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.     

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.     

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.     

男性乳腺癌病理特点及其治疗

报告３２例经病理证实的男性乳腺癌。分析其临床病理特点，旨在探索最佳治疗方法，提高生存率。其特点为年老，病程长，病期晚，易误诊。首发症状为乳晕下肿块，易使及皮肤和胸肌筋膜。病理类型多为单纯癌，里浸润性生长。癌周免疫反应差，恶性度高，极易转移。因此主张男性乳腺癌应以根治术为主，术后补加放疗和化疗，尤其是内乳区放疗，不应忽视。     

Male Breast Cancer: Epidemiology and Risk Factors

Male breast cancer is a rare malignancy that accounts for less than 1% of all cancers in men and less than 1% of all breast cancers. But the incidence is rising and in some patient groups reaching 15% over the course of their lives. The major risk factors for the development of male breast cancer include advancing age, hormonal imbalance, radiation exposure, and a family history of breast cancer. Regarding the latter, incidence can be linked to mutations in high- or low-penetrance genes. The most relevant risk factor for the development of male breast cancer is a mutation in the BRCA2 gene. Most cases present late because of a lack of awareness of the existence of such a malignancy in males and ignorance of the related risk factors. Additionally, males with breast cancer are at special risk for developing a second cancer. This in depth review highlights the epidemiology and risk factors for the development of male breast cancer.     

恶性肿瘤家族史与乳腺癌患者临床病理特征的关系CSCD

目的探讨恶性肿瘤家族史(MN-FH)与乳腺癌患者临床病理特征之间的关系。方法回顾性分析东南大学附属中大医院2016年1月—2018年12月收治的417例乳腺癌患者的临床病理资料,根据有无MN-FH分成两组。采用χ2检验分析两组患者临床病理特征之间的关系。结果417例乳腺癌患者中,有MN-FH者67例(16.1%)。有MN-FH组的患者有更高比例的脉管癌栓(P=0.046)和淋巴结转移(P=0.023),肿瘤更易表现为ER阴性(P=0.025)、PR阴性(P=0.031)和HER2阳性(P=0.041)。进一步亚组分析发现,有乳腺癌家族史的患者较无MN-FH的患者有更晚的肿瘤分期(P=0.011),肿瘤更易表现为三阴性和HER2扩增型(P=0.010)。其他恶性肿瘤家族史的患者较无MN-FH的患者有更高比例的脉管癌栓(P=0.036)和淋巴结转移(P=0.034)。结论有MN-FH的乳腺癌患者肿瘤恶性程度更高,对于有MN-FH的人群体检非常重要。     

Correlation between Ki67 and Histological Grade in Breast Cancer Patients Treated with Preoperative Chemotherapy

Background and Aim: Breast cancer (BC) is a heterogeneous disease and cell proliferation markers may helpto identify subtypes of clinical interest. We here analyzed the correlation between cell proliferation determinedby Ki67 and HG in BC patients undergoing preoperative chemotherapy (PCT). Materials and Methods: Weobtained clinical/pathological data from patients with invasive BC treated at our institution from 1999 until2012. Expression of estrogen receptor (ER), progesterone receptor (PR), epidermal growth factor receptor type2 (HER2) and Ki67 were determined by immuno-histochemistry (IHC). Clinicopathological subtypes weredefined as: Luminal A, ER and/or PR positive, HER2 negative, HG 1 or 2; Luminal B, ER and/or PR positive,HER2 negative or positive and/or HG 3; triple negative (TN), ER, PR and HER2 negative independent ofHG; HER2 positive, ER, PR negative and HER2 positive, independent of HG. By using Ki67, a value of 14%separated Luminal A and B tumors, independently of the histological grade. We analyzed correlations betweenKi67 and HG, to define BC subtypes and their predictive value for response to PCT. Results: 1,560 BC patientswere treated in the period, 147 receiving PCT (9.5%). Some 57 had sufficient clinicopathological information tobe included in the study. Median age was 52 years (26-72), with 87.7% invasive ductal carcinomas (n=50). Weperformed IHC for Ki67 in 40 core biopsies and 50 surgical biopsies, 37 paired samples with Ki67 before andafter chemotherapy being available. There was no significant correlation between Ki67 and HG (p=0.237), bothcategorizing patients into different subtypes. In most cases Ki67 decreased after PCT (65.8%). Only 3 patientshad pathologic complete response (cPR). Conclusions: In our experience we did not find associations betweenKi67 and HG. Determination of clinicopathological luminal subtypes differs by using Ki67 or HG.     

Immunohistochemical Evaluation of Ki-67 and Comparison with Clinicopathologic Factors in Breast Carcinomas

Background: Patients primarily received tamoxifen based on their menopausal status due to the lack ofimmunohistochemistry. A recent study has shown that hormonal receptors were not correlated with menopausal status,and thus, indicating that they present limited therapeutic and prognostic significance in breast cancer management.This study aimed to evaluate Ki-67 value and analyze its association with clinicopathologic parameters in breast cancerpatients. Methods: The formalin-fixed paraffin-embedded breast tissue blocks of 125 patients with primary breastcarcinomas were subjected to immunohistochemical analysis using Ventana Benchmark® GX automated immunostainer.Analysis of variance and Chi-2 test were used to examine the relationship between Ki-67 and clinicopathologicvariables. Results: The mean age of 125 patients included in the study was 47.7 years. The average score of Ki-67was 56.0%. 84.8% of patients showed Ki-67 ≥ 14%. Mean scores of Ki-67 were correlated with grade (p = 0.006),PR (p = 0.026), histological type, ER, combined ER/RP, and molecular subtype (p < 0.001). Ki-67 was independentof HER2 (p = 0.402) and menopausal status (p = 0.471). The frequency of Ki-67 according to St Gallen 2011 wasassociated with histological type (p = 0.005), grade (p = 0.005), ER (p < 0.001), combined ER/PR (p = 0.004), andmolecular subtype (p = 0.004). There was no significant relationship between the distribution of Ki-67 and the age ofthe patients (p = 0.859), menopausal status (p = 0.979), PR (p = 0.149), and HER2 (p = 0.597). Conclusion: Ki-67 isuseful for treatment decisions in primary breast cancer patients. The high value of Ki-67 was associated with adverseclinicopathologic factors. The increased Ki-67 value should be carefully investigated in triple negative patients.     

单中心非转移性男性乳腺癌临床病理特征和生存分析

目的探讨非转移性男性乳腺癌手术患者的临床病理特征、治疗策略及生存情况。方法回顾性分析152例非转移性成年男性乳腺癌患者的人口学特征、临床诊治和生存情况。结果所有病例中位发病年龄为58岁。93.4%的患者以乳房肿块为首发症状,4例为原位癌,148例浸润性癌中浸润性导管癌占86.8%,雌激素受体阳性率为93.9%(139例),人表皮生长因子阳性率仅为7.4%(11例)。手术以全乳切除为主(n=149, 98.0%),保乳少见(n=3, 2.0%),19例前哨淋巴结(SLN)活检中,4例提示转移,行腋窝淋巴结清扫(ALND),15例SLN阴性中8例行常规ALND,7例免除ALND。中位随访时间42.7(2～179.5)月。5年OS和DFS分别为82.4%和69.9%。结论淋巴结状态(N)与非转移性男性乳腺癌的无病生存时间和总生存时间明显相关,是男性乳腺癌患者预后的重要影响因素。     

不同分子分型乳腺癌的临床病理特征及预后的关系

目的 探讨乳腺癌分子分型与临床病理特征及预后的关系.方法 选择126例乳腺癌患者,按孕激素受体(PR)、雌激素受体(ER)和人类表皮生长因子受体-2(HER-2)的状态分为Luminal A型、Luminal B型、HER-2过度表达型和Basal-like型,比较不同分子分型乳腺癌患者的临床病理特征、复发转移及预后情况.结果 156例乳腺癌患者中,Luminal A型68例(54.0%)、Luminal B型22例(17.5%)、HER-2过度表达型9例(7.1%)、Basal-like型27例(21.4%).乳腺癌不同分子分型间绝经状态、肿瘤直径、淋巴结转移数目、临床分期及组织学分级的差异均有统计学意义(P<0.05).HER-2过度表达型与Basal-like型的局部复发率分别为33.3%和14.8%,远处转移率分别为55.6%和40.7%,均高于其他2种亚型,差异均有统计学意义(P<0.05).4组中位无瘤生存时间的差异有统计学意义(χ2=8.002,P<0.05),HER-2过度表达型与Basal-like型的MPFS较短.结论 HER-2过表达型和Basal-like型乳腺癌的病理学特征较差,且预后不良;而Luminal A型预后较好.     

Electromagnetic Field Exposure and Male Breast Cancer Risk: A Meta-analysis of 18 Studies

Background: The possibility that electromagnetic fields (EMF) exposure may increase male breast cancer riskhas been discussed for a long time. However, arguments have been presented that studies limited by poor qualitycould have led to statistically significant results by chance or bias. Moreover, data fo the last 10 years have notbeen systematically summarized. Methods and Results: To confirm any possible association, a meta-analysis wasperformed by a systematic search strategy. Totals of 7 case-control and 11 cohort studies was identified and pooledORs with 95% CIs were used as the principal outcome measures. Data from these studies were extracted witha standard meta-analysis procedure and grouped in relation to study design, cut-off point, exposure assessmentmethod, adjustment and exposure model. A statistical significant increased risk of male breast cancer with EMFexposure was defined (pooled ORs = 1.32, 95% CI = 1.14 -1.52, P < 0.001), and subgroup analyses also showedsimilar results. Conclusions: This meta-analysis suggests that EMF exposure may be associated with the increaserisk of male breast cancer despite the arguments raised.     

Treatment Outcomes in Male Breast Cancer: A Retrospective Analysis of 161 Patients

Aims

Male breast cancer is a rare disease with limited evidence-based guidelines for treatment. This study aimed to identify demographic, pathological and clinical factors associated with its prognosis.

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。     

Changes and Predictive and Prognostic Value of the Mitotic Index,Ki‐67, Cyclin D1, and Cyclo‐oxygenase‐2 in 710 Operable Breast Cancer Patients Treated with Neoadjuvant Chemotherapy

The current study expands upon previous work using a database of 710 patients treated with neoadjuvant chemotherapy. First, we studied phenotypic characteristics of tumors before and after chemotherapy using the following factors: the mitotic index of the Scarff–Bloom–Richardson grade, Ki‐67, cyclin D1, and cyclo‐oxygenase‐2. Second, the predictive value of these factors on response was assessed. Third, we measured the prognostic impact of these markers post‐therapy in comparison with clinical and pathological responses according to the Chevallier and Sataloff classifications. Patients were treated using different neoadjuvant chemotherapy combinations, mainly in successive prospective phase II trials. They received a median number of six cycles (range, 1–9). After neoadjuvant chemotherapy, patients underwent surgery and radiotherapy. In cases of important residual disease, some received additional courses of chemotherapy. In addition, menopausal patients with hormone receptor–positive tumors received tamoxifen for 5 years. According to our analysis, we found significant variations before and after neoadjuvant chemotherapy only for cyclin D1 and the mitotic index. Concerning the predictive value of biomarkers for response, Ki‐67 and the mitotic index were predictive on univariate analysis, both for objective clinical and pathological complete responses. Because these two factors were correlated, no multivariate analyses were conducted. We then assessed the prognostic impact of the biopathological factors. When the factors were measured before chemotherapy, all were prognostic. When evaluated after chemotherapy, the mitotic index, objective clinical response, and pathological complete response were prognostic. Because these factors were correlated, no multivariate model was done. The main clinical fact is that there were significant correlations between clinical and pathological responses and variations in the biological factors studied.     

Characteristics of Patients With Second Primary Lung Cancer Following Breast Cancer: A Retrospective Descriptive Study

BackgroundBreast cancer (BC) is the most common noncutaneous malignancy in women and survivors are at an increased risk for secondary malignancy with lung cancer (LC) being the most common. There are few studies that have explored the clinicopathological specifics of LC in BC survivors.MethodsIn this single-institution, retrospective study, we identified BC survivors who subsequently developed LC, examined their breast and LC clinical and pathological characteristics and compared them to the general BC and LC population as published in the literature.ResultsIn our study, we found the following associations that could be meaningful: an association between receiving radiation (RT) and LC (including a statistically significant P = .03 chance of ipsilateral LC after BC treatment with RT), a higher incidence and amount of smoking and LC, high BRCA positivity (78.9%) in the few patients who had germline testing, and a higher incidence of EGFR mutations in NSCLC after BC (60.9%) as well as an earlier stage of NSCLC disease.ConclusionTreatments such as RT, genetic factors such as BRCA mutations, and tobacco use may increase the risk of developing LC amongst BC survivors. Exploring this further can potentially lead to better risk stratification through modified low-dose CT chest screening protocols to catch LCs earlier and ultimately improve outcomes. Past studies have shown that BC survivors who are subsequently diagnosed with NSCLC may have improved OS compared with primary NSCLC and our study showed a high incidence of EGFR mutated NSCLC, which also suggest both improved prognosis and a different molecular profile of NSCLC, which warrants further investigation. Lastly, BC survivors who subsequently are diagnosed with NSCLC had earlier stage disease in our study, perhaps a result of surveillance, highlighting the importance of close monitoring of BC survivors.     

Taxane-Based Regimens as Adjuvant Treatment for Breast Cancer: a Retrospective Study in Egyptian Cancer Patients

Background: To evaluate the impact of adding taxanes to anthracycline-based regimens in the adjuvant settingin localized young female breast cancer patients on the overall survival (OS) and the disease free survival (DFS).Materials and Methods: This retrospective study included all female breast cancer patients who were candidatesfor adjuvant chemotherapy presenting to Kasr Al Ainy centre of clinical oncology and Cairo oncology centre(Cairo Cure) in the period from January 2005 till December 2010. Results: Our study included 865 patients, 732of whom received anthracycline based regimens and 133 taxane based regimens. The mean age of patients was39 years. After a median follow up of 50 months the median DFS was 48.4 months. Survival analysis indicatedthat the tumor size (>5cm vs. <5cm) p=0.001), nodal involvement (Yes vs. No) p=0.0001) and pathology (invasivelobular vs. ductal) p=0.048) affected DFS. As regards hormonal status, ER, PR and HER 2neu positive patientshad longer DFS (p=0.001, 0.003, 0.106). On multivariate analysis DFS was affected by tumor size and lymph nodeinvolvement (p=0.014, 0.007). Subgroup analysis showed improvement in arms treated with taxanes in terms ofDFS with positive Her2neu, ER and PR, but this was not statistically significant. Conclusions: Adding adjuvanttaxanes to anthracyclines is beneficial for treatment of localized breast cancer among all subgroups, especiallyhigher risk groups .The type of adjuvant chemotherapy regimens and tumor characteristics have direct effectson DFS.     

Localized Therapy for Male Breast Cancer: Functional Advantages With Comparable Outcomes Using Breast Conservation

BackgroundMale breast cancer (MBC) accounts for approximately 1% of all breast cancers. Given the rarity of this disease, treatment of MBC generally follows the same principles as treatment of female breast cancer. However, the traditional surgical approach for MBC is modified radical mastectomy (MRM) or total simple mastectomy (TSM) instead of breast conservation surgery (BCS). The purpose of this study was to examine the feasibility of BCS as an alternative to mastectomy for MBC with respect to musculoskeletal functionality and treatment outcome.Patients and MethodsA retrospective analysis was undertaken of all male patients with breast cancer who presented to Massachusetts General Hospital or Boston Medical Center for localized therapy from 1990 to 2003. Musculoskeletal functionality (tissue fibrosis, arm edema, and range of motion) and treatment outcome (local-regional control, disease-free survival, and overall survival) were evaluated. Functional/cosmetic outcomes were assessed by multidisciplinary review of patient follow-up visits and were scored as either “good-excellent” or “fair-poor” to account for subjectivity between different clinicians.ResultsForty-two patients in total were identified to undergo localized treatment. Thirty patients (71%) received MRM, 4 (10%) had TSM, and 8 (19%) underwent BCS. Actuarial overall 1-year fair-poor documented tissue fibrosis, arm edema, and decreased range of motion rates were 13%, 23%, and 27% for patients receiving MRM; 25%, 0%, and 50% for patients who underwent TSM; and 13%, 0%, and 0% for those undergoing BCS, respectively. Overall survival and disease-free survival were not statistically different between the groups.ConclusionsThese data suggest that breast conservation therapy may be considered a reasonable local treatment option for male patients presenting with breast cancer because it may offer functional advantages over mastectomy with comparable rates of local control and disease-free survival and overall survival.     

乳腺癌HER2基因扩增的临床病理意义

目的 检测乳腺癌组织中HER2基因扩增状态,评价其临床病理意义。方法 应用FISH、IHC方法分析55例乳腺癌HER2基因扩增/蛋白表达状态与临床病理特征的关系,比对IHC法与FISH检测的一致性程度。结果 55例乳腺癌FISH检测有32例（58.2%）HER2基因扩增。IHC法HER2（+++）22例中21例（95.5%）HER2基因扩增;HER2（++）12例中10例（83.3%）HER2基因扩增;HER2（+/－）21例中1例（4.7%）HER2基因扩增。39例浸润性导管癌中30例（76.9%）有HER2基因扩增,12例浸润性小叶癌中仅1例（8.3%）HER2基因扩增。HER2基因扩增在浸润性导管癌的组织学分级间差异有统计学意义（P<0.001）,组织学Ⅲ级的浸润性导管癌较Ⅰ、Ⅱ级有较高的HER2基因扩增率。HER2基因扩增与ER、PR阴性状态及腋淋巴结转移有显著相关性（P<0.01）,与患者是否绝经无相关性（P>0.05）。结论 浸润性小叶癌,ER、PR阳性以及组织学Ⅰ级的浸润性导管癌常少有HER2基因扩增;对于组织学Ⅲ的浸润性导管癌,同时ER、PR阴性者尽管IHC检测结果为阴性,仍需做FISH检测以明确是否有HER2基因扩增。     

男性乳癌特征分析(附31例报告)

目的：了解男性乳癌特点，提高其早期诊断率及治疗效果。方法：对31例男性乳癌进行了回顾性分析。结合随访资料，应用Kaplan-Meier法进行生存分析。结果：男性乳癌少见，病因不清，发病多在50岁以上，临床病例晚期多见，容易侵犯皮肤及胸肌，乳头常受累，可伴乳头溢血，淋巴结转移较早，雌激素受体阳性率高，治疗以手术为主，主要是改良根治术，包括化疗，内分泌治疗和放疗的综合治疗，预后与腋淋巴结转移状况有关。结论：男性乳癌晚期多见，治疗以综合治疗为主。预后与腋淋巴结转移状况相关。