic tumors. The objective of this research was to determine discordant rate of ER, PR and HER2 status between primary breast cancer and synchronous axillary lymph node metastasis of individual breast cancer patients in Thammasat University Hospital. Methods: A prospective observational study of all breast cancer patients who have axillary metastasis and underwent surgery at Thammasat Hospital between January 2011 to December 2015. Tumor staging, ER, PR, and HER2 status on primary breast tumor were recorded. Synchronous axillary lymph node metastasis was evaluated with immunohistochemistry for ER, PR, and HER2. Results: The ER-positive rate from primary tumor to synchronous axillary lymph node metastasis decreased from 74.7% to 71.7%; the HER2 overexpression rate was decreased from 26% to 24%. In contrast, PR positive rate were 71% in both primary tumor and synchronous axillary lymph node metastasis. In case to case comparison, discordance rate of ER, PR and HER2 status between primary breast cancer and synchronous axillary lymph node metastasis were 11.1%, 20.2% and 10.1%, respectively. Furthermore, the tumor staging was not significant associated with discordance of ER, PR and HER2. Conclusion: ER, PR and HER 2 biomarkers showed significant concordance between primary tumor and synchronous axillary lymph node metastasis. Hence, if we cannot assess the ER, PR and HER2 status in primary tumor, then synchronous axillary lymph node metastasis can be studied instead. However, the repeat of biomarker testing in node-positive breast cancer patients may be beneficial for tailored adjuvant therapy, especially for patients with negative hormone receptor and/or HER2 profile on primary tumor.     

Prognostic impact of discordance between triple-receptor measurements in primary and recurrent breast cancer

BackgroundWe evaluated discordance in expression measurements for estrogen receptor (ER), progesterone receptor (PR), and HER2 between primary and recurrent tumors in patients with recurrent breast cancer and its effect on prognosis.MethodsA total of 789 patients with recurrent breast cancer were studied. ER, PR, and HER2 status were determined by immunohistochemistry (IHC) and/or FISH. Repeat markers for ER, PR, and HER2 were available in 28.9%, 27.6%, and 70.0%, respectively. Primary and recurrent tumors were classified as triple receptor-negative breast cancer (TNBC) or receptor-positive breast cancer (RPBC, i.e. expressing at least one receptor). Discordance was correlated with clinical/pathological parameters.ResultsDiscordance for ER, PR, and HER2 was 18.4%, 40.3%, and 13.6%, respectively. Patients with concordant RPBC had significantly better post-recurrence survival (PRS) than discordant cases; patients with discordant receptor status had similarly unfavorable survival as patients with concordant TNBC. IHC scores for ER and PR showed weak concordance between primary and recurrent tumors. Concordance of HER2–FISH scores was higher.ConclusionsConcordance of quantitative hormone receptor measurements between primary and recurrent tumors is modest consistent with suboptimal reproducibility of measurement methods, particularly for IHC. Discordant cases have poor survival probably due to inappropriate use of targeted therapies. However, biological change in clinical phenotype cannot be completely excluded.     

Topoisomerase II alpha expression and the Ki-67 labeling index correlate with prognostic factors in estrogen receptor-positive and human epidermal growth factor type-2-negative breast cancer

Background

Topoisomerase II alpha (Topo IIa) is involved in DNA replication and is a molecular target for anthracycline-based chemotherapy. The Ki-67 labeling index (LI) is an evaluation of tumor cell proliferation. The objective of this study was to evaluate relationships among Topo IIa expression, the Ki-67 LI, and prognostic factors in estrogen receptor (ER)-positive, human epidermal growth factor type-2 (HER2)-negative breast cancer.

Materials and methods

Seventy-one patients were diagnosed with ER-positive, HER2-negative breast cancer between July 2003 and December 2004. Formalin-fixed, paraffin-embedded tumor specimens were stained for Topo IIa expression and Ki-67 LI. We investigated the correlation of the level of Topo IIa expression and the Ki-67 LI with clinical factors such as age, tumor size, progesterone receptor status, nodal status, nuclear grade, and lymphovascular invasion (LVI).

Results

Statistically significant differences were observed between Topo IIa overexpression, nuclear grade (p?=?0.036), and LVI (p?=?0.029). Topo IIa overexpression was statistically correlated with the Ki-67 LI (p?p?=?0.01). Survival analysis revealed the significant prognostic value of Ki-67 LI in patients with ER-positive, HER2-negative breast cancer (p?=?0.003).

Conclusions

Ki-67 LI is a strong prognostic factor in ER-positive HER2-negative breast cancer. Topo IIa overexpression was significantly correlated with the Ki-67 LI, nuclear grade, and LVI. These findings suggest use of Topo IIa expression as a proliferation marker and a prognostic factor in ER-positive, HER2-negative breast cancer.     

乳腺浸润性导管癌免疫组化分层法的预后价值(英文)

Objective:Gene expression profiling of breast cancer has identified five molecularly distinct subtypes of breast cancer that have different biological behavior and clinical outcomes. These subtypes are termed luminal A, luminal B, luminal HER2, HER2-enriched and triple negative breast cancers (TNBC). We aimed at identification of breast cancer subtypes among Egyptian population and their clinicopathologic features using ER, PR and HER2, Ki-67 and CK5/6. Methods:Tumors from 100 patients with invasive duct carcinoma were subtyped by immunohistochemistry using ER, PR, HER2, Ki-67 and CK5/6. The prognostic value of the immunohistochemical assignment for breast cancer disease-specific survival was investigated by using Kaplan-Meier curves. Results:Immunohistochemical profiling classified 22 cases as luminal A, 33 cases as luminal B, 9 cases as luminal HER2, 26 cases as HER2-enriched and 10 cases as TNBC. Tumors that measured more than 3.5 cm, showed predominance of HER2-enriched subtype. HER2-enriched and luminal B subtypes dominated the node positive cases (35.4% and 33.8%; respectively). Large tumor size (> 3.5 cm), hormone receptor negative state and HER2 positive state were associated with poor prognosis. Disease free survivals (DFSs) were significantly different (P<0.0001) among different breast subtypes with worst 2-year DFS for HER2-enriched subtype (40.77%) followed by luminal A (63.56%). DFS was almost similar in the remaining other subtypes, and luminal B, luminal HER2 and TNBC which were 86.85%, 87.5% and 88.89%; respectively. Conclusion:ER, PR, HER2 and Ki-67 constituted a strong surrogate for molecular breast cancer subtypes and can be easily applied. HER2-enriched subtype carries worse features being associated with large tumor size, nodal metastasis and is associated with poor outcome. Luminal A is a heterogeneous subtype with underlying several factors that can turn its prognosis adversely. TNBC subtype may behave unexpected in a favorable way.     

Estrogen receptor-negative and human epidermal growth factor receptor 2-negative breast cancer tissue have the highest Ki-67 labeling index and EGFR expression: gene amplification does not contribute to EGFR expression

Estrogen receptor (ER) and human epidermal growth factor 2 (HER2) are well-investigated molecules and the focus of many breast cancer therapies. There is a group of breast cancers lacking ER and HER2, but it is not fully understood. Treatment for these patients is limited to cytotoxic chemotherapy. The purpose of present study is to examine ER(-)/HER2(-) breast cancers, with a particular focus on epidermal growth factor receptor (EGFR). EGFR is a target molecule for which novel medicines have been recently developed for other organ cancers, however biological significance in breast cancer is not yet well demonstrated. Breast cancer specimens (n=58) were categorized into four groups: i) ER(+)/HER2(-) (51.7%); ii) ER(+)/HER2(+) (8.6%); iii) ER(-)/HER2(+) (20.7%); and iv) ER(-)/HER2(-) (19.0%). They were immunohistochemically (IHC) examined using antibodies for EGFR, platelet derived growth factor receptor (PDGFR)alpha, PDGFRbeta, parathyroid hormone (PTH) receptor, Ki-67, cyclinD1, p53, and vimentin. The Ki-67 labeling index (LI) was highest in ER(-)/HER2(-) (36.5%), and decreased in order from ER(-)/HER2(+) (31.4%), ER(+)/HER2(+) (17.7%), to (ER(+)/HER2(-) (15.9%) (p=0.001). EGFR, p53 and vimentin were highly expressed in ER(-)/HER2(-) breast cancer cells (p<0.01). CyclinD1 was inversely expressed to Ki-67 LI (p<0.001). Gene amplification of EGFR was examined by two in situ hybridization techniques, fluorescence in situ hybridization (FISH) and chromogenic in situ hybridization (CISH) in serial sections to IHC. Only 1 of 14 EGFR-positive breast cancers showed gene amplification at low levels by CISH. Overall, the ER(-)/HER2(-) breast cancer showed the highest Ki-67 LI, the most frequent expression of EGFR, p53 and vimentin, as well as the lowest expression of cyclinD1. It is unlikely that gene amplification contributes to EGFR expression. ER(-)/HER2(-) breast cancers have potential in the development of novel therapeutics, including targeted medicines.     

Receptor conversion in distant breast cancer metastases

Introduction

When breast cancer patients develop distant metastases, the choice of systemic treatment is usually based on tissue characteristics of the primary tumor as determined by immunohistochemistry (IHC) and/or molecular analysis. Several previous studies have shown that the immunophenotype of distant breast cancer metastases may be different from that of the primary tumor (receptor conversion), leading to inappropriate choice of systemic treatment. The studies published so far are however small and/or methodologically suboptimal. Therefore, definite conclusions that may change clinical practice could not yet be drawn. We therefore aimed to study receptor conversion for estrogen receptor alpha (ERα), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in a large group of distant (non-bone) breast cancer metastases by re-staining all primary tumors and metastases with current optimal immunohistochemical and in situ hybridization methods on full sections.

Methods

A total of 233 distant breast cancer metastases from different sites (76 skin, 63 liver, 43 lung, 44 brain and 7 gastro-intestinal) were IHC stained for ERα, PR and HER2, and expression was compared to that of the primary tumor. HER2 in situ hybridization (ISH) was done in cases of IHC conversion or when primary tumors or metastases showed an IHC 2+ result.

Results

Using a 10% threshold, receptor conversion by IHC for ERα, PR occurred in 10.3%, 30.0% of patients, respectively. In 10.7% of patients, conversion from ER+ or PR+ to ER-/PR- and in 3.4% from ER-/PR- to ER+ or PR+ was found. Using a 1% threshold, ERα and PR conversion rates were 15.1% and 32.6%. In 12.4% of patients conversion from ER+ or PR+ to ER-/PR-, and 8.2% from ER-/PR- to ER+ or PR+ occurred. HER2 conversion occurred in 5.2%. Of the 12 cases that showed HER2 conversion by IHC, 5 showed also conversion by ISH. One further case showed conversion by ISH, but not by IHC. Conversion was mainly from positive in the primary tumor to negative in the metastases for ERα and PR, while HER2 conversion occurred equally both ways. PR conversion occurred significantly more often in liver, brain and gastro-intestinal metastases.

Conclusions

Receptor conversion by immunohistochemistry in (non-bone) distant breast cancer metastases does occur, is relatively uncommon for ERα and HER2, and is more frequent for PR, especially in brain, liver and gastro-intestinal metastases.     

Status of HER2 amplification, polysomy 17 and histopathological features of 425 Pakistani breast cancer patients

HER2 gene amplification in invasive breast cancer is a robust predictive marker for response to transtuzumab therapy. This study was undertaken to measure concordance between immunohistochemistry (IHC) and FISH for HER2 gene amplification in invasive breast tumors, as well as the presence of polysomy 17 and possible correlation with demographics and histopathological variables, including ER and PR positivity. A total of 425 cases of infiltrating carcinoma of breast (99% IDC-NOS) were studied. HER2 over expression was tested by IHC and FISH methods. Association between IHC and FISH in both subsets was calculated by amplification ratio including polysomy 17. Out of 425 specimens, 128 (30%) were positive for HER2 amplification by FISH test, whereas only 78 (24%) tumors with 2+ expression showed amplification. In contrast, 39 (74%) demonstrated 3+ IHC score and HER2 gene amplification. The histological variables including tumor size, tumor type, and lymph node involvement did not influence the outcome of FISH analysis. The ER and PR status showed significantly greater positivity in patients negative for HER2 amplification. Polysomy 17 was detected in 23.7% patients and was positively associated with ER and PR expression (P= <0.05). Our study showed a concordance of 24% between 2+ IHC and FISH amplification, while in 3+ IHC cases the concordance was 74%. Significant links of HER2 amplification was seen with ER andPR negativity and higher tumor grade. In addition, non-significant correlations were noted with other variables like tumor type, size and lymph node status.