Personalized Medicine in Breast Cancer: A Systematic Review

The recent advent of "-omics" technologies have heralded a new era of personalized medicine. Personalized medicine is referred to as the ability to segment heterogeneous subsets of patients whose response to a therapeutic intervention within each subset is homogeneous. This new paradigm in healthcare is beginning to affect both research and clinical practice. The key to success in personalized medicine is to uncover molecular biomarkers that drive individual variability in clinical outcomes or drug responses. In this review, we begin with an overview of personalized medicine in breast cancer and illustrate the most encountered statistical approaches in the recent literature tailored for uncovering gene signatures.     

A Review of Breast Density Implications and Breast Cancer Screening

Breast density is an independent risk factor for breast cancer and significantly decreases the sensitivity of mammography. Assessing a woman’s risk of developing breast cancer is becoming increasingly important for establishing individual screening recommendations and preventive strategies. This article reviews the factors influencing mammographic density (MD), the available methods of MD assessment, and its effect on breast cancer. Finally, we discuss the supplemental screening methods for women with dense breast tissue.     

VSIG4在乳腺癌中的表达及其与免疫浸润和预后的相关性

目的 分析M2型巨噬细胞在乳腺癌组织中的浸润丰度,探索VSIG4与M2型巨噬细胞的相关性及调控乳腺癌侵袭和迁移的潜在机制.方法 下载TCGA-BRCA的RNA-seq数据,CIBERSORT评估样本的免疫细胞浸润丰度,构建预后风险预测模型.分析M2型巨噬细胞及VSIG4对乳腺癌患者预后的影响,基因集富集分析VSIG4参...     

Histopathological predictors of axillary lymph node metastases in patients with Breast Cancer

Background  A tumor 30 mm or less in diameter is a standard candidate for breast conserving surgery (BCS) in Japan. Axillary lymph node metastases (ALNM) is the most important prognostic factor for survival in patients with breast cancer, but the role of axillary node dissection has been controversial. Histopathological predictive factors of axillary lymph node involvement have not been established. The purpose of this study was to determine the association between the incidence of ALNM and histopathological factors by univariate and multivariate analysis. Methods  Sixty-five patients with noninvasive ductal carcinoma, and 993 patients with tumors 30 mm or less in diameter who underwent axillary dissection between 1988 and 1997 at our institute were reviewed. The association between ALNM and 13 histopathological factors (size, age, histological subtype, histological invasiveness, lymphatic invasion, vascular invasion, macroscopic classification, histological daughter mass, ductal spread, ER, PgR, p-53, and c-erbB-2) were analyzed by univariate and, when significant, by multivariate analysis. Results  Only one patient with noninvasive ductal carcinoma had ALNM, and 33.1% of 993 patients with a tumor 30 mm or less in size had ALNM. Multivariate analysis identified six factors as independent predictors for ALNM: lymphatic invasion, size, histological invasiveness, macroscopic classification, age and histological daughter mass. Conclusions  Axillary lymph node dissection can be omitted in patients with noninvasive ductal carcinoma. Histopathological features of tumors 30 mm or less in diameter can be used to estimate the risk of ALNM, and routine axillary node dissection might be spared in selected patients at minimal risk of ALNM, if the treatment decision is not influenced by lymph node status, such as in elderly patients.     

Research Progress in Applying Proteomics Technology to Explore Early Diagnosis Biomarkers of Breast Cancer,Lung Cancer and Ovarian Cancer

According to the China tumor registry 2013 annual report , breast cancer, lung cancer, and ovarian cancer arethree common cancers in China nowadays, with high mortality due to the absence of early diagnosis technology.However, proteomics has been widespreadly implanted into every field of life science and medicine as an importantpart of post-genomics era research. The development of theory and technology in proteomics has provided newideas and research fields for cancer research. Proteomics can be used not only for elucidating the mechanismsof carcinogenesis focussing on whole proteins of the tissue or cell, but also seeking the biomarkers for diagnosisand therapy of cancer. In this review, we introduce proteomics principles, covering current technology used inexploring early diagnosis biomarkers of breast cancer, lung cancer and ovarian cancer     

乳腺癌中雌激素受体与靶基因的结合预测内分泌治疗的敏感性观察

目的为提高乳腺癌患者内分泌治疗的敏感性,建立雌激素受体与靶基因结合活性的测定。方法使用凝胶阻滞方法,用γ-32P-ATP标记雌激素效应元件(ERE)作为探针检测89例乳腺癌组织中ER与靶基因DNA的结合活性。结果89例乳腺癌患者中50例ER(+)者中35例ERE(+),占70%;ER(+)、PR(+)的22例中18例ERE(+);而ER(-)患者中有7例为ERE(+)占ER(-)患者的18%。结论依照ERE的测定结果,结合ER,PR状态对临床乳腺癌的预后和抗激素治疗作出预测,并分为二大类Ⅰ类为ER(+)、ERE(+)、PR(+),这组患者预后较好,可优先考虑抗激素治疗Ⅱ类为ER(-)、ERE(-)、PR(-),抗激素治疗无效;ER(+)、PR(-)组依据ERE(+)归于Ⅰ类,ERE(-)归于Ⅱ类;对于ER(-)、PR(+)组ERE(+)为Ⅰ类,ERE(-)为Ⅱ类。经过这样的分类可增加科学性,减少临床用药的盲目性。     

几种乳腺癌标志物联检的临床价值

７８例乳腺癌患者血清癌胚抗原（ＣＥＡ），铁蛋白和人绒毛膜促性腺激素（ＨＣＧ）作为肿瘤标志物用酶免疫吸附法（ＥＬＩＳＡ）检测。ＣＥＡ高于５ｎｇ／ｍｌ，铁蛋白高于８０ｎｇ／ｍｌ和ＨＣＧ高于５０ｍＩＵ／ｍｌ分别见于４５％，６２％和１８％的病人。聚丙烯酰胺凝胶电泳法分析血清乳酸脱氢酶（ＬＤＨ）同工酶，ＬＤＨ４和ＬＤＨ５在５８％患者明显升高。四项指标同时检测，乳腺癌的诊断符合率达９３％（７３／７８）。经治疗     

Diet, Serum Markers and Breast Cancer Mortality in China

This county-based correlation study examined associations of breast cancer mortality with dietary habits and certain serum biochemical markers, utilizing data collected from an ecological survey in 65 Chinese rural counties. Univariate correlation and multivariate regression analysis showed that consumption of animal foods, including eggs, fish and meat, was positively linked to county-wide mortality rates of breast cancer in Chinese women. No clear associations between breast cancer mortality rates and consumption of green vegetables, carrots and fruits were observed in this study. A modest inverse correlation between serum vitamin C levels and breast cancer mortality was observed, while selenium levels were positively related to the mortality rates. Positive correlations for serum ferritin and hemoglobin were found, in agreement with recent reports of an elevated cancer risk with increased body iron stores. Limitations of these ecological data preclude causal inferences, but the findings provide clues to breast cancer risk and protective factors in a low incidence area of the world.     

2001—2010年乳腺癌预后基因临床研究文献的计量学分析

目的多角度评价近10年来国内外乳腺癌预后基因临床研究概况,为进一步研究提供参考。方法以Embase、Pubmed及Biosis Preview为文献检索数据库(2001年1月—2010年12月),对纳入的876篇文献分别对其出版年、国家、期刊、研究机构、作者及所研究基因进行计量学分析。结果近10年来该领域发文量逐渐增多,且2005年后增长幅度明显增大;发文量最多的国家、期刊、机构及作者分别为美国、《Breast Cancer Research and Treatment》、Netherlands Cancer Institute、Bieche I;研究内容以非多基因模型研究为主,其中又以研究ErbB-2基因最多（157篇）,多基因模型研究逐年增多,其中以MammaPrint及Oncotype DX两模型为主。结论乳腺癌预后基因临床研究日益受世界的关注,寻找其敏感和特异的基因及多基因模型为未来的重要研究方向。     

Clinicopathologic Implications of EpCAM and Sox2 Expression in Breast Cancer

BackgroundThe purpose of this study was to investigate the clinicopathologic significance of EpCAM and Sox2 expression in breast cancer and to study their correlation during breast cancer progression.Patients and MethodsEpCAm and Sox2 expression were assessed using immunohistochemistry in ductal carcinoma insitu (DCIS), invasive breast cancer (IBC) and matched lymph node metastasis (LNM), if present.ResultsEpCAM overexpression was found in 63.2% of DCIS, 72.2% of IBC and 74.4% of LNM. In IBC cases, EpCAM overexpression was associated with high grade (P < .001), large tumor size (P = .051), poor Nottingham Prognostic Index (NPI) (P = .006), histological tumor types (P = .044) and the triple negative phenotype (P = .008). LNM frequently reflected the expression phenotype of the matched primary tumors with no significant differences between LNM and their primary tumors (P = .564). Sox2 expression was detected in 47.4%, 33.3% and 54.7% of DCIS, IBC and LNM respectively. In DCIS group, Sox2 expression was significantly associated with comedo type (P = .037), negative ER (P = .012) and PR (P = .037) and the triple negative phenotype (P = .006). In IBC cases, Sox2 expression showed significant associations with high grade (P = .045), nodal spread (P = .037), poor NPI (P = .018) and the triple negative phenotype (P < .001). LNM showed significantly higher Sox2 expression rates than primary tumors (P < .001). Significant positive associations between EpCAM overexpression and Sox2 positivity in DCIS (P = .027), IBC (P = .001) and LNM (P < .001) were found.ConclusionThis study emphasized the potential role of EpCAM and Sox2 in breast carcinogenesis and revealed their involvement during breast cancer progression and LN metastases.     

乳腺癌恶性胸腔积液的临床特征及预后因素分析

目的研究有症状乳腺癌恶性胸腔积液患者的临床特征及影响疗效的相关因素。方法回顾性总结分析了2008年11月至2010年12月我科收治的36例有症状胸腔积液乳腺癌患者的一般临床资料[年龄、东部肿瘤协作组(ECOG)、手术病理分期、手术后无病生存期(DFS)、胸腔积液是否为初次复发部位、是否复发后一线化疗、是否伴有其他积液、是否双侧胸腔积液],胸腔积液的情况[是否血性胸腔积液、胸水细胞数、胸水单核细胞数、乳酸脱氢酶(LDH)、癌胚抗原(CEA)、CA153、CA125、蛋白、胸水量]及胸腔积液的治疗情况(胸腔局部治疗方式、胸腔局部化疗药物、是否使用IL-2)中各种因素对于胸腔积液疗效及控制时间的影响。结果患者手术至出现胸腔积液的中位时间44月(0～180月)。手术至出现胸腔积液的时间>44月有效率显著高于手术后DFS≤44月者(P=0.046),分别为66.7%,33.3%;复发后一线化疗者有效率显著高于复发后二线及以上化疗者(P=0.044),分别为65.0%和31.3%;胸水单核细胞数>1×106/L的患者有效率显著高于胸水单核细胞数≤1×106/L(P=0.046)的患者,分别为66.7%,33.3%。胸腔积液中位控制时间为4月,胸腔积液LDH≤400 u/ml较LDH>400 u/ml的患者的胸腔积液控制时间显著延长(P=0.032),胸腔积液中位控制时间分别为6月和2月。结论胸腔积液是乳腺癌患者常见的临床表现,术后DFS时间长、复发后一线化疗及胸水单核细胞高者有效率高,胸腔积液LDH浓度高是胸水控制时间短的不良预后因素。     

Clinicopathologic Characteristics and Prognosis of Breast Cancer Patients Associated with Pregnancy and Lactation: Analysis of Case-Control Study in Japan

Clinicopathologic characteristics and prognosis of breast cancer patients associated with pregnancy and lactation were clarified by means of a case-control study of matched non-pregnant and non-lactating patients with breast cancer. From 18 institutions in Japan, a total of 192 subjects with breast cancer diagnosed during pregnancy (72 cases) and lactation (120 cases) were collected between 1970 and 1988, accounting for 0.76% of all breast cancer patients. The duration of symptoms was longer and tumor size was larger in the study subjects. Although the disease-free interval was longer than that in the control patients, the survival time was shorter. There was no characteristic difference in histologic type. Vascular invasion and lymph node metastasis were found more frequently in the subjects. The positive rates of estrogen receptor and progesterone receptor were lower in the subjects. The 5- and 10-year survival rates of the study patients were 65% and 55%, respectively, and these survivals were significantly lower than those of the control ( P < 0.001). The survival rates were poorer in the subjects, in accordance with stage and lymph node metastasis. The results suggest that most of the patients with breast cancer diagnosed during pregnancy and lactation are in a more advanced stage because of a delay in detection and diagnosis, and hence have unfavorable prognosis. Therefore, it is important to diagnose and treat early for improvement of prognosis in patients with breast cancer during pregnancy and lactation.     

Research on Clinical Effectiveness of Aspirin for Treating Breast Cancer and Cell Protein Biomarkers on Aspirin Treatment in Drug-Resistant Estrogen Receptor-Positive Breast Cancer Cells

Background: Aspirin (ASA) has been reported to have an antitumor effect but the role of ASA in the prevention and treatment of breast cancer (BC) is still controversial. This study aimed to identify clinical effectiveness of ASA in the treatment of BC and explore the antitumor target proteins of ASA that may be involved in overcoming tamoxifen resistance in estrogen receptor (ER)-positive BC cells. Materials and Methods: Randomized controlled trials (RCTs) of ASA in the treatment of BC were queried from the databases, including PubMed, Web of Science, Cochrane Library, WanFang, and Chinese National Knowledge Infrastructure. According to the quality standard recommended in the Newcastle-Ottawa Scale (NOS), the outcome indexes were analyzed by RevMan 5.3 and Stata 12.0 software. Cell culture experiments were performed to explore the effect of tamoxifen combined with ASA on the proliferation of ER-positive BC cell lines MCF-7 and MCF-7/TAM. Cell cytotoxicity was determined by the 3-(4, 5-di-2-yl)-2, 5-ditetrazolium bromide (MTT) assay. A quantitative proteomic analysis was conducted between the control and experimental groups to identify differentially expressed proteins (DEPs). Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were used for bioinformatic analysis of DEPs. The protein expression in patients of ER-positive BC was analyzed by immunochemistry (IHC). Results: Nine RCTs including 162,381 patients were selected for this study. The meta-analysis revealed that daily ASA use, as compared with its non-use, was associated with a decreased risk of BC death: relative risk (RR) = 0.83%, 95% CI [0.73, 0.94], Z = 2.89, P = 0.004 (P < 0.05). Cell culture experiments showed that tamoxifen combined with ASA can drastically inhibit the cell growth of MCF-7 and MCF-7/TAM cells more than the administration of tamoxifen alone (P < 0.05). Fifty-seven DEPs were up-regulated, while eighty-five DEPs were down-regulated in MCF-7/TAM cells after the ASA combination treatment. Several GO terms were significantly enriched, such as neutrophil degranulation, retinal metabolic process, sterol biosynthetic process, and prostaglandin metabolic process. KEGG pathway enrichment analysis also verified three associated pathways including metabolic pathways, chemical carcinogenesis-reactive oxygen species, and biosynthesis of amino acids. In ER-positive BC patients with Ki67 > 20%, the positive expression of one significantly DEP MYC was much higher than in BC patients with Ki67 ≤ 20% (40.91% vs. 12.50%, P < 0.05). There was no significant difference in MYC protein expression among the other subgroups (P > 0.05). Conclusions: Our results show that ASA has a clinical value in the treatment of BC. ASA could overcome tamoxifen resistance in ER-positive BC cells through some key proteins, which may be potential therapeutic targets for patients with tamoxifen resistance.     

妊娠期及哺乳期乳腺癌的治疗和预后因素分析

分析了７０例妊娠期及哺乳期乳腺癌的治疗和预后因素,其中妊娠期乳腺癌３２例,哺乳期乳腺癌３８例;Ⅰ期１１例,Ⅱ期４３例,Ⅲ期１６例。总的５ａ生存率为５５．７％,根治术与改良根治术患者５ａ生存率分别为６８．４％和６２．５％,非根治术患者５ａ生存率为４５．７％（Ｐ＜０．０５）。妊娠期及哺乳期乳腺癌与普通乳腺癌相比病期较晚,预后较差,相同病期和年龄患者的预后相同。治疗性终止妊娠和治疗后再次妊娠不影响预后（Ｐ＞０．０５）。结果表明,妊娠期及哺乳期乳腺癌的治疗和预后与同龄普通乳腺癌患者相同,首选治疗为改良根治术并根据患者不同情况辅以放射治疗、化疗或内分泌治疗,妊娠因素不能改变生存率     

Predictive factors for response to endocrine therapy in patients with recurrent Breast Cancer

Predictive markers and variables for response to anticancer therapy provide cancer patients with refinement of therapeutic options and a decreased likelihood of receiving an ineffective therapy. The best-established predictive marker for response to endocrine therapy for breast cancer is the status of estrogen receptors (ER) in the primary breast tumor. However, although patients with ER-positive tumors have a greater than 50% objective response rate to endocrine therapy, other patients can not obtain an objective response. Therefore additional markers, such as better molecular biologic markers, are needed. Our previous study using multivariate analysis revealed that the ER status of primary tumors and the dominant site of metastasis are independent predictors for response to first-line endocrine therapy and that a response to first-line endocrine therapy is only an independent predictor for response to second-line endocrine therapy. However, all these factors are already well-established predictive markers for response to endocrine therapy. Recently, a number of new hormonal agents, such as more selective aromatase inhibitors and specific antiestrogens, have been developed and introduced. However, several questions, such as the best sequences when using hormonal agents, remain to be elucidated. On the other hand, several molecular biologic markers predicting response to endocrine therapy, such as the expression of the HER family of tyrosine kinase receptors, pS2, Bcl-2, and vascular endothelial growth factor, have been reported. To elucidate the most effective use of endocrine therapy for recurrent breast cancer, classical and new predictive factors for response to endocrine therapy are reviewed, and the clinical implications of these factors are discussed.     

Functional Disability in Women Submitted to Breast Cancer Treatment

The objective of the study presented herein was to verify the prevalence of functional disability and its associated factors in women submitted to breast cancer treatment. A cross-sectional study was carried out, in 101 women diagnosed with malignant breast cancer neoplasm, who underwent cancer treatment at least 12 months before the study, and remained under clinical monitoring. Functional disability was measured by the DASH instrument. Data collection included variables related to socioeconomic characteristics, life habits, health conditions, clinical tumor characteristics and therapeutic approach. Bivariate analysis was carried out by Pearson’s chi-square test or Fisher’s exact test, calculating the prevalence ratio with a 95% confidence interval. Multivariate analysis utilized Poisson’s Regression with robust variance. A statistical significance of 0.05 was considered. Prevalence of functional disability in the studied sample was 22.8% (CI95% 13.9-31.6). Functional disability was statistically significantly associated with age (p = 0.035) and access to health services (p = 0.028). It was concluded that younger patients suffered higher impact of breast cancer treatment on disability. Regarding access to health services, women that received public clinical monitoring reported higher occurrences of functional disability. This pointed towards the necessity of more organized, less bureaucratic, and effective health services in the assistance network, directed to the minimization of the impacts of cancer treatment on health and life conditions of breast cancer survivors.     

乳腺癌保留乳房治疗10a疗效分析

目的:研究评价保乳治疗的效果,分析1985年—1995年111例在该院行保乳治疗患者的远期疗效。方法:111例临床Ⅰ期、Ⅱ期患者行保乳手术,术后行全乳放疗,局部缩野照射。用SAS软件分析患者年龄,肿瘤大小,组织学类型,切缘,淋巴结转移,术后放疗与复发的关系,分析切除组织量与复发率和美容效果的关系。结果:中位随访10 a,10 a复发率10 % ,转移率27 %,生存率81 %。年龄、组织学类型、淋巴结转移与复发无显著性关系(P >0.05)。肿瘤大小,切缘情况与复发有关(P <0.01)。术后未行放疗的复发率高,达75 %。60Co放疗复发率高于加速器(11 % vs 5 %)。单纯局部复发与转移无明显相关性(P >0.05)。行象限切除复发率不低于肿瘤扩大切除(P >0.05),但明显影响美容效果。结论:保乳治疗适合不同年龄、不同组织学类型的早期乳腺癌,在保证切缘阴性的前提下,扩大切除范围不提高疗效反而会影响美容效果。放疗技术的提高有助于减少复发。