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     

Oral squamous cell carcinoma cells modulate osteoclast function by RANKL-dependent and -independent mechanisms

Oral squamous cell carcinoma (SCC) cells frequently invade mandibular bone, and bone invasion is a common clinical problem. Recent studies have revealed that bone resorption by osteoclasts is an important step in the progress of bone invasion by oral SCCs. We previously reported that oral SCC cells induce osteoclastogenesis by suppressing osteoprotegerin (OPG) in host cells. In the present study, we examined the effects of oral SCCs on osteoclast function. Both BHY cells, a human oral SCC cell line, and its conditioned medium (BHY-CM) stimulated osteoclast survival by suppressing Bim, a pro-apoptotic protein, depending on extracellular signal-regulated kinase (ERK) and multinucleation. Adding BHY cells but not BHY-CM induced pit-forming activity by osteoclasts and adding OPG abrogated the activity. Thus, oral SCC cells regulate not only osteoclastogenesis but also its function.     

破骨细胞体外分离培养及其骨吸收活动的观察

目的 建立大鼠破骨细胞体外分离培养方法，为体外研究破骨细胞骨吸收机理奠定基础。方法 采用出生24h内的Wistar大鼠，从其四肢长骨中分离出破骨细胞，与盖玻片、骨磨片共同培养，观察破骨细胞的形态结构及体外骨吸收活性。结果 相差显微镜及光镜观察到分离的细胞含多个核，能够移动，胞浆有伪足样突起，这些细胞用目前公认的鉴定破骨细胞的标志—抗酒石酸酸性磷酸酶染色呈阳性反应，扫描电镜观察到这些细胞能在骨片上形成典型的骨吸收陷窝。结论 用此方法分离培养的细胞为具有骨吸收活性的破骨细胞。     

骨唾液酸蛋白与乳腺癌骨转移相关性的研究进展

多项研究已证实骨唾液酸蛋白(BSP)与乳腺癌骨转移具有相关性,而目前研究的热点是BSP诱导乳腺癌骨转移的具体作用机制及参与BSP基因表达调控的因子种类,这将为今后研究治疗骨转移相应靶向药物提供直接理论依据。同时将BSP与其他骨代谢指标如OPN、TRACP5b、NTx、PTHrP等联合检测可提高乳癌骨转移高风险人群筛选的精确性,并且这些因子可以作为乳腺癌的独立预后因素。     

Molecular interactions between breast cancer cells and the bone microenvironment drive skeletal metastases

Breast cancer cells preferentially spread to bone. Bone metastases are currently incurable and therefore better treatments need to be developed. Metastasis is an inefficient, multi-step process. Specific aspects of both breast cancer cells and the bone microenvironment contribute to the development of bone metastases. Breast cancers express chemokine receptors, integrins, cadherins, and bone-resorbing and bone-forming factors that contribute to the successful and preferential spread of tumor to bone. Bone is rich in growth factors and cell types that make it a hospitable environment for breast cancer growth. Once breast cancer cells enter the bone, a highly complex vicious cycle develops, in which breast cancer cells secrete factors that act on bone cells and other cells within the bone (stem cells, T cells, platelets, adipocytes, fibroblasts, and endothelial cells), causing them to secrete factors that act on adjacent cancer cells. The steps in the metastatic cascade and the vicious cycle within bone offer unique targets for adjuvant treatments to treat and cure bone metastases.     

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。     

乳腺癌骨髓转移特点及治疗方法探讨

目的探讨乳腺癌患者骨髓转移临床表现的特殊性、转移规律及治疗策略。方法回顾性分析62例女性乳腺癌骨髓转移患者的临床及随访资料,包括乳腺癌骨髓转移发生时间、激素受体状况等及不同治疗策略对预后的影响。24例联合化疗,25例单药化疗,13例未接受化疗。生存率用Kaplan—Meier方法计算,用Log—rank方法进行生存曲线比较。结果62例患者中位年龄39岁（30～71岁）,中位病程21个月（1～49个月）。雌激素受体（ER）和（或）孕激素受体（PR）阳性患者30例（48．4％）,阴性19例（30．6％）。发热14例（22．6％）和（或）血象的一系或三系降低34例（62．9％）是乳腺癌骨髓转移的常见表现。联合化疗和单药化疗中位生存期分别为10个月和16个月（QPH=7．38,P=0．0335）,未接受化疗者中位生存期仅1个月。骨髓转移发生偏晚,一般有多处转移尤其是骨转移的背景。结论骨髓穿刺有利于早期发现骨髓转移;骨髓转移晚期体质较弱,单药化疗可能是有效的治疗策略之一,与联合化疗组的患者相比具有生存优势。     

乳腺癌骨转移药物治疗的现状和进展

乳腺癌骨转移的发生率较高,应根据具体病情制订个体化的综合治疗方案,以减少或避免骨相关事件、延长患者的生存期、改善生活质量。其主要治疗手段包括抗肿瘤治疗、骨改良药物治疗、手术、放疗、止痛和支持治疗等。本文就乳腺癌骨转移的药物治疗作一综述。     

New treatment strategy for bone metastases from breast cancer

Breast cancer patients frequently develop bone metastasis. Parathyroid hormone-related protein, an osteoclast activating factor, might be necessary for tumorto erode bone and grow at skeletal site. Bisphosphonates have an affinity for bone and are potent inhibitors of osteoclastic bone resorption. In light of this,53 patients with bone metastasis from breast cancer were treated with chemoendocrine(mainly high-dose medroxyprogesterone acetate as the endocrine therapy) therapy + bisphosphonate (pamidronate, Aredia (R)). During the previous 6 years (median 27 months), 53 breast cancer patients with bone metastasis were treated with pamidronate + chemoendocrine therapy. The regimen consisting of pamidronate + chemoendocrine agent was administered to 27 patients as a post relapse first-line regimen and to the remaining 26 cases, which failed first- or second-line treatment as a second or third line regimen. As a result of the combination therapy, sclerotic changes were observed in the osteolytic lesions in 31 of the 53 patients (59%). The effect on the osteolytic lesions did not correlate with the duration of disease free interval, estrogen receptor (ER) status, presence/absence of previous therapy or number of " hot spot(s) ] on bone scintigraphy. Lessening of pain from the bone metastasis was achieved in 83% of the patients after 3 months of pamidronate administration. Pamidronate + chemoendocrine therapy seems highly promising.     

乳腺癌骨转移的临床病程

目的 探讨乳腺癌骨转移的临床病程和规律。方法 回顾性分析345例乳腺癌患骨转移好发部位、病灶特点、发生时间、激素受体分布情况及预后等规律。结果 乳腺癌骨转移好发部位依次是腰椎、胸椎、骨盆、肋骨和股骨；几乎全部是溶骨性病灶；中位发生骨转移时间是术后33个月；88．7％患就诊时有相应症状；骨转移患中激素受体阳性比例较高；首发骨转移的预后介于软组织和内脏之间；延缓骨转移与内脏转移的间隔时间有利于生存期的改善。结论 对乳腺癌骨转移规律的认识有助于临床诊断和治疗。     

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.     

骨改良药物在乳腺癌骨转移治疗中的应用进展

骨改良药物包括在临床上应用的双膦酸盐及2010年FDA批准上市的新药地诺单抗,是目前治疗恶性肿瘤骨转移、高钙血症及骨质疏松症的主要药物。该类药物在临床上应用广泛,种类较多,近年来在药物的应用时机、用法及毒副反应方面有一定进展和争议。本文就骨改良药物在乳腺癌骨转移治疗中的临床应用进行探讨。     

乳腺癌脑转移的信号通路和分子机制的研究进展

乳腺癌是女性发病率较高的癌症之一,经常发生转移的部位是肺、骨、肝脏和中枢神经系统,其中中枢神经系统转移的发生率大约为15%.目前已知乳腺癌发生脑转移的信号通路可能有Wnt和Notch通路、EGFR和PTEN通路,与乳腺癌脑转移相关的受体可能有VEGF和STAT3、微管蛋白和TOP2A、BNC1、GALNT9、CCDC8、HER2、HER3、MMP、FBPS、肌氨酸等.本文对可能导致乳腺癌脑转移的信号通路和分子机制进行综述,希望为乳腺癌脑转移的靶向治疗提供新的思路.     

乳腺癌术后骨转移回顾性分析

目的 分析乳腺癌术后骨转移的临床特征.方法 对407例原发乳腺癌术后发生骨转移的情况进行回顾性分析.结果 50例患者术后发生骨转移.这50例患者中,术后30个月内发生骨转移的病例占54.0%,5年内骨转移发生率为76.0%,发病年龄≤50岁的占60%.病理类型以浸润性导管癌为主的占82.0%.骨转移部位最多发生在脊柱,以胸椎、腰椎为主.其次是骨盆、肋骨、胸骨、颅骨、下肢骨.乳腺癌术后是否出现骨转移在年龄、腋淋巴结转移、孕激素受体(PR)、癌基因CerbB2表达方面无统计学差异(P＞0.05).但在肿瘤病理类型及雌激素受体(ER)表达方面的差异有统计学意义(P＜0.05).结论 乳腺癌术后30个月内为骨转移高发期,骨转移部位以脊柱及骨盆、肋骨、胸骨多见.乳腺癌术后发生骨转移与年龄、腋淋巴结转移、PR、CerbB2表达方面无关,与肿瘤病理类型、ER有关.     

Rapamycin inhibits osteolysis and improves survival in a model of experimental bone metastases

Breast cancer metastasis to bone results in pain, pathological fractures and hypercalcemia. Activation of osteoclasts is critical for the formation of osteolytic lesions by metastasizing tumors. Although the potent drugs, zoledronic acid and Denosumab were introduced, the presence of resistant or intolerant cases necessitated the continued search of osteoclast-targeting treatments. Rapamycin acts through the mTOR pathway, which is important for osteoclast formation. Mouse mammary carcinoma 4T1 cells were injected into the tibia of balb/c mice. Rapamycin treatment significantly decreased the osteoclast population and osteolysis associated with experimental metastases. Our data indicate the benefit of rapamycin in treating metastases-associated osteolytic disease.     

The bisphosphonate incadronate for bone metastases of breast cancer

Background. Bisphosphonates are bone resorption inhibitors which are effective in the treatment of diseases of increased bone turnover, such as hypercalcemia of malignancy and osteolytic bone metastasis. The safety and efficacy of incadronate, a third-generation bisphosphonate, were evaluated in breast cancer patients with bone metastases. Methods. Fifteen breast cancer patients with bone metastasis were enrolled. Incadronate's safety, its effectiveness in relieving bone pain, and its effects on bone metabolic markers and a tumor marker were assessed in 8 patients treated with a 10-mg IV infusion once a week for 5 weeks (10 mg × 5), 3 patients treated with a single 20-mg IV infusion (20 mg × 1), and 4 patients treated with a 20-mg IV infusion once a week for 5 weeks (20 mg × 5). Pain assessment was performed only in the patients with the repeated infusion regimens. Results. All incadronate treatment regimens were administered without any serious adverse reactions. Minimal fever was noted in 6 patients, but it subsided without any treatment. Incadronate relieved bone pain in 10 of the 12 patients who received repeated infusions. Levels of bone resorption markers dropped transiently, but the decreases in the individual markers of bone resorption varied. Levels of bone formation markers did not change significantly. Levels of a tumor marker specific to breast cancer, carbohydrate antigen (CA)15-3 decreased in patients whose metastases were limited to bone. Conclusion. The third-generation bisphosphonate, incadronate, was administered safely at dosages of up to 20 mg once a week for 5 weeks. Incadronate reduced bone pain, bone resorption marker levels, and CA15-3 tumor marker levels in breast cancer patients with bone metastases. Received: November 9, 1999 / Accepted: March 6, 2000     

乳腺癌转移相关机制

乳腺癌在女性中有着高发病率和死亡率.虽然目前针对乳腺癌有了多种治疗方法,但是乳腺癌的转移仍是一个棘手的医学问题.目前,乳腺癌相关转移机制主要涉及上皮-间质转化、细胞外基质的溶解、循环肿瘤细胞或播散性肿瘤细胞、肿瘤血管和肿瘤微环境等.乳腺癌相关转移机制的明确对预测和治疗乳腺癌转移有一定的指导意义.     

Diagnostic value of magnetic resonance imaging and scintigraphy in patients with metastatic breast cancer of the axial skeleton: a comparative study

Purpose The goal of this study was to compare the sensitivity of MRI and scintigraphy for detecting metastatic bone disease involving the axial skeleton. Patients and Methods A total of 59 patients (58 women and 1 man, age range 28–83 years, mean age 53.0 years) with histopathologically proven breast cancer during a 15-month period (between April 2003 and January 2004) were included in the study. All the patients underwent scintigraphy and MRI examinations for staging, follow-up, or evaluation of bone pain. Results MR imaging revealed 59 metastases in 59 patients (sensitivity, 95%; specificity, 100%; positive predictive value, 100%). Four lesions detected by MRI were classified as of uncertain origin (grade 2) and 36 lesions were regarded as definitely benign (grade 1). Scintigraphy revealed 44 metastases in 59 patients (sensitivity, 70%; specificity, 94%; positive predictive value, 95%). A total of 29 lesions were considered as of uncertain origin (grade 2), and 26 lesions were regarded as definitely benign (grade 1). About five lesions were graded as grade 2 in scintigraphy, while MRI graded them as degeneration or benign compression (Grade 1). For 11 lesions the same grade was regarded in both MRI and scintigraphy. Two lesions graded as grade 3, and eleven lesions graded as grade 2 in scintigraphy demonstrated no pathological signal intensity in MRI. In total, 18 lesions with no activity in scintigraphy were graded as grade 3 lesions in MRI. Conclusion MRI is more sensitive than scintigraphy in the detection of bone metastases. MRI appears to be able to screen patients more effectively than scintigraphy if the spine and pelvis are included because metastases merely outside the axial skeleton are rare.     

Molecular pathogenesis of bone metastases in breast cancer: Proven and emerging therapeutic targets

Metastatic occurrence is the principal cause of death in breast cancer patients. The high osteotropism makes breast cancer the most common primary tumor type associated with metastatic bone disease. The peculiar clinical aspects associated with metastases limited to the skeletal system suggest considering these cases as a distinctive subset of metastatic patients with a better prognosis. Because bone is frequently the first metastatic site in disease relapse, it is feasible that the next improvement in therapeutic options for bone metastatic disease could be associated with an improvement of survival expectation and quality of life in breast cancer patients. Study of the molecular basis of bone remodeling and breast cancer osteotropism has allowed identification of several therapeutic candidates involved in formation and progression of bone metastases. These targets are frequently the determinants of positive feedback between the tumor and bone cells whose clinical outcome is osteolytic lesions. In this review, we discuss the physiopathologic features underlying targeted therapeutic strategies aimed at interfering with the aberrant bone remodeling associated with breast cancer metastases.