云南省乳腺癌分子分型与临床病理特点分析

目的：了解云南省乳腺癌患者的分子分型与临床病理特点.方法：收集2012年1月-2012年12月云南省肿瘤医院乳腺病科所收治的经根治性手术后病理确诊为原发性乳腺癌的初诊患者587例,统计分析分子分型与患者年龄、民族、病理类型、病灶大小、淋巴结分期、病理分期、p53等的相关性.结果：不同民族、病灶大小、淋巴结分期、p53表达与分子分型之间差异无统计学意义.不同年龄段与分子分型之间差异有统计学意义,P=0.033.不同病理类型与分子分型之间差异有统计学意义,P=0.022.不同病理分期与分子分型之间差异有统计学意义,P=0.004.结论：云南省乳腺癌不同年龄段、不同病理分期的分子分型存在差异.     

An experimental approach to the breast cancer, reserpine problem

Reserpine was administered intraperitoneally 3 times weekly to inbred female Syrian BIO hamsters of the 15.16 strain previously shown to be susceptible to methylcholanthrene (MC) induction of mammary cancer. Other groups of hamsters received non-carcinogenic doses of MC along with the reserpine administrations, and an additional group received a carcinogenic dose of MC alone. This last group demonstrated that BIO 15.6 females were indeed susceptible to MC mammary cancer induction, since 4 mg of MC administered by stomach tube (a total dose of 200 mg) caused mammary cancer in 52% of the animals. Mammary cancer was not observed in any of the animals given reserpine or reserpine in combination with the non-carcinogenic dose of MC.     

乳腺癌的分子分型与临床病理特征的关系

目的探讨乳腺癌组织ER、PR、HER2、CK5、CK14的表达及分子分型与临床病理特征的关系。方法采用ER、PR、HER2、CK5、CK14单克隆抗体对370例原发性乳腺癌组织进行免疫组化染色,根据上述指标的表达情况进行分子分型,结合临床病理特征进行比较统计。结果发现不同分子分型在肿瘤大小及组织学分级方面有显著差异。结论对乳腺癌进行分子分型,有利于判断患者的临床预后和指导临床治疗方案的制定。     

乳腺癌不同分子亚型的临床特点和生存分析

目的探讨乳腺癌各分子亚型的临床特点及其预后情况。方法回顾性分析482例可手术乳腺癌患者资料．以免疫组织化学技术为基础,把乳腺癌分为4种分子亚型：luminalA型[ER（＋）或PR（＋）且HER-2（-）],luminalB型[ER（＋）或pR（＋）且HER-2（＋）],HER-2过表达型[ER（-）、PR（-）且HER-2（＋）j和basal—like型[ER（-）、PR（-）且HER-2（-）],并分析其临床特点及预后情况。结果全组共482例,其中luminalA型占46．1％（222／482）,luminalB型占14．7％（71／482）,HER-2过表达型占10．4％（50／482）,basal—like型占28．8％（139／482）。运用x。检验各分子亚型在年龄、月经状况、肿瘤大小、淋巴结状况和临床分期等的差异均无统计学意义。全组有完整随访资料者共441例,中位随访时间62个月。随访结果显示．HER-2过表达型和basal—like型的远处转移率均高于luminalA型,且差异有统计学意义（x2=11．659,P=0．009）;运用Kaplan—Meier法分析各分子亚型的生存预后,luminalA型的无病生存率、无远处转移生存率和总生存率最高,HER-2过表达型和basal-like型的预后最差,差异有统计学意义（Log—Rank检验,P均〈0．050）。结论乳腺癌分子分型对患者预后的判断具有重要临床意义,有望成为今后制定乳腺癌个体化治疗的重要依据。     

Individualization of breast cancer based on histopathological features and molecular alterations

Histopathological findings and molecular alterations well reflect the biological properties of individual primary breast carcinomas. Specifically, pT (size of the invasive component), pN (number of metastatic lymph nodes), histological or nuclear grade, lymphovascular invasion, hormone receptors, and HER2 (c-erbB-2) gene overexpresison or amplification are known to be effective markers for assessing the risk of operable primary breast carcinoma, albeit incompletely. It is expected that additional molecular markers and novel diagnostic tools will be developed in the future to facilitate a more accurate characterization of higher risk node-negative breast carcinomas. This article is based on a presentation delivered at Presidential Symposium 1, “Breast cancer: individualized diagnosis for tailored treatment,” held on 29 June 2007 at the 15th Annual Meeting of the Japanese Breast Cancer Society in Yokohama.     

不同分子亚型乳腺癌的临床病理特征及预后分析

目的 探讨乳腺癌各分子亚型的临床特点及其预后情况.方法 分析1153例可手术乳腺癌患者的临床病理资料,根据雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体2(Her-2)的表达情况将乳腺癌分为4种分子亚型,即Luminal A型、Luminal B型、Her-2过表达型和Basal-like型.分析各分子亚型乳腺癌患者在年龄、肿瘤大小、淋巴结转移状况、临床分期和预后的差异及影响预后的因素.结果 1153例患者中,Luminal A型791例(68.6%),Luminal B型50例(4.3%),Her-2过表达型53例(4.6%),Basal-like型259例(22.5%).各分子亚型在年龄、肿瘤大小、淋巴结转移状况、临床分期的差异均无统计学意义(均P>0.05).有完整随访资料的1006例患者中,Her-2过表达型的远处转移率(17.0%)显著高于其他亚型(P=0.005),而各分子亚型间的局部复发率差异无统计学意义(P>0.05).Kaplan-Meier法分析结果显示,Her-2过表达型患者的7年无病生存率和9年总生存率最低(均P<0.05).单因素和多因素分析结果均显示,淋巴结转移状况和分子分型是影响乳腺癌患者无病生存及总生存的独立预后因素.结论 Her-2过表达型乳腺癌患者的预后最差.乳腺癌的分子分型对判断患者预后可能具有重要临床意义,有望成为今后制订乳腺癌个体化治疗方案的重要依据.

Abstract：

Objective To investigate the clinical characteristics and prognosis of different breast cancer molecular subtypes.Methods Clinicopathological and follow-up data of 1153 cases of operable breast cancer were analyzed retrospectively.Their molecular subtypes were categorized as luminal A, luminal B, Her-2 over-expressing and basal-like subtypes, based on detection of ER, PR, Her-2 expression.The correlation of prognosis of different molecular subtypes with age, tumor size, lymph node status and clinical staging was analyzed.Results Among the 1153 cases, 791 cases (68.6%) were of luminal A subtype, 50 cases (4.3%) luminal B subtype, 53 cases (4.6%) Her-2( + )subtype, and 259 cases (22.5%) basallike subtype.There were no statistically significant differences among different molecular subtypes regarding the age, tumor size, lymph node status, and clinical stage.1006 cases had complete follow-up data and the analysis showed that distant metastasis of Her-2 over-expressing subtype was significantly higher than that in other subtypes ( P = 0.005 ), but the differelices of local recurrence rate in different molecular subtypes was not statistically significant (P >0.05).Kaplan-Meier method was used to analyze the survival prognosis of different molecular subtypes, showing both DFS rate and OS rate of Her-2 over-expressing subtype were the lowest, with a statistically significant difference (Log rank test, P < 0.05 ).Univariate and multivariate analyses showed that molecular typing and lymph node status were independent prognostic factors affecting both DFS and OS.Conclusions Her-2 over-expressing subtype has the worst prognosis.Molecular subtypes may provide important information to predict the prognosis of breast cancer and might be an important basis for individualized treatment of breast cancer in future.     

An alternative approach for treatment of breast cancer

Summary Since adjuvant chemotherapy and hormonal therapy generally extend disease free survival in breast cancer rather than provide a cure, we have examined the current breast cancer paradigm. Heterogeneity is a fundamental characteristic of breast cancer tissue and a well recognized aspect of the disease. There are variations in natural history, histopathology, biochemistry and endocrinology, and molecular biology of cancer tissues and cells within the tissues. A variety of data indicate that growth kinetics are also variable, not only from tumor to tumor, but also during the natural history of an individual's tumor. To better understand kinetic heterogeneity, a stochastic numeric computer model of the natural history of breast cancer has been developed. To be consistent with inter- and intratumor kinetic heterogeneity and with late relapse, the model predicts that tumors grow in an irregular fashion with alternating periods of growth and periods of dormancy rather than the generally accepted modified exponential, or Gompertzian fashion. The prediction of irregular growth has been compared to data relevant to growth characteristics of human breast cancer. Much data support the concept of irregular kinetics and temporary dormancy rather than steady, Gompertzian growth of human breast cancer. Thus, in addition to drug resistance, kinetic heterogeneity may help explain the limited impact that traditional chemotherapeutic treatment has had on mortality from breast cancer. Although the mechanisms underlying irregular growth need to be better understood, non-Gompertzian growth kinetics indicates that there may be alternative approaches for breast cancer treatment.     

Tissue microarrays for comparing molecular features with proliferation activity in breast cancer

Tissue microarrays (TMAs) are potentially suited to find associations between molecular features and clinical outcome. Enhanced cell proliferation, as measured by Ki67 immunohistochemistry, is related to poor patient prognosis in many different tumor types. Ki67 expression shows considerable intratumoral heterogeneity. It is unclear if the TMA format is suitable for the analysis of potentially heterogeneous markers because of the small size of TMA spots. We have analyzed a breast cancer TMA containing 2,517 breast tissues, including 2,222 neoplastic and 295 normal or premalignant samples, for Ki67 labeling index (Ki67 LI) and additional markers with a known relationship to Ki67 LI by immunohistochemistry (ER, PR, Bcl-2, Egfr, p16, p53) and Fluorescence in situ hybridization (HER2, MDM2, CCND1, MYC). A high Ki67 LI was linked to tumor phenotype including grade (p < 0.0001), stage (p < 0.0001), nodal stage (p = 0.0018), and patient prognosis (p < 0.0001), elevated protein levels of p53, p16 and Egfr, reduced levels of Bcl2, ER, and PR (p < 0.0001 each), as well as amplifications of HER2, MYC, CCND1 and MDM2 (p < 0.0001 each). In summary, all expected associations between Ki67 and the analyzed molecular markers could be reproduced with high statistical significance using a TMA containing only one tissue sample per tumor, measuring 0.6 mm in diameter. We conclude that associations with cell proliferation can be reliably analyzed in a TMA format.     

浸润性乳腺癌X线影像学表现与其分子分型的相关性研究

  目的  探讨浸润性乳腺癌X线影像学表现与其分子分型的相关性。  方法  收集2016年1月至2016年3月182例天津医科大学总医院及天津医科大学肿瘤医院的女性乳腺癌患者临床病理资料, 均经手术后病理证实为浸润性乳腺癌, 且术前行乳腺X线影像检查。采用BI-RADS分类标准对图像进行析, 依据2013年St.Gallen会议专家共识对浸润性乳腺癌进行乳腺癌分子分型, 分析乳腺X线影像表现与浸润性乳腺癌分子分型的相关性。  结果  乳腺癌分子分型与乳腺X线影像钙化表现具有相关性(V=0.221, P < 0.05), 其中三阴性乳腺癌(18/20)相较于Luminal A型(12/20)、Luminal B型(80/132)及HER-2过表达型(4/10)多表现为非钙化型病变(P < 0.05)。相较于非Luminal型乳腺癌(1/16), Luminal型乳腺癌(30/85)的肿块型病变多表现为边缘毛刺(P < 0.05)。  结论  浸润性乳腺癌的X线影像表现与其分子分型具有一定的相关性。      

A global approach to inflammatory breast cancer

Inflammatory breast cancer (IBC) is the most aggressive and deadly form of breast cancer. In spite of the comprehensive multidisciplinary approach to the management of this disease, the prognosis remains dismal. Moreover, there have been no major advancements in understanding the etiology and biology of IBC and no significant improvements in the diagnosis of the disease. The International Inflammatory Breast Cancer Conference was established in 2008 with the intention of creating a forum for the discussion, collaboration and development of proposals and working hypotheses. Furthermore, the conference represented an opportunity to raise awareness regarding IBC. The second international conference reported on several new exciting projects based on work from investigators and research teams devoted to making a difference in the fight against this disease.     

Traditional breast cancer risk factors in relation to molecular subtypes of breast cancer

At least four major categories of invasive breast cancer have been reproducibly identified by gene expression profiling: luminal A, luminal B, HER2-type, and basal-like. These subtypes have been shown to differ in their outcome and response to treatment. Whether this heterogeneity reflects the evolution of these subtypes through distinct etiologic pathways has not been clearly defined. We evaluated the association between traditional breast cancer risk factors and risk of previously defined molecular subtypes of breast cancer in the Nurses’ Health Study. This analysis included 2,022 invasive breast cancer cases for whom we were able to obtain archived breast cancer tissue specimens. Tissue microarrays (TMAs) were constructed, and slides were immunostained for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), cytokeratin 5/6 (CK5/6), and epidermal growth factor receptor (EGFR). Using immunostain results in combination with histologic grade, cases were grouped into molecularly defined subtypes. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). We observed differences in the association between risk factors and subtypes of breast cancer. In general, many reproductive factors were most strongly associated with the luminal A subtype, although these differences were not statistically significant. Weight gain since age 18 showed significant differences in its association with molecular subtypes (P-heterogeneity = 0.05) and was most strongly associated with the luminal B subtype (P-trend 0.001). Although there was not significant heterogeneity for lactation across subtypes, an inverse association was strongest for basal-like tumors (HR = 0.6, 95% CI 0.4–0.8; P-heterogeneity = 0.88). These results support the hypothesis that different subtypes of breast cancer have different etiologies and should not be considered as a single group. Identifying risk factors for less common subtypes such as luminal B, HER2-type and basal-like tumors has important implications for prevention of these more aggressive subtypes.     

An alternative approach to nonpalpable breast biopsies

Traditionally, when a negative specimen radiograph is obtained during biopsy of a nonpalpable breast lesion, immediate re-excision is performed in an attempt to successfully remove the lesion. Based on a retrospective study of the biopsy results of 792 nonpalpable breast lesions, the authors suggest delaying the re-excision, despite a negative specimen x-ray, until postoperative mammography confirms the persistence of the lesion. Utilization of this approach was associated with a comparably low incidence of missed lesions (3%) and had the added advantages of preserving breast tissue and decreasing operative time.     

Use of a case definition approach to identify cancer-related fatigue in women undergoing adjuvant therapy for breast cancer.

PURPOSE: Use a proposed case-definition approach to identify the prevalence of cancer-related fatigue (CRF), demographic, clinical and psychosocial predictors of subsequent CRF, and psychosocial factors associated with concurrent CRF. PATIENTS AND METHODS: Women (n = 288) undergoing adjuvant therapy for early-stage breast cancer were recruited from two outpatient clinics. Women completed a baseline assessment before adjuvant therapy and a post-treatment assessment at the conclusion of an initial course of adjuvant chemotherapy or radiotherapy. At both assessments, women completed a clinical interview and measures of fatigue, distress, coping, and quality of life (QOL). The clinical interview consisted of modules from the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) and a diagnostic interview to identify cases of CRF. RESULTS: CRF prevalence at the baseline and post-treatment assessments was 10% and 26%, respectively. Multivariate analyses identified factors prospectively associated with greater risk for CRF at the post-treatment assessment, including receipt of adjuvant chemotherapy and a tendency to catastrophize in response to fatigue. Patients with and without CRF differed on a host of concurrent measures of fatigue, depression, functioning, and QOL with mean effect sizes in the range of 1.0 standard deviation. CONCLUSION: CRF is a clinical syndrome experienced before and during adjuvant therapy for breast cancer. Results suggest CRF has a multifactorial etiology and support use of the proposed case definition approach to defining CRF. Future research is necessary to determine the scientific value of these criteria for understanding the etiology and management of fatigue in the oncology setting.     

Lipidomic approach to identify patterns in phospholipid profiles and define class differences in mammary epithelial and breast cancer cells

Breast cancer is the leading cause of cancer-related deaths in women. Altered cellular functions of cancer cells lead to uncontrolled cellular growth and morphological changes. Cellular biomembranes are intimately involved in the regulation of cell signaling; however, they remain largely understudied. Phospholipids (PLs) are the main constituents of biological membranes and play important functional, structural and metabolic roles. The aim of this study was to establish if patterns in the PL profiles of mammary epithelial cells and breast cancer cells differ in relation to degree of differentiation and metastatic potential. For this purpose, PLs were analyzed using a lipidomic approach. In brief, PLs were extracted using Bligh and Dyer method, followed by a separation of PL classes by thin layer chromatography, and subsequent analysis by mass spectrometry (MS). Differences and similarities were found in the relative levels of PL content between mammary epithelial and breast cancer cells and between breast cancer cells with different levels of aggressiveness. When compared to the total PL content, phosphatidylcholine levels were reduced and lysophosphatydilcholines increased in the more aggressive cancer cells; while phosphatidylserine levels remained unchanged. MS analysis showed alterations in the classes of phosphatidylcholine, lysophosphatidylcholine, sphingomyelin, and phosphatidylinositides. In particular, the phosphatidylinositides, which are signaling molecules that affect proliferation, survival, and migration, showed dramatic alterations in their profile, where an increase of phosphatdylinositides saturated fatty acids chains and a decrease in C20 fatty acids in cancer cells compared with mammary epithelial cells was observed. At present, information about PL changes in cancer progression is lacking. Therefore, these data will be useful as a starting point to define possible PLs with prospective as biomarkers and disclose metabolic pathways with potential for therapy.     

218例不同分子亚型浸润性乳腺癌患者的临床特征

目的：探讨浸润性乳腺癌分子亚型在中国人群中的分布,以用于判断临床预后和指导治疗。方法：回顾分析218例浸润性乳腺癌患者,根据雌激素受体（ER）、孕激素受体（PR）、人类表皮生长因子受体2（HER2）的水平划分为4个分子亚型。对比分析4型患者的分布比例、发病年龄、病理组织学分类、肿瘤最大径以及淋巴结转移等相关因素。结果：在4型中,luminal A型例数最多,共131例（60.1%）;basal-like型共有63例（28.9%）;luminal B型和HER2过表达型所占比例较少,均为12例（5.5%）。发病年龄以40岁～59岁年龄段发生乳腺癌例数最多,达到77.06%。HER2过表达型在50岁～59岁年龄段发病例数显著增高,与其余3组相比有显著性差异（P〈0.05）。病理分类显示,浸润性导管癌最多,各型之间无显著性差异（P〉0.05）;从淋巴结阳性病例中,HER2过表达型和luminal B型多枚淋巴结转移比例更高（P〈0.05）。肿瘤最大径分析显示,HER2过表达型和basal-like型病例肿瘤最大径2cm～5cm的比例较高,而luminal A型和luminal B型的肿瘤最大径多小于2cm（P〈0.05）。结论：在4型中,luminal A型所占比例最高;HER2过表达型在50岁～59岁年龄段发病较多见;浸润性导管癌是最常见的病理组织类型;HER2过表达型和luminal B型多枚淋巴结转移情况更多发生;HER2过表达型和basal-like型肿瘤较luminal A型更大。