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.     

Identification of patients who may benefit from the prophylactic cranial radiotherapy among breast cancer patients with brain metastasis

Background To identify the candidates for prophylactic cranial radiotherapy (PCI) among the patients with early and advanced-stage breast cancer. Methods The demographic, pathologic and clinical features and survival results of 182 brain metastatic breast cancer patients treated with cranial radiotherapy were examined. Results Early stage patients who progressed with isolated brain metastasis had longer survival (13 months vs. 4 months P = 0.006). Lobular/mixed type histology (P = 0.033), high nuclear (P = 0.046) and high histological grade (P = 0.034) were the prognostic factors for isolated brain metastases. The most significant factor for the time to brain metastasis was the number of involved of lymph nodes (P = 0.004). In 60% of 148 patients with metastatic breast cancer, a progression with isolated brain metastasis was developed while the systemic disease was under control. Isolated brain metastasis progression was related to the presence of the hepatic metastasis at the first relapse (P = 0.001) and with ErbB-2 overexpression (P = 0.034). The time to the brain metastasis from the first extracerabral metastasis was associated with the high nuclear grade (P = 0.040) and with chemoresistance (P = 0.037). The median survival time after the brain metastases in chemosensitive patients was longer than in chemoresistant patients (8 months vs. 3 months P = 0.044). In chemoresistant patients (P = 0.0028) and/or in triple negative patients (P = 0.05) the development of the brain metastasis was early and the survival after brain metastasis was short. Discussions Since there is a tendency to early brain metastasis in early stage patients with high-grade, lobular/mixed type histology tumors and with a high number of involved lymph nodes, the value of PCI can be explored in these patients by a well designed prospective trial. Advanced stage chemosensitive patients with ErbB-2 over-expression and/or with hepatic metastasis at their first relapse may be candidates for PCI. There is no place for PCI in chemoresistant and triple-negative breast cancer patients.     

乳腺癌肝转移机制研究进展

肝脏是乳腺癌常见的转移部位。乳腺癌肝转移的过程包括多个步骤,涉及乳腺癌细胞和肝脏微环境中的多种因素。在本文中,我们综述了与乳腺癌肝转移相关的分子（包括连接蛋白类、蛋白激酶类、miRNAs）、信号转导通路（包括CXCL12－CXCR4轴、Wnt／β－catenin信号通路、AF1q／TCF7／CD44调节轴、层黏连蛋白受体／Akt／ERK信号通路、瘦素／ERK／IL－8信号通路）以及肝脏微环境中的影响因素（包括缺氧诱导因子、肿瘤相关成纤维细胞、脂肪基质干细胞、金属蛋白酶、选择性配体、炎性细胞免疫浸润）。     

Parotid gland metastasis of a breast cancer

Abstract Parotid gland metastases from malignant tumors are extremely rare. A 61-year-old woman was diagnosed with an early breast cancer with no expression of oestrogen and progesterone receptors. Five years later the patient presented a tumour in parotid gland. After total parotidectomy, microscopic analysis of the gland demonstrated an invasive duct carcinoma (IDC) with positive expression of oestrogen receptor. The patient was treated with chemotherapy followed by complementary local radiotherapy. Diagnosis of a metastasic tumour in parotid gland poses a challenge. In our case an immunohistochemical study of oestrogen receptor was fundamental to establish a diagnosis.     

Systematic analysis of early phase clinical studies for patients with breast cancer: Inclusion of patients with brain metastasis

PurposeThis systematic review aims to better define the limitations and patterns with which patients with MBC and CNS metastasis are enrolled into early phase developmental therapeutics trials.MethodsIn June 2016, PubMed search was conducted using the following keywords: “Breast cancer”. Drug-development phase 1, phase 2 or phase 1/2 trials for patients with MBC were included. Multiple-histology trials and trials without an efficacy endpoint were excluded.ResultsIn total, 1474 studies were included; Inclusion criteria for 423 (29%) allowed for CNS metastasis, 770 (52%) either excluded or did not document eligibility of patients with CNS disease. Trials accruing patients with HER2-positive MBC and including targeted therapies had higher odds of allowing for patients with CNS disease (adjusted OR 1.56, 95% CI 1.08–2.2.6; p = 0.019 and 1.49, 95% 1.08–2.06; p = 0.014, respectively). There were also higher odds of accrual of patients with CNS involvement into clinical trials over time (odds ratio = 1.10, 95% CI 1.07–1.12; p < 0.0001).ConclusionMost published early phase clinical trials either did not clearly document or did not allow for accrual of patients with CNS disease. Early phase trials with targeted agents or enrolling HER2+ MBC had higher odds of permitting CNS metastases.     

乳腺癌骨转移患者生存分析

目的 提高对乳腺癌骨转移患者预后影-向因素的进一步认识，指导临床个体化治疗。方法 回顾分析有完整病例资料的乳腺癌骨转移患者68例。结果 68例患者的中位生存期20个月，乳腺癌骨转移合并肝脏和/或肺转移同时存在时，患者的中位生存期13．5个月；乳腺癌骨转移不合并肝脏和/或肺转移患者的中位生存期为26个月；仅有骨转移而不合并其他脏器转移的患者的平均生存时间为44.2个月。结论 乳腺癌转移患者中肝脏和/或肺转移是预后不良指标。骨转移而不合并其他转移的患者生存期较长，其次是骨转移合并肺转移者、合并淋巴结转移、骨转移合并多个脏器转移者及合并肝脏转移者。     

Analysis of gene expression involved in brain metastasis from breast cancer using cDNA microarray

BACKGROUND: Brain metastases occur in 15% to 30% of breast cancer patients, usually as a late event. The patterns of metastases to different organs are determined by the tumor cell phenotype and interactions between the tumor cells and the organ environment. METHODS: We investigated the gene expression profile occurring in brain metastases from a breast cancer cell line. We used cDNA microarrays to compare patterns of gene expression between the mouse breast cancer cell line Jyg MC (A) and a subline that often metastasis to brain, (B). RESULTS: By Microarray analysis about 350 of 21,000 genes were significantly up-regulated in Jyg MC (B). Many candidate genes that may be associated with the establishment of brain metastasis from breast cancer were included. Interestingly, we found that the expression of astrocyte derived cytokine receptors (IL-6 receptor, TGF-beta receptor and IGF receptor) were significantly increased in Jyg MC (B) cells. These results were confirmed by RT-PCR. CONCLUSIONS: These results suggest that cytokines produced by glial cells in vivo may contribute, in a paracrine manner, to the development of brain metastases from breast cancer cells.     

SRT联合拉帕替尼治疗HER2阳性乳腺癌脑转移疗效及预后分析

目的 探讨立体定向放射治疗(Stereotactic radiotherapy,SRT)联合拉帕替尼治疗HER2阳性乳腺癌脑转移的疗效及预后。方法 回顾性分析91例HER2阳性乳腺癌脑转移患者接受拉帕替尼靶向治疗的同时接受全脑放疗或SRT的情况,其中42例患者接受SRT的同时进行拉帕替尼联合卡培他滨治疗(SRT组),另外49例患者采用全脑放疗同时进行拉帕替尼联合卡培他滨治疗(全脑放疗组)。评价其疗效和毒性,定期随访,并行多因素Cox回归分析其预后相关因素。结果 放疗结束后1月SRT组脑部病灶客观缓解率为92.86%(39/42),全脑放疗组客观缓解率为77.55%(38/49),SRT组优于全脑放疗组(χ²=4.070,P=0.044)。SRT组和全脑组12个月受照射肿瘤病灶无进展生存率分别为95.20%及83.10%, SRT组优于全脑放疗组(χ²=10.851,P=0.001)。 SRT组无颅内转移生存率与全脑放疗组无统计学差异(P＞0.05)。SRT组和全脑放疗组1年生存率分别为85.70%和69.40%,2年生存率分别为66.70%和55.10%,两组中位生存期分别为31.56个月和25.00个月,SRT组优于全脑放疗组(P=0.002)。多因素Cox回归分析结果表明无颅外转移(HR=0.527,95% CI:0.290~0.957,P=0.035),颅内病灶≤3个(HR=2.457,95% CI:1.223~4.933,P=0.012),放疗方式SRT(HR=1.746,95% CI:1.055~2.888,P=0.030)是HER2阳性乳腺癌脑转移放疗预后的独立保护因素。结论 SRT联合拉帕替尼在局部控制率以及生存率上优于全脑放疗联合拉帕替尼。颅内病灶个数少、无颅外转移灶和放疗方式是HER2阳性乳腺癌脑转移治疗的良好预后因素。     

Clinical efficacy of bisphosphonate therapy for bone metastasis from breast cancer

Bisphosphonates inhibit osteoclastic bone resorption and are being used as treatment for bone metastases from breast cancer. Intravenous bisphosphonate therapy can significantly reduce skeletal related events (SREs) when administered concurrently with chemotherapy or endocrine therapy. In addition, intravenous bisphosphonate monotherapy is also able to alleviate cancer induced bone pain, and to improve bone metastases in some patients. Oral bisphosphonates are not routinely used for the treatment of bone metastases due to their low bioavailability. However, minodronate, a bisphosphonate 100-fold more potent than pamidronate, is now in phase II clinical studies in Japan, and may alter the role of oral bisphosphonates in the treatment of bone metastasis from breast cancer. The ASCO guidelines recommend that patients with osteolytic bone metastases be treated not with bisphosphonate monotherapy, but with concurrent bisphosphonate and systemic therapy. In addition, it is also recommended that current standards of care for cancer pain, analgesics and radiotherapy, should not be replaced with bisphosphonate therapy.     

乳腺癌转移抑制基因1抑制肿瘤转移的作用机制

乳腺癌转移抑制基因1 (BRMS1)在多种恶性肿瘤细胞中表达降低或缺失,具有明显降低癌细胞侵袭和转移的作用.BRMS1基因通过磷酸肌醇信号及核转录因子-κB(NF-κB)信号通路等调节基因转录和蛋白翻译,还可与mSin3-组蛋白去乙酰化酶(HDAC)复合体、雌激素受体等蛋白相互作用、修复细胞间隙通讯等途径抑制肿瘤细胞的侵袭及转移.BRMS1基因将可能成为有效抑制肿瘤转移基因治疗的新靶点.     

肿瘤标志物与乳腺癌骨转移的诊治

 骨转移是乳腺癌远处转移的最常见部位，及时和准确的诊断和治疗对提高患者生活质量、延长生存期具有重要意义。近年来，肿瘤标志物在乳腺癌骨转移中的作用日益受到重视。对部分肿瘤标志物在乳腺癌骨转移诊断、治疗以及疗效监测等方面研究进展进行了综述。     

Biological and clinical studies relevant to metastasis of breast cancer

The progression of neoplastic epithelial proliferation in the breast does not inevitably lead to an infiltrating carcinoma. The carcinoma-in-situ which do metastasize apparently produce cells whose first moves through tissue are facilitated by lysing inert intercellular material (types I and IV collagen). Metastasis, defined as the capability of tumor cells to disseminate to distant sites in the body and set up secondary neoplasms, is a propeny separate and additional to tumorigenicity or local invasiveness. The driving engine of the metastatic process is identified as regulatory genomic disturbances in the population of cells within the tumor. Success or failure of secondary tumor growth in distant sites depends upon the outcome of interaction with local microenvironmental factors and systemic endocrine and immunological conditions.     

Clinical features of surgical resection for pulmonary metastasis from breast cancer

Background and objectives

Metastatic breast cancer has been defined as a systemic disease. The discussion concerning the resection of lung metastases in patients with breast cancer is controversial. To confirm the role of resection of pulmonary metastases from breast cancer and to identify possible prognostic factors, we reviewed our institutional experience.

Methods

Between 1991 and 2007, 41 patients with pulmonary metastases from breast cancers underwent complete pulmonary resection. All patients had obtained or had obtainable locoregional control of their primary tumors. Various perioperative variables were investigated retrospectively to confirm the role of metastasectomy and to analyze prognostic factors for overall survival after metastasectomy.

Results

All patients were female with a median age of 55 years (range, 35–81 years). The overall survival rate after metastasectomy was 51% at 5 and 10 years. On multivariate analysis, fewer than four pulmonary metastases and a disease-free interval of more than 3 years were significantly favorable prognostic factors for overall survival (p = 0.023 and 0.024, respectively).

Conclusions

The current practice of pulmonary metastasectomy for breast cancers in our institution was well justified. Pulmonary metastasectomy in patients with previous breast cancer might be justified when fewer than four pulmonary metastases or a disease-free interval of more than 3 years.     

Brain metastasis from prostatic cancer

Four cases of prostatic carcinoma with metastasis to brain are described. Two of those cases are diagnosed antemortem. Our experience from postmortem case studies and review of the literature point to the fact that metastasis to brain from a prostatic cancer remains a rare occurrence.     

Implication of video assisted thoracoscopic surgery in the diagnosis of pulmonary metastasis of breast cancer

Purpose  To determine pulmonary metastasis, video assisted thoracoscopic surgery (VATS) was performed on the patients who had undergone breast cancer surgery. Patients and Methods p Nineteen patients with a history of breast cancer underwent VATS, because of subsequent abnormal pulmonary shadows on chest computed tomograms (CT). All patients were suspected to have pulmonary metastasis from breast cancer.   Results  The VATS procedure showed 10 (52%) patients to have pulmonary metastasis, but, 9 (48%) had primary lung cancers or benign lesions. In the patients of pulmonary metastasis, 7 had nodular lesions (5 had a single nodule and 2 had two nodules with a median diameter of 8.5 mm), and 3 patients had pleural dissemination. The follow-up period of the patients with pulmonary metastasis ranged from 3 to 28 months. Three patients died of brain metastasis and respiratory failure, 3 suffered recurrence and 4 were free from disease after VATS. Conclusion  VATS was useful for distinguishing small metastatic lesions from other diseases and a minimally invasive surgical approach in the follow-up of breast cancer patients suspected of pulmonary metastasis.     

Endobronchial metastasis of breast cancer 5 years after breast-conserving therapy

A 42-year-old woman, who had received right breast-conserving therapy 5 years previously, was admitted with hemoptysis. Chest X-rays showed a tumor shadow in the left pulmonary hilus with partial atelectasis in the left lower lobe. Bronchofiberscopic examination showed a polypoid tumor arising from the endobronchial wall, with bleeding and a white surface coat. Although, microscopically, the tumor resembled the breast cancer resected previously, as we could not rule out primary lung carcinoma, and as the tumor seemed to be localized, thoracotomy was performed. During posterolateral thoracotomy, however, pleural metastatic nodules were found; therefore, only sampling of these nodules and the administration of 50 mg of cisplatin (CDDP) into the thoracic cavity were performed. From a comparison of the histopathological features of the original tumor and the intrathoracic tumor, and from the hormone receptor positivity of the pleural metastasis, we diagnosed the intrathoracic tumor as being highly suspicious of metastasis from breast cancer. The measurement of hormone receptor was informative for the diagnosis of and for selecting a therapeutic strategy for the metastatic breast cancer. Received: August 17, 2000 / Accepted: January 12, 2001     

Radiotherapeutic management of brain metastases from breast cancer

We have reviewed the medical records of 28 breast cancer patients with brain metastases who were treated with radiotherapy at our clinic from 1980 through 1994 (4 patients, postoperatively; 24 patients, radiotherapy alone). Radiotherapy was delivered as whole brain irradiation using lateral opposed 10 MV X-rays. Ten patients received an additional boost to a reduced field. One patient was treated with localized stereotactic irradiation alone. The radiation dose for tumors ranged from 32 Gy to 60 Gy (mean, 49 Gy) in 2 or 3 Gy daily fractionated doses. The brain was the first site of metastatic involvement in only two patients. In the 26 evaluable patients, neurologic functional improvement was achieved in 24 patients (92%) with complete response (CR) in 1 2 patients (46%) and partial response (PR) in 1 2 patients (46%). The survival rates from the initial treatment were 39% at 5 years and 16% at 10 years (median survival time, 50 months), and those after treatment of brain metastases were 29% at one year and 18% at 2 years (median survival time, 6 months). Performance status tended to be associated with survival (p=0.10), and the presence of liver metastasis was the most important risk factor concerning survival (p=0.056). Two patients suffered severe chronic complications. One patient developed severe dementia after whole brain irradiation with a total dose of 45 Gy in 3 Gy daily fractionated dose, and another patient developed widespread brain necrosis after combined radiotherapy with intrathecal local infusion of methotrexate. Radiotherapeutic management is useful for breast cancer patients with brain metastasis, and long-term survival may also be possible even if patients have preexisting extracranial metastases, except for hepatic involvement. Radiation-related complications should therefore be avoided in these patients.     

Exosomes in development,metastasis and drug resistance of breast cancer

Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano‐sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life‐threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome‐delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti‐cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti‐cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system.     

超声判断乳腺癌患者腋淋巴结转移的多因素分析

目的 观察乳腺癌患者原发灶及腋下淋巴结（LN）的超声诊断图像和彩色Doppler特点,分析淋巴结转移（LNM）的相关因素,以获得超声诊断乳腺癌患者腋下LNM的较佳组合指标。方法 超声观察113例乳腺癌患者的原发灶和腋LN。观察原发灶的位置、最大径、数量、内部钙化灶边带回声、边界、肿瘤内部的血流丰富程度分级（0-Ⅲ级）、最高流速和阻力指数;观察患侧腋LN目最大径、纵横比、纵切面皮质厚度与淋巴门厚度比值（皮／门比）、皮质局部最大厚径、淋巴结的血流分布类型、最高流速和阻力指数。全部患者均进行乳房改良根治术,以腋LN清扫的病理结果作为金标准,对与LNM相关的影像及临床因素进行单因素及多因素分析（Logistic回归）,并利用受试者工作率性（ROC）曲线评价诊断指标。结果 113例乳腺癌患者的超声观察指标单因素分析结果显示,原发灶的最大径、多发或弥漫、血流丰富度,对腋LNM有影响,差异有统计学意义（P=0．029-0．005）腋LN的纵横比、皮／门比、皮质局部最大厚径、血流分布类型与腋LNM有关,差异有统计学意义（P=0．000）。将单因素分析有意义的指标进行多因素分析,与腋LNM有关的影响因素为：LN的皮／门比LN的纵横比以及原发灶的最大径,利用ROC曲线评价各单项指标及其不同组合指标的诊断价值结果显示,LN皮／门比＋LN纵横比＋原发灶最大径这一组合指标最优,其ROC曲线的线下面积最大,即灵敏度和特异度之和最大。结论 对乳腺癌患者进行腋LN超声扫查,综合考虑原发灶大小LN的纵横比、皮质厚度及其与淋巴门厚度的比例关系,将有助于提高超声诊断腋LNM的正确率,较为准确地判断腋LN的状态。     

Bone metabolic markers in bone metastasis of breast cancer

Background. The efficacy and cost-performance benefit of radionuclide bone scintigraphy in monitoring metastatic bone activity remain controversial. Bone metabolic markers are now expected to play a role in the diagnosis and follow-up of bone metastasis. Methods. We investigated several bone metabolic markers in patients with breast cancer. We measured three metabolic markers of bone resorption: pyridinoline cross-linked carboxy terminal telopeptide (ICTP), C-telopeptides of type I collagen (CTx), and the free form of deoxypyridinoline (fDPD), and four metabolic markers of bone formation: procollagen I carboxy terminal peptide (PICP), total alkaline phosphatase (Al-p), bone-specific alkaline phosphatase (BAl-p), and osteocalcin (BGP) in 210 patients without and 268 patients with bone metastasis. Patients without bone metastasis were analyzed in terms of menstruation status. Patients with bone metastasis were analyzed in terms of bone metastatic burden and tumor lesion "condition" (ie, determination by X-ray and/or computed tomography and bone scan findings of new lesion, progression of disease, no change, improvement, and complete remission, according to the criteria of the International Unite Against Cancer). Results. In patients without bone metastasis, ICTP did not change with menopause. All markers other than ICTP were significantly elevated with menopause. In patients with bone metastasis, all markers, except for BGP, were significantly elevated according to metastatic bone tumor burden. Among the seven markers, ICTP showed the best receiver operating characteristic curves. ICTP also showed the best correlation to bone metastatic burden among the markers by Spearman's rank correlation coefficient. In patients stratified by "condition", ICTP, CTx, fDPD, Al-p, and BAl-p showed significant elevation in patients with progression, new lesion, and no change, while PICP and BGP showed only minimal elevation in those patients. Conclusion. Bone metabolic markers, particularly ICTP, appear to be valuable for the diagnosis of bone metastasis from breast cancer. Received: April 22, 1999 / Accepted: July 15, 1999