阿帕替尼治疗晚期难治性三阴性乳腺癌的临床疗效观察

  目的  评价阿帕替尼治疗晚期难治性三阴性乳腺癌的临床疗效及不良反应。  方法  回顾性分析2015年7月至2016年11月就诊于天津医科大学肿瘤医院,经病理学确诊为晚期三阴性乳腺癌,既往接受过两线以上化疗后疾病进展(progressive disease,PD)、服用阿帕替尼500 mg/d治疗的8例患者临床资料,所有患者均在接受2个周期以上治疗后评价疗效,观察PD时间、有效率、临床获益率及不良反应。  结果  8例患者共接受平均4个周期的治疗,经过中位随访时间为8 (4~11) 个月,其中部分缓解(partialremission,PR) 4例,疾病稳定(stable disease,SD) 3例,PD 1例;疾病控制率(disease control rate,DCR)为87.5%(7/8),客观缓解率(objective response rate,ORR)为50% (4/8),平均无进展生存期(progression free survival,PFS)为4.2个月。不良反应为手足综合征(3/8)、骨髓抑制(4/8)、高血压(2/8)、蛋白尿(3/8)、咯血(1/8)、恶心(2/8)、乏力(2/8) 等。  结论  阿帕替尼在三阴性乳腺癌的治疗中可获得一定的疗效及生存获益,且安全性好,不良反应可控。      

钙黏蛋白与三阴乳腺癌

 钙黏蛋白与自身同型的钙依赖性黏附素特异性结合从而介导同型细胞间的黏附作用,主要包括上皮型、胎盘型及神经型3种亚型。近年来,国内外越来越多的研究报道表明钙黏蛋白与三阴乳腺癌（TNBC）密切相关,钙黏蛋白对TNBC的预后判断及治疗具有重要的意义。     

Metastatic triple-negative breast cancer

The triple-negative class (oestrogen receptor-negative, progesterone receptor-negative and human epidermal growth factor receptor 2 [HER2]-negative) comprises about 15% of breast cancer. It is associated with a poor prognosis compared with tumours that are positive for hormone receptors or HER2. Despite being sensitive to chemotherapy, many women with metastatic triple-negative breast cancer (TNBC) relapse quickly, and commonly develop visceral metastasis, including lung, liver and brain metastasis. TNBC has molecular features that overlap with breast cancer in BRCA1 germline mutation carriers and with those of the basal-like molecular class of tumours. Furthermore, tumours with the triple-negative phenotype have specific features and express markers that are potential therapeutic targets, for example an impaired DNA repair mechanism and increased expression of proliferation and basal-associated markers. The presence of these features has important implications for clinical practice and for the design of clinical trials looking at novel therapies. Targeted agents that are currently being investigated include poly (ADP-ribose) polymerase inhibitors, epidermal growth factor receptor inhibitors and anti-angiogenic compounds. Here we discuss the epidemiology, morphological and molecular spectrum of TNBC, the clinical significance of this important class of breast cancer and the current treatment options.     

早期三阴性乳腺癌与非三阴性乳腺癌VEGF和MVD表达的比较

目的探讨血管内皮生长因子（vascularendothelialgrowthfactor,VEGF）、微血管密度（microvesseldensity,MVD）在早期三阴性乳腺癌组织中与非三阴性乳腺癌组织中的表达水平。方法采用免疫组化染色法检测我院2007年1～12月行根治性手术切除、经病理证实的乳腺癌组织蜡块89例（其中早期三阴性乳腺癌21例,非三阴性乳腺癌68例）癌组织中VEGF的表达及MVD值,分析VEGF的表达及MVD值在早期三阴性乳腺癌和非三阴性乳腺癌组织中的差别,以及VEGF和MVD之间的关系。结果早期三阴性乳腺癌癌组织中VEGF表达的阳性率高于非三阴性乳腺癌（71．43％vs25．00％,P〈O．001）。MVD在早期三阴性乳腺癌与非三阴性乳腺癌组间的差异无统计学意义（P=0．105）。结论VEGF表达与乳腺癌血管生成密切相关,VEGF及MVD在三阴性乳腺癌中的生物学意义值得进一步探讨。     

三阴乳腺癌研究进展

三阴乳腺癌(TNBC)是最近才分出来的乳腺癌亚型,目前尚无有效的个体化治疗方案,全身化疗还是该亚型患者的主要治疗模式,并且与非TNBC相比,该亚型患者使用常用的治疗方案具有较高的局部复发和远处转移率.TNBC组织学分化差,大部分可以归类于basal-like乳腺癌,且其与BRCA1相关的乳腺癌有许多相似之处.     

Immunotherapy in triple-negative breast cancer

Breast cancer can be classified based on the expression or lack of expression of protein receptors including estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth receptor 2 (Her2). The basal molecular subtype is mostly made up of breast cancers that do not express ER/PR or Her2, triple-negative breast cancers (TNBC) (Bertucci et al. in Int J Cancer 123(1):236, 2008). TNBC tends to be more aggressive as there are no approved targeted treatments and the only treatment option currently is cytotoxic chemotherapy. Recent data show that some chemotherapies, specifically anthracyclines, not only have cytotoxic effects but also use the immune system by activating CD8+ T cell responses to kill cancer cells (Stagg et al. in Ther Adv Med Oncol 5(3):169–181, 2013), and thus, tumor-infiltrating lymphocytes respond well to chemotherapy. Currently, systemic immunotherapy which utilizes the patient’s own immune system directly to eradicate and target neoplastic cells is being explored as treatment for TNBC as this type of breast cancer has been shown to be immunogenic (Yu et al. in Int J Environ Res Public Health 14:68, 2017). According to the Cancer Genome Atlas, TNBC has higher PD-L1 mRNA expression (Mittendorf et al. Cancer Immunol Res 2(4):361–370, 2014). Higher rates of CD8+ T cell infiltration were also found in TNBC according to a study by Liu et al. (Breast Cancer Res 14:R48, 2012). In TNBC patients, Pembrolizumab, a monoclonal antibody that targets programmed cell death protein 1 (PD-1), and Atezolizumab, a monoclonal antibody that targets its ligand, have been investigated to assess dose tolerability and side effects. Further studies involving vaccines, immunotherapy that targets cytotoxic T lymphocyte-associated protein-4 and PD-L1, are currently being investigated for treatment of TNBC. This review outlines the systemic immunotherapies that are currently being investigated for patients with TNBC.     

三阴乳腺癌研究进展

三阴乳腺癌(TNBC)具有独特的生物学行为和临床特征,目前尚没有针对TNBC的标准治疗.近年来在TNBC的流行病学、分子特征、化学治疗和靶向治疗等方面进行了许多研究与探索,特别是Ⅱ期或Ⅲ期临床研究初步结果显示,新的化疗方案和靶向治疗对TNBC可能具有很好的疗效.     

三阴乳腺癌治疗研究进展

Triple-negative breast cancers (TNBCs) neither express estrogen receptor and progesterone receptor nor overexpress human epidermal growth factor receptor-2. Because of the special molecular features, triple-negative breast cancer is not either sensitive to endocrine therapy or targeted therapy of trastuzumab. There has not been standard treatment regimen for triple-negative breast cancer yet and chemotherapy has still been the chief therapy currently. However, with the great progress of oncology and molecular biology, the understanding of the natural history, pathophysiology and molecular features of this disease has been greatly improved, and a growing number of novel and effective therapies and discoveries of new biological targets for this phenotype of breast cancers have been reported, which provide new insights into therapeutic strategies for the women suffering from it.     

受体三阴性乳腺癌的研究进展

根据免疫组化染色的特征,将ＥＲ、ＰＲ和ＨＥＲ２受体均阴性的乳腺癌称之为受体三阴性乳腺癌,三阴性乳腺癌是具有独特生物学及临床特征的乳腺癌亚型,与基底细胞样乳腺癌有较高的一致性,复发早、进展快、生存短。对于三阴性乳腺癌的治疗,目前并没有推荐的化疗方案,而针对三阴性乳腺癌的靶向治疗正在进行临床研究。     

EZH2与乳腺癌及三阴性乳腺癌相关性的研究

目的:分析EZH2表达与乳腺癌及三阴性乳腺癌(TNBC)的相关性.方法:利用免疫组化法对82例乳腺癌和20例乳腺良性病变检测EZH2表达情况,收集82例乳腺癌的临床病理资料及TNBC表达情况,并与EZH2表达情况进行比较,Kaplan-Meier法分析乳腺癌的5年无瘤生存率.结果:乳腺良性病变中EZH2阳性表达率为20.0%,乳腺癌病例中EZH2阳性表达率为51.2%,两者比较差异有统计学意义,x2=6.329,P=0.012;82例乳腺癌患者中,EZH2阳性表达患者与阴性表达患者比较,在肿瘤直径、组织学分级、淋巴结转移方面差异均有统计学意义(P<0.05),而在患者年龄、是否绝经、有无乳腺癌家族史方面差异无统计学意义,P>0.05.82例乳腺癌患者中,TNBC的EZH2阳性率为89.5%,非TNBC的EZH2阳性率为39.7%,两者差异有统计学意义,x2=14.484,P=0.000;82例乳腺癌患者中,5年无瘤生存率EZH2阳性组为64.3%,EZH2阴性组为85.0%,差异有统计学意义,Log-rank=3.995,P=0.046.结论:EZH2阳性表达在乳腺癌患者中要高于乳腺良性病变,其在乳腺癌患者中比阴性表达患者更易复发转移,且与TNBC的发生更为密切.     

What is triple-negative breast cancer?

Triple-negative (ER-negative, PR-negative, HER2/neu not overexpressed) breast cancer has distinct clinical and pathologic features, and is a clinical problem because of its relatively poor prognosis, aggressive behaviour and lack of targeted therapies, leaving chemotherapy as the mainstay of treatment. Most triple-negative tumours fall into the basal-like molecular subtype of breast cancer, but the terms are not completely synonymous. Among the intriguing characteristics of triple-negative breast cancer is its association with cancers arising in BRCA1 mutation carriers, in young women and in African–American women. The reasons for these associations are unclear but may ultimately provide avenues for prevention and targeted therapy. This review discusses the definitions and characteristics of as well as current and evolving therapies for triple-negative and basal-like breast cancer.     

三阴乳腺癌的研究进展(英文)

Triple-negative breast cancer (TNBC) is a unique subgroup defined by a lack expression of ER (estrogen receptor), PR(progesterone receptor) and HER2 (human epidermal growth factor receptor 2), which has distinctly biological, clinical and pathological characteristics. This subgroup has close relationship with basal-like and BRCA1 (breast cancer susceptibility gene-1) breast cancers. Since endocrine and HER2-targered therapy can not be applied, chemotherapy is the major mean of therapy. Some studies show tha...     

MR imaging of triple-negative breast cancer

Little is known about the MR imaging features of triple-negative breast cancer (TNBC), but TNBC has a worse prognosis because it has no effective therapeutic targets, such as estrogen receptor for endocrine therapy and human epidermal growth factor receptor 2 (HER2) for anti-HER2 therapy. MR findings of a unifocal lesion, mass lesion type, smooth mass margin, rim heterogeneous enhancement, persistent enhancement pattern, and very high signal intensity on T2-weighted images are typical features of breast MR imaging associated with TNBC. Although TNBC can mimic a benign morphology, the early MR imaging recognition of TNBC could assist in both the pretreatment planning and the prognosis, as well as adding to our understanding of the biological behavior of TNBC.     

ER、PR、HER-2阴性乳腺癌研究进展

ER、PR、HER-2均为阴性的乳腺癌(三阴乳腺癌)常较早发生远处转移,内脏转移率高于骨转移,预后较差.由于没有内分泌和靶向HER-2治疗的机会,因此只能将化疗作为主要的治疗手段.其主要增殖信号和分子学特征提示针对表皮生长因子受体(EGFR)、C-kit和BRCA1等靶点的靶向治疗可能发挥较好的治疗效果.但目前的研究结果还不能明确三阴乳腺癌的生物学特点和最佳治疗策略.     

Metabolic phenotypes in triple-negative breast cancer

The aim of study was to investigate the metabolism of tumor and stromal cells necessary to determine differential tumor–stroma metabolic interactions according to the molecular subtypes of triple-negative breast cancer (TNBC). Tissues from 132 patients of TNBC were prepared for use as tissue microarrays (TMA). Expression of CK5/6, EGFR, claudin 3, claudin 4, claudin7, E-cadherin, AR, GGT1, STAT1, and interleukin-8 was evaluated by immunohistochemical staining using TMA to classify molecular subtypes of TNBC. In addition, immunohistochemical staining for Glut1, CAIX, BNIP3, MCT4, Beclin-1, LC3A, LC3B, and p62 was performed. According to glycolytic status determined by the immunohistochemical expression of Glut-1 and CAIX in tumor and stroma, the metabolic phenotypes of the TNBCs were defined as follows: Warburg type (tumor: glycolysis, stroma: non-glycolysis), reverse Warburg type (tumor: non-glycolysis, stroma: glycolysis), mixed metabolic type (tumor: glycolysis, stroma: glycolysis), and metabolic null type (tumor: non-glycolysis, stroma: non-glycolysis). TNBCs were classified as follows: 79 Warburg type (59.8 %), 7 reverse Warburg type (5.3 %), 24 mixed metabolic type (18.2 %), and 22 metabolic null type (16.7 %). There was no statistical significance between the metabolic phenotypes and molecular subtypes (P?=?0.706). Reverse Warburg type showed the most dysfunctional mitochondrial status for stromal cells, while Warburg type showed the most functional mitochondrial status (P?=?0.036). Regarding stromal autophagy status, reverse Warburg type showed the most activated status, while all of the Warburg and metabolic null types showed a non-activated status (P?<?0.001). In conclusion, Warburg type was the most common metabolic phenotype in TNBC, while reverse Warburg type was the most unusual. Metabolic phenotypes did not differ among the molecular subtypes of TNBCs.     

Prognostic markers in triple-negative breast cancer

BACKGROUND: Triple-negative breast cancer (estrogen receptor-negative, progesterone receptor-negative, and HER2-negative) is a high risk breast cancer that lacks the benefit of specific therapy that targets these proteins. METHODS: In this study, the authors examined a large and well characterized series of invasive breast carcinoma (n = 1944) with a long-term clinical follow-up (median, 56 months) by using tissue microarray. The series were also stained with concurrent immunohistochemical prognostic panels (estrogen receptor, progesterone receptor, HER-2, androgen receptor, epidermal growth factor receptor (EGFR), P-cadherin, E-cadherin, and basal (CK5/6, CK14), and p53), to characterize this specific subgroup of breast cancer and to identify prognostic markers that can identify tumors with more aggressive behavior. RESULTS: Of informative cases, 16.3% were of the triple-negative phenotype. The majority of these tumors were grade 3, ductal/no-specific-type carcinomas. There were positive associations with larger size, pushing margins, poorer Nottingham Prognostic Index, development of recurrence and distant metastasis, and poorer outcome. In addition, associations were found with loss of expression of androgen receptor and E-cadherin, and positive expression of basal cytokeratins (basal phenotype), P-cadherin, p53, and EGFR. In all tumors, tumor size, lymph node stage, and androgen receptor were the most useful prognostic markers. In the lymph node-positive subgroup, both size and androgen receptor retained their prognostic significance. However, in the lymph node-negative tumors, basal phenotype was the sole prognostic marker identified in this subgroup. Other parameters including age, histological grade, tumor size, vascular invasion or other biomarkers included in the current study were not significant. CONCLUSIONS: The authors concluded that assessment of androgen receptor and basal phenotype, in addition to the established pathologic variables, mainly lymph node status and tumor size, can be used to select high-risk and low-risk patients at the time of primary surgery and can provide valuable information on treatment options in these triple-negative tumors.