乳腺癌原发灶和转移灶激素受体与HER2表达差异及其影响因素

目的 乳腺癌的治疗已经进入分子分型时代,雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone receptor,PR)和人类表皮生长因子受体-2(human epidermal growth factor receptor 2,HER2)的表达对指导制订乳腺癌治疗方案及评价患者预后等尤为重要.许多研究证实,部分乳腺癌患者原发灶及转移灶激素受体与HER2表达存在差异,影响术后辅助及解救治疗方案的制订,进而影响患者的治疗效果及预后.本研究探讨乳腺癌原发灶与腋窝及远处转移灶之间激素受体与HER2表达的差异及其临床意义,同时分析了造成差异的影响因素.方法 以乳腺癌、激素受体(ER和PR)、HER2、原发灶和转移灶为关键词,检索PubMed、CNKI数据库和万方数据库1995-01-2016-10的相关文献.共505篇文章被检索到.纳入标准:原发灶与腋窝转移灶激素受体及HER2表达差异情况,原发灶与远处转移灶激素受体及HER2表达差异情况,原发灶与转移灶激素受体及HER2表达差异情况的临床意义.根据纳入标准最终纳入分析38篇文献.结果 在部分乳腺癌患者中,原发灶与腋窝转移灶及远处转移灶激素受体及HER2表达情况存在差异,多数文献报道,乳腺癌原发灶与转移灶ER表达状况变化(阳性转阴性或阴性转阳性)比例约为20％,PR约为20％,HER2约为15％.“肿瘤异质性、抗肿瘤治疗和检测方法”等是影响其表达差异的影响因素.结论 推荐对于存在局部及远处转移的乳腺癌患者,同时检测并综合原发灶及转移灶的激素受体及HER2表达情况制订治疗方案.     

HER2阳性乳腺癌脑转移3例并文献复习

0 引言 乳腺癌已成为女性最常见的恶性肿瘤,晚期乳腺癌所占比例越来越高,脑转移成为晚期乳腺癌患者死亡的主要原因之一[1].在乳腺癌不同亚型里,脑转移最多见的是HER2阳性乳腺癌和三阴乳腺癌[2].国内外学者对HER2阳性乳腺癌发生脑转移的流行病学、发病机制、治疗方法均进行了大量探索.本文通过回顾湖北省肿瘤医院3例HER2阳性乳腺癌患者脑转移的发生时间、治疗手段、治疗经过以及疾病的转归,探讨HER2阳性乳腺癌脑转移的综合治疗手段以及曲妥珠单抗等靶向治疗药物对脑转移患者预后的影响,试图提高该类患者的总生存期,改善其生活质量.     

229例人表皮生长因子受体2阳性Ⅳ期乳腺癌患者曲妥珠单抗的治疗分析

目的探讨曲妥珠单抗对人表皮生长因子受体2(HER2)阳性Ⅳ期乳腺癌的治疗效果及患者预后的影响因素。方法收集229例应用曲妥珠单抗治疗的HER2阳性Ⅳ期乳腺癌患者的临床资料,采用Cox比例风险回归模型分析HER2阳性Ⅳ期乳腺癌患者无进展生存时间(PFS)和总生存时间(OS)的影响因素。结果229例HER2阳性Ⅳ期乳腺癌患者行曲妥珠单抗总体治疗的客观有效率为44.5%,疾病控制率为90.8%,中位PFS为10个月(95%CI:8.748~11.252),中位OS为29个月(95%CI:27.551~30.449)。单因素分析结果显示,激素受体状态和曲妥珠单抗不同线治疗均可能与HER2阳性Ⅳ期乳腺癌的PFS有关,激素受体状态、曲妥珠单抗不同线治疗和进展后是否继续行曲妥珠单抗治疗均可能与HER2阳性Ⅳ期乳腺癌的OS有关(P﹤0.05)。多因素分析结果显示,激素受体状态和曲妥珠单抗不同线治疗是HER2阳性Ⅳ期乳腺癌PFS和OS的独立影响因素(P﹤0.05)。结论一线应用曲妥珠单抗是治疗HER2阳性Ⅳ期乳腺癌的有效手段,在治疗进展后继续应用曲妥珠单抗治疗仍有生存获益。     

HER2阳性乳腺癌治疗的研究进展

人表皮生长因子受体2(HER2)阳性乳腺癌因其侵袭性高、预后差而一直备受关注。随着曲妥珠单抗的应用,早期HER2阳性乳腺癌患者的预后已得到显著改善,由于其仍存在耐药性和不良反应,在标准治疗中加入新的抗HER2药物又成为新的研究重点,这些药物包括帕妥珠单抗、抗体药物偶联物曲妥珠单抗-美坦新(T-DM1)和各种小分子抑制剂(拉帕替尼、来那替尼、吡咯替尼)。同时PD1及PD-L1抑制剂如帕博利珠单抗在HER2阳性乳腺癌中的研究也在进行中,并有部分基础研究和病例报道已经证实了其疗效和安全性。本文旨在对目前HER2阳性乳腺癌的治疗方案和支持HER2阳性乳腺癌治疗的最新证据进行综述。     

乳腺癌发生脑转移的相关因素分析

目的探讨转移性乳腺癌发生脑转移的危险因素.方法采用临床分析的方法对199例转移性乳腺癌病例归纳总结,并采用COX模型单变量和多变量分析法对临床特征进行统计分析.结果肺转移的存在(比值比=4.26,95%,CI:1.9%～9.3%,P=0.0003)和激素受体阴性状态:(比值比=4.15,95%,CI:1.6%～10%,P=0.002),CerbB-2阳性(比值比=4.22,95%,CI:1.5%～11%,P=0.0006)是脑转移发生的预测因素.结论在转移性乳腺癌患者中,肺转移是首发转移位置,激素受体阴性CerbB-2阳性是发生脑转移的危险因素,应在这些患者中进行预防性治疗.     

HER-2阳性乳腺癌靶向药物治疗的研究进展

人表皮生长因子受体-2（human epidermal growth factor receptor-2,HER-2）阳性乳腺癌占全部乳腺癌分子类型的15%~20%,该类型乳腺癌恶性程度高,预后差。抗HER-2靶向药物能有效降低这部分乳腺癌复发和转移的风险,延长患者生存,并改善预后。目前多种抗HER-2靶向药物（如帕妥珠单抗、T-DM1、吡咯替尼等）相继问世,使乳腺癌治疗策略不断优化,为HER-2阳性乳腺癌提供更精准的治疗方案。本文针对HER-2阳性乳腺癌靶向药物治疗的最新研究结果进行相关综述。      

预防性脑照射的临床共识与进展

预防性脑照射是临床上处理肿瘤脑转移的有效手段,该手段对于微小病灶的杀灭能够有效降低脑转移的发生率,改善患者预后.其有效性在小细胞肺癌中得到了验证,而在非小细胞肺癌(NSCLC)以及乳腺癌中的应用仍然处于探索阶段,对于手术及辅助化疗后ⅢA-N2期NSCLC患者以及曲妥珠单抗治疗的人表皮生长因子受体-2阳性的乳腺癌患者,预防性脑照射有望成为这两类患者的常规治疗手段.     

乳腺癌的内分泌疗法

自1896年Beatson首次报道卵巢切除治疗晚期乳腺癌获得成功后,从此,开辟了内分泌治疗恶性肿瘤的新途径.1974年Bethesda召开的国际会议上确认激素受体含量与内分泌治疗疗效之间存在正相关后内分泌治疗乳腺癌的研究更是得到深入的发展.内分泌疗法是乳腺癌治疗的主要手段之一.它不仅用于某些晚期乳腺癌的治疗,也可用于可手术乳腺癌的辅助化疗.但内分泌疗法仅适用于激素依赖性乳腺癌,而不适用于非激素依赖性乳腺癌.ER( )(雌激素受体阳性)者内分泌治疗有效率达50～70%,ER     

三阴性乳腺癌基因学分子分型和个体化治疗新进展

目的 三阴性乳腺癌(triple negative breast cancer,TNBC)作为乳腺癌的一种特殊类型,具有高侵袭性,极易出现局部复发和远处转移.近年来关于TNBC进一步亚分类,并且针对各亚型进行相应靶向治疗的基础研究和临床研究均较多.本研究对国内外TNBC的分子分型和个体化治疗新进展进行综述分析.对国内外三阴性乳腺癌(triple negarive breast cancer,TNBC)的分子分型以及个体化治疗新进展进行综述分析.方法 应用PubMed及CNKI期刊全文数据库检索系统,以“三阴性乳腺癌、TNBC、分子分型、治疗”等为关键词,检索2011-01-2016-05相关文献,共检索到英文文献240条,中文文献449条.纳入标准:(1)TNBC的生物学功能;(2)TNBC的分子分型;(3)TNBC的个体化治疗.剔除标准:(1)乳腺癌的分子分型;(2)乳腺癌的个体化治疗.根据剔除标准剔除中文文献130条,英文文献141条,最后纳入分析63篇文献.结果 TNBC从基因学角度分为6个亚型,针对每个亚型均有不同的个体化治疗靶向药物,包括表皮生长因子受体(epidermal growth factor receptor,EGFR)抑制剂、铂类、聚腺苷酸二磷酸核糖转移酶(poly-AD-ribose polymerase,PARP)抑制剂、蒽环/紫衫、免疫治疗、血管内皮生长因子受体(vascular endothelial growth factor receptor,VEGFR)抑制剂、雄激素受体(androgen receptor,AR)拮抗剂以及各靶向治疗手段的联合使用.结论 TNBC是异质性疾病,其分子分型的确定对于理解肿瘤的生物学特征和临床行为,以及发展TNBC个体化治疗都是必需的.由于TNBC肿瘤信号通路之间的交联,发展不同靶向药物的联合应用才有望真正的提高该疾病的总生存.     

HER2阳性型乳腺癌脑转移的研究进展

近年来曲妥珠单抗的广泛应用大大提高了HER2（人表皮生长因子受体 2）过度表达乳腺癌患者的生存率,在全身性控制率提高和生存期延长的同时,脑转移瘤的发病率也有所增加;同时,脑转移是造成HER2阳性型乳腺癌晚期患者死亡的一项越来越重要的具有临床挑战性的因素——常常是在颅外疾病控制良好的情况下。本文将HER2阳性型乳腺癌脑转移的早期检测和预防的价值,靶向治疗的进展及新靶向药物的开发情况加以总结。     

Challenges in the treatment of hormone receptor-positive,HER2-negative metastatic breast cancer with brain metastases

Brain metastases are a major cause of morbidity and mortality for women with hormone receptor (HR)-positive breast cancer, yet little is known about the optimal treatment of brain disease in this group of patients. Although these patients are at lower risk for brain metastases relative to those with HER2-positive and triple-negative disease, they comprise the majority of women diagnosed with breast cancer. Surgery and radiation continue to have a role in the treatment of brain metastases, but there is a dearth of effective systemic therapies due to the poor penetrability of many systemic drugs across the blood-brain barrier (BBB). Additionally, patients with brain metastases have long been excluded from clinical trials, and few studies have been conducted to evaluate the safety and effectiveness of systemic therapies specifically for the treatment of HER2-negative breast cancer brain metastases. New approaches are on the horizon, such as nanoparticle-based cytotoxic drugs that have the potential to cross the BBB and provide clinically meaningful benefits to patients with this life-threatening consequence of HR-positive breast cancer.     

Brain metastases in breast cancer

Despite therapeutic advances, the development of breast cancer brain metastases (BCBM) is still the harbinger of a dismal prognosis. Patient outcomes vary depending on factors, including tumor phenotype, extent of disease within and outside the brain, as well as patient performance status. Treatment includes surgery, radiation therapy and systemic therapy determined by patient and tumor characteristics. Despite these approaches, novel treatments are needed and there is growing interest in systemic therapies. However, the efficacy of pharmacologic agents is hampered by poor penetration of drugs across the blood–brain barrier. Therefore, there is a pressing need for a greater understanding of the natural history of BCBM to guide the development of further therapies. This review analyzes prognosis and treatment of BCBM by tumor phenotype and discusses ongoing research into new therapies.     

Risk factors for brain relapse in patients with metastatic breast cancer.

BACKGROUND: The occurrence of brain metastases is an emerging problem in patients with metastatic breast cancer. In the present study, we looked at risk factors for brain metastasis among patients with metastatic breast cancer. PATIENTS AND METHODS: The risk factors for brain metastasis were first determined in a series of 215 patients with metastatic breast cancer. Risk factors identified in the multivariate analysis were re-evaluated in a confirmatory series of 199 patients with metastatic breast cancer. All the patients had been included in prospective randomized trials that evaluated chemotherapy or endocrine therapy in an adjuvant setting. RESULTS: In the first series, the presence of lung metastases (hazard ratio = 4.3, 95% CI: 1.9-9.3, P=0.0003) and negative hormone receptor status (hazard ratio = 4.2, 95% CI: 1.7-11, P=0.002) were the only predictive factors associated with the occurrence of brain metastases in the multivariate analysis. The second series confirmed that the presence of lung metastases and negative hormone receptor status were associated with the occurrence of brain metastases. CONCLUSION: The presence of lung metastases as the first site of relapse and a negative hormone receptor status are predictive for the occurrence of brain metastases in patients with metastatic breast cancer. A prophylactic treatment should be evaluated in these subsets of patients.     

Systemic Therapy in the Setting of Central Nervous System (CNS) Metastases in Breast Cancer

Purpose of Review

Over 25% of patients with metastatic breast cancer will develop brain metastases. Recent advances in systemic therapy, especially molecularly targeted agents, have improved control of extracranial disease, but have had limited effect on intracranial disease. In this review, we discuss the barriers and challenges associated with employing systemic therapy to treat brain metastases. We also provide an overview of current systemic therapy used as standard of care in all subtypes of breast cancer that have metastasized to the brain, as well as describe novel agents that are currently under study in preclinical models or clinical trials.

Recent Findings

While there are few systemic therapies that are standard of care for the treatment of breast cancer brain metastases, there are many novel agents currently in development or under active investigation. Detailed genomic analysis has led to a better understanding of the molecular aberrations that drive metastasis in the different subtypes of breast cancer, leading to rational approaches to the development of targeted molecular therapy.

Summary

The most promising systemic therapeutic modalities for treating breast cancer brain metastases utilize targeted molecular agents or molecular exploitation of the blood-brain barrier in combination with cytotoxic chemotherapy to enhance entry into the CNS.

     

Developmental therapeutics for patients with breast cancer and central nervous system metastasis: current landscape and future perspectives

Breast cancer is the second-leading cause of metastatic disease in the central nervous system (CNS). Recent advances in the biological understanding of breast cancer have facilitated an unprecedented increase of survival in a subset of patients presenting with metastatic breast cancer. Patients with HER2 positive (HER2+) or triple negative breast cancer are at highest risk of developing CNS metastasis, and typically experience a poor prognosis despite treatment with local and systemic therapies. Among the obstacles ahead in the realm of developmental therapeutics for breast cancer CNS metastasis is the improvement of our knowledge on its biological nuances and on the interaction of the blood–brain barrier with new compounds. This article reviews recent discoveries related to the underlying biology of breast cancer brain metastases, clinical progress to date and suggests rational approaches for investigational therapies.     

Brain metastases of breast cancer

Brain metastases of breast cancer remain a difficult problem for clinical management. Their incidence appears to be increasing, which is likely due to longer survival times for advanced breast cancer patients as well as additional and improved tools for detection. Molecular features of tumors associated with this syndrome are not yet understood. In general, survival may be improving for brain metastases due to better local control in the CNS, as well as improvements in systemic disease management. Selected patients with brain metastases are able to undergo surgical resection, which has been associated with extended disease control in some patients. However, whole-brain radiation has been the mainstay for treatment for most patients. Stereotactic radiosurgery is playing an increasing role in the primary treatment of brain metastases, as well as for salvage after whole-brain radiation. Recent series have reported median survivals of 13 months or longer with stereotactic radiosurgery. Further improvements in radiation-based approaches may come from ongoing studies of radiosensitizing agents. The ability of systemic treatments to impact brain metastases has been debated, and specific treatment regimens have yet to be defined. New approaches include chemotherapy combinations, biologic therapies and novel drug-delivery strategies.     

Targeted Therapies for Breast Cancer Brain Metastases

The management of breast cancer, the most common cancer in the female population, has changed dramatically over years with the introduction of newer therapies. An increased incidence of brain metastases in recent years has created a challenge for oncologists because this population continues to have a poorer prognosis compared to metastatic breast cancer without central nervous system involvement. Historically, the exclusion of breast cancer patients with brain metastases from clinical trials has made treatment options even more limited. Nonetheless, more recently, this unmet need has been recognized by basic and clinical researchers and has led to the development of targeted therapies with better blood–brain barrier penetration and intracranial efficacy. Here we review targeted therapies directed at human epidermal growth factor receptor type 2 (HER2), vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR), epidermal growth factor receptor (EGFR), cyclin-dependent kinase 4 and 6 (CDK4/6) and poly(ADP-ribose) polymerase (PARP) for breast cancer patients with brain metastases. These therapies aim to be more efficacious and less toxic to represent a paradigm shift in the management of breast cancer brain metastases.     

A case of recurrent breast cancer with brain metastases successfully treated with vinorelbine and anastrozole after multiple chemo-endocrine therapies

We report a case of recurrent hormone receptor-positive breast cancer with brain metastases that showed good response to vinorelbine(VNR)and anastrozole(ANA). A 49-year-old woman with a history of left breast cancer had initially undergone modified radical mastectomy, but was diagnosed with lung metastases 8 years postoperatively. Despite treatment with docetaxel and tamoxifen, multiple brain metastases were detected 10 years postoperatively. To achieve prompt improvement of neurological symptoms, surgical resection was performed for two large brain foci. Stereotactic radiosurgery using a gamma- knife was applied for the remaining multiple brain metastases. Histological examination identified the brain tumors as estrogen receptor-positive, HER2-negative metastatic breast cancer. Despite the use of cyclophosphamide, adriamycin and 5- fluorouracil(CAF therapy)and capecitabine, brain metastases recurred twice along with pleuritis carcinomatosis and bone metastasis. In addition to gamma-knife re-treatment, therapy was started with VNR and ANA. All metastatic sites including brain showed a good response to therapy with few adverse reactions, and no recurrence has been observed over 3 years.     

Breast cancer brain metastases

Breast cancer is the most common malignancy in woman in the USA. Metastasis is a major cause of morbidity and mortality in breast cancer patients. Total incidence of brain metastases of breast cancer is about 30%. Because of the improvements in control of systemic disease, for example the successful use of Trastuzumab, and the consequent prolonged life span, the incidence of brain metastases is increasing in breast cancer patients. The progressive neurological disabilities not only impair the quality of life, but also decrease the survival in patients. However, current treatments are of limited effectiveness. This is partially caused by the unique structure of the blood brain barrier. So far very little is known about the mechanisms how breast cancer metastizes to the brain. Some studies showed that ErbB2 overexpression is associated with the brain metastatic phenotype. Other molecules, like vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs) and chemokine receptor CXCR4 are also involved in the metastasis of breast cancer cell to the brain. The current review will briefly overview the clinical features of brain metastasis of breast cancer and discusses the relationship of blood brain barrier and ErbB2 signal pathway to brain metastasis in breast cancer.