骨转移癌分子靶向治疗进展

常见恶性肿瘤患者不但骨转移的发生率较高,而且骨相关事件（skeletal related events,SRE）也频繁出现,严重影响着患者的生活质量。双膦酸盐是肺癌骨转移全身治疗的基础用药,能将首次发生骨相关事件的中位时间平均延迟2～3个月,但患者的肾功能状况及不良反应限制了其在临床中的应用。随着骨转移癌机制研究的深入,越来越多的临床前或临床研究验证了靶向药物如地诺单抗等在延迟乳腺癌、前列腺癌、多发性骨髓瘤和其他实体肿瘤骨转移癌所致骨相关事件的发生方面优效于双膦酸盐。     

乳腺癌骨转移靶向性机制研究进展

骨骼是乳腺癌优先且最常见的转移部位之一。患者常先出现骨骼微转移（转移前龛影）,进而发展为明显的转移灶,这一过程有赖于骨微环境提供的生长支持和癌细胞对这一环境的适应能力。骨微环境可产生多种因子促进肿瘤细胞的生长和骨转移的进展,而癌细胞也经常模拟骨和骨髓环境的细胞行为和基因表达。对乳腺癌骨转移的特异性分子与机制的研究对乳腺癌晚期骨转移的治疗有重要意义。     

镇痛药联合双膦酸盐治疗恶性肿瘤骨转移的相关进展

骨转移是晚期恶性肿瘤最常见的并发症之一.最常见的发生骨转移的恶性肿瘤,主要包括肺癌、乳腺癌、前列腺癌、肾癌、胃肠道肿瘤等.晚期肿瘤一旦发生骨转移,会引起局部的骨质破坏,从而引起骨痛、病理性骨折、神经压迫、高钙血症等一系列骨相关事件(SREs),严重影响患者的生活质量,甚至导致患者脊髓压迫,引起截瘫.晚期恶性肿瘤骨转移的...     

乳腺癌骨转移机制研究进展

乳腺癌是一种容易发生骨转移的女性常见恶性肿瘤。乳腺癌细胞的特异性、骨微环境及两者间相互作用是形成骨转移的共同因素。乳腺癌细胞表达的趋化因子受体、整合素、溶骨因子和成骨因子等使肿瘤细胞易于扩散到骨,而骨微环境可以为肿瘤细胞的生长提供丰富的生长因子和细胞因子。一旦乳腺癌细胞侵入骨质,肿瘤细胞分泌的因子就会作用于骨的外在结构和内在结构（如造血干细胞、T细胞、血小板、内皮细胞等）,使骨质破坏且分泌相关因子反作用于癌细胞,从而引起转移的级联反应和恶性循环形成。     

双膦酸盐治疗乳腺癌骨转移患者的临床病理特征及预后分析*

目的：探讨乳腺癌骨转移患者的临床、病理、治疗及预后因素。方法：收集2005年1 月至2013年4 月天津医科大学肿瘤医院收治的183 例至少接受6 个月双膦酸盐治疗的乳腺癌骨转移患者的临床资料,根据双膦酸盐类型分为帕米膦酸二钠组、唑来膦酸组及帕米膦酸二钠序贯唑来膦酸组,探讨骨转移的特点、骨相关事件（skeletal-related events,SREs）、治疗及预后特征。结果：胸椎和肋骨为骨转移的常见转移部位,骨转移至发生首次SREs的中位时间为4.2 个月,51.9%（95/ 183）患者发生SREs,累计SREs事件数达167 次,其中110 次（65.9%）发生在骨转移后1 年内,SREs类型以骨放疗为主。患者在不同双膦酸盐药物组的SREs发生率差异无统计学意义（P > 0.05）。 183 例患者骨转移后的中位生存期为43.1 个月,激素受体状态、无病生存期、是否合并内脏转移及脊柱转移与否是乳腺癌骨转移患者的独立预后因素（P < 0.05）。 结论：胸椎和肋骨是乳腺癌骨转移的常见转移部位,SREs主要发生在骨转移后1 年内并以骨放疗为主。激素受体阴性、无病生存期短、合并内脏及脊柱转移是影响乳腺癌患者骨转移不良预后的独立因素。     

地诺单抗用于骨转移癌治疗的研究

癌症转移是致死的主要原因,骨是排第三的好发转移部位。OPG／RANKL—RANK骨调节轴是影响破骨细胞发育及功能的唯一途径。地诺单抗（denosumab）是全人源化结合RANKL的中和抗体,由FDA于2010年11月批准用于实体瘤骨转移的治疗。本文就地诺单抗用于骨转移癌治疗的机制及临床实验研究作一综述,为临床医生更合理的选择骨改构药物用于骨转移癌的治疗做指导。     

骨质疏松与乳腺癌骨转移

乳腺癌是女性最常见的恶性肿瘤之一。近年来,研究表明乳腺癌与骨病密切相关。乳腺癌发病率随着年龄增加迅速上升,45—50岁较多,绝经后发病率继续上升,同时,骨质疏松症也在绝经后高发。而且,乳腺癌患者易发生骨转移。乳腺癌骨转移以溶骨性损伤为主,已经有研究表明乳腺癌细胞可以抑制成骨细胞活性¨引,同时导致破骨细胞活性增加。骨质疏松的机制恰恰也是破骨活动大于成骨活动。那么骨质疏松与乳腺癌骨转移之间在骨髓微环境方面是不是存在着某种联系呢？笔者从骨髓微环境调控方面就骨质疏松与乳腺癌骨转移之间的关系作一综述。     

血清Tracp5b在乳腺癌骨转移诊断和治疗效果监测方面的临床价值

目的:探讨血清抗酒石酸酸性磷酸酶5b(tartrate-resistant acid phosphatase 5b,Tracp5b)在诊断乳腺癌骨转移以及评价乳腺癌骨转移治疗效果方面的价值.方法:采用酶联免疫吸附法(enzyme-linked immumosorbent assay,ELISA)检测30例无骨转移乳腺癌患者及22例乳腺癌骨转移患者的血清Tracp5b水平,并检测骨转移患者应用化疗或内分泌治疗同时加用双膦酸盐治疗4个月后血清Tracp5b水平,对检测结果的差异性进行比较.结果:相对于乳腺癌无骨转移组,骨转移组血清Tracp5b的水平明显升高,差异有统计学意义(P＜0.05);在化疗或内分泌治疗同时加用双膦酸盐治疗4个月后,骨转移组患者的血清Tracp5b水平明显下降,差异有统计学意义(P＜0.05).结论:血清Tracp5b在发生乳腺癌骨转移时明显升高,在治疗显效后显著下降,Tracp5b可作为诊断乳腺癌骨转移和评价乳腺癌骨转移治疗效果的血清学指标.     

乳腺癌骨转移过程中的分子机制

乳腺癌患者易发生骨转移。乳腺癌骨转移依赖多种细胞因子及蛋白的参与,是癌细胞与骨微环境相互作用的结果。骨转移患者常见骨痛、病理性骨折等骨相关事件(skeletal related event,SRE),严重影响患者生活质量及预后。了解乳腺癌骨转移的分子机制有助于对乳腺癌骨转移患者的诊断及治疗。作者就参与乳腺癌骨转移相关因子及分子机制进行了综述。     

双膦酸盐治疗恶性肿瘤骨转移新进展

恶性肿瘤骨转移可以引起多种骨并发症,包括病理性骨折、需要放射治疗的严重骨骼疼痛、脊髓压迫以及危及生命的恶性高钙血症（骨相关事件）。本文回顾了双膦酸盐在多种恶性肿瘤骨转移中的临床研究结果及安全性。结果表明,双膦酸盐在多种恶性肿瘤骨转移所引起的骨相关事件的治疗中意义明确,然而其不良反应及治疗也值得进一步研究。     

145例乳腺癌骨转移临床病理分析

目的：探讨乳腺癌骨转移的相关因素及处理对策。方法：本文对１９５４年１月～１９７７年１２月我院收治的２８０３例原发乳腺癌术后发生骨转移的１４５例患者临床资料进行回顾性分析。结果：乳腺癌术后骨转移发生率５．１％,骨转移部位分布较广泛,多数出现在脊柱,术后前５年发生率占７６．４％,腋淋巴结阳性患者较阴性患者较早发生转移。出现转移后经治疗患者较未治疗患者生存期有显著性差异。结论：乳腺癌术后骨转移出现时间与其分布有其规律,综合治疗后乳腺癌患者可延缓出现转移的时间。出现骨转移后,积极治疗,可达到延长生存期改善生存质量的目的。     

Effect of zoledronic acid on the doxycycline-induced decrease in tumour burden in a bone metastasis model of human breast cancer

Bone is one of the most frequent sites for metastasis in breast cancer patients often resulting in significant clinical morbidity and mortality. Bisphosphonates are currently the standard of care for breast cancer patients with bone metastasis. We have shown previously that doxycycline, a member of the tetracycline family of antibiotics, reduces total tumour burden in an experimental bone metastasis mouse model of human breast cancer. In this study, we combined doxycycline treatment together with zoledronic acid, the most potent bisphosphonate. Drug administration started 3 days before the injection of the MDA-MB-231 cells. When mice were administered zoledronic acid alone, the total tumour burden decreased by 43% compared to placebo treatment. Administration of a combination of zoledronic acid and doxycycline resulted in a 74% decrease in total tumour burden compared to untreated mice. In doxycycline- and zoledronate-treated mice bone formation was significantly enhanced as determined by increased numbers of osteoblasts, osteoid surface and volume, whereas a decrease in bone resorption was also observed. Doxycycline greatly reduced tumour burden and could also compensate for the increased bone resorption. The addition of zoledronate to the regimen further decreased tumour burden, caused an extensive decrease in bone-associated soft tissue tumour burden (93%), and sustained the bone volume, which could result in a smaller fracture risk. Treatment with zoledronic acid in combination with doxycycline may be very beneficial for breast cancer patients at risk for osteolytic bone metastasis.     

Increased Dickkopf-1 expression in breast cancer bone metastases

The aim of this study was to determine whether Dickkopf-1 (Dkk-1) expression in breast cancer was associated with bone metastases. We first analysed Dkk-1 expression by human breast cancer cell lines that induce osteolytic or osteoblastic lesions in animals. Dickkopf-1 levels were then measured in the bone marrow aspirates of hind limbs from eight NMRI mice inoculated with breast cancer cells that induced bone metastases and 11 age-matched non-inoculated control animals. Finally, Dkk-1 was measured in the serum of 17 women with breast cancer in complete remission, 19 women with breast cancer and bone metastases, 16 women with breast cancer and metastases at non-bone sites and 16 healthy women. Only breast cancer cells that induce osteolytic lesions in animals produced Dkk-1. There was a six-fold increase in Dkk-1 levels in the bone marrow from animals inoculated with MDA-B02 cells when compared with that of control non-inoculated animals (P=0.003). Median Dkk-1 levels in the serum of patients with breast cancer and bone metastases were significantly higher than levels of patients in complete remission (P=0.016), patients with breast cancer having metastases at non-bone sites (P<0.0001) and healthy women (P=0.047), although there was a large overlap in individual levels between the different groups. In conclusion, Dkk-1 is secreted by osteolytic human breast cancer cells lines and increased circulating levels are associated with the presence of bone metastases in patients with breast cancer. Measurements of circulating Dkk-1 levels may be useful for the clinical investigation of patients with breast cancer and bone metastases.     

A phase 2 trial exploring the effects of high‐dose (10,000 IU/day) vitamin D3 in breast cancer patients with bone metastases

BACKGROUND:

Vitamin D deficiency has potential roles in breast cancer etiology and progression. Vitamin D deficiency has also been associated with increased toxicity from bisphosphonate therapy. The optimal dose of vitamin D supplementation is unknown, but daily sunlight exposure can generate the equivalent of a 10,000‐IU oral dose of vitamin D₃. This study therefore aimed to assess the effect of this dose of vitamin D₃ in patients with bone metastases from breast cancer.

METHODS:

Patients with bone metastases treated with bisphosphonates were enrolled into this single‐arm phase 2 study. Patients received 10,000 IU of vitamin D₃ and 1000 mg of calcium supplementation each day for 4 months. The effect of this treatment on palliation, bone resorption markers, calcium metabolism, and toxicity were evaluated at baseline and monthly thereafter.

RESULTS:

Forty patients were enrolled. No significant changes in bone resorption markers were seen. Despite no change in global pain scales, there was a significant reduction in the number of sites of pain. A small but statistically significant increase in serum calcium was seen, as was a significant decrease in serum parathyroid hormone. Treatment unmasked 2 cases of primary hyperparathyroidism, but was not associated with direct toxicity.

CONCLUSIONS:

Daily doses of 10,000 IU vitamin D₃ for 4 months appear safe in patients without comorbid conditions causing hypersensitivity to vitamin D. Treatment reduced inappropriately elevated parathyroid hormone levels, presumably caused by long‐term bisphosphonate use. There did not appear to be a significant palliative benefit nor any significant change in bone resorption. Cancer 2010. © 2010 American Cancer Society.     

Sclerostin blockade promotes bone metastases of Wnt-responsive breast cancer cells

The secreted protein sclerostin is primarily produced by osteocytes and suppresses osteoblast differentiation and function by inhibiting the canonical Wnt signaling pathway. Genetic and pharmacological inhibition of sclerostin has been shown to increase bone formation and an anti-sclerostin antibody has been clinically approved for the treatment of osteoporosis. Canonical Wnt signaling is also involved in the progression of several types of cancers including breast cancer. Here, we studied the effects of sclerostin inhibition on the development of bone metastases of breast cancer using mouse models. TOPFLASH assay and real-time PCR analysis of AXIN2, a target of canonical Wnt signaling, revealed that, among four cell lines tested, MDA-MB-231 human breast cancer cells responded highly to the canonical Wnt ligand Wnt3a, whereas other cell lines exhibited marginal responses. Consistent with these results, treatment with an anti-sclerostin antibody significantly increased the bone metastases of MDA-MB-231 but not those of other breast cancer cells. Immunohistochemical studies demonstrated that an anti-sclerostin antibody induced intracellular accumulation of β-catenin in bone-colonized MDA-MB-231 cells. Suspension culture assays showed that Wnt3a accelerated the tumorsphere formation of MDA-MB-231 cells, whereas monolayer cell proliferation and migration were not affected. Furthermore, the numbers of osteoclasts and their precursor cells in bone metastases of MDA-MB-231 were significantly increased in mice treated with an anti-sclerostin antibody. These results collectively suggest that sclerostin blockade activates canonical Wnt signaling in ligand-responsive breast cancer cells metastasized to bone, thereby increasing bone metastases, likely to have been mediated at least in part by enhancing stem cell-like properties of cancer cells and osteoclastogenesis.     

乳腺癌骨转移差异基因的生物信息学分析

目的:在生物信息学数据库中挖掘乳腺癌骨转移的差异表达基因(differentially expressed genes,DEGs),探讨DEGs的细胞定位、分子功能及其潜在的分子机制,寻找乳腺癌骨转移的潜在治疗靶点和预后预测基因.方法:通过在基因表达数据库(GEO)中筛选乳腺癌骨转移相关芯片数据,使用RStudio对芯...     

乳腺癌骨转移放射治疗临床分析(附32例报告)

目的　探讨乳腺癌骨转移的临床特点及放射治疗效果。方法　回顾分析 3 2例乳腺癌骨转移资料 ,转移灶单发 10例 ,多发 2 2例 ,共 68处病灶 ,其中脊柱占 2 7 9% ,骨盆占 2 2 1% ,肋骨占 13 2 %、股骨占10 3 % ,其余依次为肱骨、颅骨、肩胛骨、胫骨、锁骨。 2 2例行放射治疗 ,放疗前中度疼痛 17例 ,重度疼痛 5例 ,6例功能障碍。结果　 2 2例治疗后完全缓解 16例 ,部分缓解 6例 ,卡氏评分有所改善 ,功能障碍均恢复 ,治疗后的 1、2、3年生存率分别为 5 9 1%、2 2 7%、4 5 % ,中位生存期 15月 ,而未治组 10例的中位生存期为 4 5月 (P <0 0 1)。结论　乳腺癌骨转移行放射治疗 ,止痛作用快而持久 ,提高了患者的生存质量 ,是一种简单有效的治疗方法     

Significant addition to treatment options for bone metastasis in prostate cancer

Pathologic fractures, spinal compression, and pain take a great toll on the healthcare costs and well-being of men with prostate cancer metastatic to the bone. For almost 10 years, the only drug proven to prevent these skeletal-related adverse events was the bisphosphonate zoledronic acid. In a study published by Fizazi et al. in The Lancet, the monoclonal antibody to RANKL, denosumab, is shown to be superior to zoledronic acid in the prevention of these events. The only notable adverse event more frequent in either arm was increased hypocalcemia in the denosumab arm. There was a greater frequency of osteonecrosis of the jaw in the denosumab treatment group that did not reach statistical significance, but is of great concern. While further analysis is needed to determine the value of denosumab in preventing adverse events and improving quality of life, this new therapy is a significant addition to the treatment of men living with metastatic prostate cancer.     

Pain outcomes in patients with advanced breast cancer and bone metastases

BACKGROUND:

In this study, the authors evaluated the effect of denosumab versus zoledronic acid (ZA) on pain in patients with advanced breast cancer and bone metastases.

METHODS:

The prevention of pain, reduction in pain interference with daily life activities, and the proportion of patients requiring strong opioid analgesics were assessed in a randomized, double‐blind, double‐dummy phase 3 study comparing denosumab with ZA for preventing skeletal‐related events in 2046 patients who had breast cancer and bone metastases. Patients completed the Brief Pain Inventory‐Short Form at baseline and monthly thereafter.

RESULTS:

Fewer patients who received denosumab reported a clinically meaningful worsening of pain severity (≥2‐point increase) from baseline compared with patients who received ZA, and a trend was observed toward delayed time to pain worsening with denosumab versus ZA (denosumab, 8.5 months; ZA, 7.4 months; P = .08). In patients who had no/mild pain at baseline, a 4‐month delay in progression to moderate/severe pain was observed with denosumab compared with ZA (9.7 months vs 5.8 months; P = .002). Denosumab delayed the time to increased pain interference by approximately 1 month compared with ZA (denosumab, 16.0 months; ZA, 14.9 months; P = .09). The time to pain improvement (P = .72) and the time to decreased pain interference (P = .92) were similar between the groups. Fewer denosumab‐treated patients reported increased analgesic use from no/low use at baseline to strong opioid use.

CONCLUSIONS:

Denosumab demonstrated improved pain prevention and comparable pain palliation compared with ZA. In addition, fewer denosumab‐treated patients shifted to strong opioid analgesic use. Cancer 2013. © 2012 American Cancer Society.