乳腺癌骨转移机制与靶向治疗进展

乳腺癌骨转移是晚期乳腺癌常见的症状,乳腺癌细胞通过局部浸润、渗入血管和或淋巴管、随循环系统转移到骨、移出血管和或淋巴管、在骨定居并增殖引起溶骨性骨损伤。乳腺癌骨转移的发生发展取决于乳腺癌细胞与骨局部微环境之间相互作用,最后形成骨的结构破坏及功能受损。本文主要从分子水平阐述乳腺癌骨转移机制,并且综述针对乳腺癌骨转移关键靶点的抗骨转移药物的临床应用。     

乳腺癌骨转移疼痛的综合治疗

目的　探讨缓解乳腺癌骨转移疼痛 ,恢复患者活动能力的方法。方法　 31例乳腺癌骨转移患者采用以CMFP或CAFP方案化疗为主 ,辅以放射性同位素或双磷酸盐类药物综合治疗 ,观察治疗后疼痛缓解、活动能力恢复及骨外转移灶的变化情况。结果　全组骨痛缓解率为 87.1 % (2 7/ 31 ) ,功能活动恢复 85 .7% (6/ 7) ,骨外转移灶的有效率为 67.9% (1 9/ 2 8)。结论　以化疗为主的综合治疗 ,不仅能较好地控制骨外转移灶的发展 ,而且能显著地缓解骨痛 ,恢复患者的活动能力     

A phase II trial of the vitamin D analogue Seocalcitol (EB1089) in patients with inoperable pancreatic cancer

Inoperable cancer of the exocrine pancreas responds poorly to most conventional anti-cancer agents, and new agents are required to palliate this disease. Seocalcitol (EB1089), a vitamin D analogue, can inhibit growth, induce differentiation and induce apoptosis of cancer cell lines in vitro and can also inhibit growth of pancreatic cancer xenografts in vivo. Thirty-six patients with advanced pancreatic cancer received once daily oral treatment with seocalcitol with dose escalation every 2 weeks until hypercalcaemia occurred, following which patients continued with maintenance therapy. The most frequent toxicity was the anticipated dose-dependent hypercalcaemia, with most patients tolerating a dose of 10-15 microg per day in chronic administration. Fourteen patients completed at least 8 weeks of treatment and were evaluable for efficacy, whereas 22 patients were withdrawn prior to completing 8 weeks' treatment and in 20 of these patients withdrawal was due to clinical deterioration as a result of disease progression. No objective responses were observed, with five of 14 patients having stable disease in whom the duration of stable disease was 82-532 days (median=168 days). The time to treatment failure (n=36) ranged from 22 to 847 days, and with a median survival of approximately 100 days. Seocalcitol is well tolerated in pancreatic cancer but has no objective anti-tumour activity in advanced disease. Further studies are necessary to determine if this agent has any cytostatic activity in this malignancy in minimal disease states.     

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。     

Intravenous ibandronate does not affect time to renal function deterioration in patients with skeletal metastases from breast cancer: phase III trial results

As patients with metastatic bone disease typically receive long-term treatment with bisphosphonates, and often antineoplastic compounds, drug-related safety is of considerable importance. Clinical trial data for intravenous (i.v.) ibandronate suggest that its nephrotoxic potential is comparable with placebo. We conducted a post hoc Kaplan-Meier analysis of time to serum creatinine increase with i.v. ibandronate throughout 2 years of treatment. After 96 weeks, 12% of patients in the placebo group and 6% in the ibandronate 6 mg group (ns, P = 0.22) had defined serum creatinine increases. After 12 treatment months (48 weeks), 4% of patients receiving placebo and 2% of patients receiving ibandronate 6 mg showed increased serum creatinine. These results suggest that there is no clinically relevant change in serum creatinine levels with i.v. ibandronate 6 mg infused every 3-4 weeks for 2 years. Comparative trials to examine the renal safety of ibandronate and other i.v. bisphosphonates are warranted.     

Oral paricalcitol (19-nor-1,25-dihydroxyvitamin D2) in women receiving chemotherapy for metastatic breast cancer: A feasibility trial

The vitamin D hormone, [1,25(OH)₂D, calcitriol], inhibits proliferation and angiogenesis in breast cancer but its therapeutic use is limited by hypercalcemia. Synthetic analogs of 1,25(OH)₂D that are less calcemic, such as paricalcitol (19-nor-1,25-Dihydroxyvitamin D₂), are used to treat hyperparathyroidism associated with chronic kidney disease. We sought to determine the safety and feasibility of taking oral paricalcitol with taxane-based chemotherapy in women with metastatic breast cancer (MBC). Oral paricalcitol was considered safe if it did not result in excessive toxicity, defined as grade 3 or higher serum calcium levels. It was considered feasible if the majority of women could take eight weeks of continuous therapy in the first three months. Serum calcium was monitored weekly and the paricalcitol dose was adjusted based on its calcemic effect. Intact parathyroid hormone (iPTH) was monitored as a marker of paricalcitol activity. Twenty-four women with MBC were enrolled. Twenty women (83%) received eight weeks of continuous therapy. Paricalcitol was well-tolerated with no instances of hypercalcemia grade 2 or greater. Fourteen women (54%) were able to escalate the dose. The dose range of paricalcitol in the first 3 mo was 2–7 ug/day. Serum iPTH levels at baseline were significantly higher in women with serum 25-Hydroxyvitamin D (25-OHD) levels less than 30 ng/ml (96.4 ± 40.9 pg/ml) vs. 46.2 ± 20.3 pg/ml (p = 0 0.001) (iPTH reference 12–72 pg/ml). We conclude that paricalcitol is safe and feasible in women with MBC who are receiving chemotherapy.     

Vitamin D‐effective solar UV radiation,dietary vitamin D and breast cancer risk

Vitamin D is well known for its important role in calcium and phosphor homeostasis. Recent research suggests that vitamin D also prevent some type of cancers. We studied solar vitamin D effective UV radiation (VD dose), dietary vitamin D, sun‐seeking holidays, use of solarium, frequency of sunburn and breast cancer risk in a large population‐based cohort study. A total of 41,811 women from the prospective Norwegian Women and Cancer Study, aged 40–70 years at baseline, were followed from 1997/1998 to 2007. Dietary vitamin D intake was calculated at baseline. Information on historical VD dose was used as a proxy for cutaneously obtained vitamin D status. Cox proportional hazards model was used. We adjusted for age, height, BMI, baseline menopausal status, use of hormone replacement therapy, use of oral contraception, alcohol, mother's history of breast cancer, mammography and parity. During 8.5 years of follow‐up, 948 new cases of breast cancer were registered using data from the Norwegian Cancer Registry. We found no significant associations between VD dose, or vitamin D intake, or sun‐seeking holidays, or use of solarium, or frequency of sunburn, and breast cancer risk. Relative risks (95% confidence intervals) for highest versus lowest category were 1.17 (0.95–1.44), 0.95 (0.75–1.21), 1.07 (0.87–1.32), 0.93 (0.76–1.14) and 1.10 (0.89–1.36), respectively. Our results do not support an association between vitamin D status, and breast cancer risk.     

Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: a randomised, crossover study of community vs hospital bisphosphonate administration

Patients with bone metastases from breast cancer often experience substantial skeletal complications -- including debilitating bone pain -- which negatively affect quality of life. Zoledronic acid (4 mg) has been demonstrated to reduce significantly the risk of skeletal complications in these patients and is administered via a short, 15-min infusion every 3 weeks, allowing the possibility for home administration. This study compared the efficacy and safety of zoledronic acid administered in the community setting vs the hospital setting in breast cancer patients with > or =1 bone metastasis receiving hormonal therapy. After a lead-in phase of three infusions of 4 mg zoledronic acid in the hospital setting, 101 patients were randomized to receive three open-label infusions in the community or hospital setting, followed by three infusions in the opposite venue (a total of nine infusions). The Brief Pain Inventory (BPI) and the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire 30 (EORTC QLQ-C30) were used to assess potential benefits of zoledronic acid therapy. At study end, analysis of the BPI showed significant reductions in worst pain (P=0.008) and average pain in the last 7 days (P=0.039), and interference with general activity (P=0.012). In each case, there were significantly greater improvements in pain scores after treatment in the community setting compared with the hospital crossover setting for worst pain (P=0.021), average pain (P=0.003), and interference with general activity (P=0.001). Overall global health status showed a significant median improvement of 8.3% (P=0.013) at study end. Physical, emotional, and social functioning also showed significant overall improvement (P=0.013, 0.005, and 0.043, respectively). Furthermore, physical, role, and social functioning showed significantly greater improvements after treatment in the community setting compared with the hospital crossover setting (P=0.018, 0.001, and 0.026, respectively). There was no difference between hospital and community administration in renal or other toxicity, with zoledronic acid being well tolerated in both treatment settings. These data confirm the safety and quality-of-life benefits of zoledronic acid in breast cancer patients with bone metastases, particularly when administered in the community setting.     

Simulated bone metastases: A case study of two patients with breast cancer

Two case studies are used to discuss topical issues current in follow-up management of patients with early stage breast cancer. These issues include the role of screening and diagnostic bone scintigraphy and patient self-advocacy in clinical management.     

来曲唑治疗绝经后乳腺癌骨转移

目的 研究来曲唑解救治疗绝经后乳腺癌骨转移的疗效和副作用。方法：36例绝经后乳腺癌骨转移患者给予来曲唑2．5mg，每日1次，口服至少2月。结果：36例可评价疗效和毒副作用患者中，完全缓解(CR)2例，部分缓解(PR)8例，总有效率占27．7％。稳定(SD)20例占55．5％，其中病情稳定≥6月者ll例，临床获益患者(CR PR SD)≥6月21例占58．3％，病情进展6例占16．6％。治疗中无严重不良反应。结论：来曲唑治疗绝经后乳腺癌骨转移有一定疗效，药物不良反应轻，患者容易耐受。     

OPG‐Fc inhibits ovariectomy‐induced growth of disseminated breast cancer cells in bone

Dormant disseminated tumour cells can be detected in the bone marrow of breast cancer patients several years after resection of the primary tumour. The majority of these patients will remain asymptomatic, however, ～15% will go on to develop overt bone metastases and this condition is currently incurable. The reason why these dormant cells are stimulated to proliferate and form bone tumours in some patients and not others remains to be elucidated. We have recently shown that in an in vivo model, increasing bone turnover by ovariectomy stimulated proliferation of disseminated tumour cells, resulting in formation of bone metastasis. We now show for the first time that osteoclast mediated mechanisms induce growth of tumours from dormant MDA‐MB‐231 cells disseminated in the bone. We also show that disruption of RANK–RANKL interactions following administration of OPG‐Fc inhibits growth of these dormant tumour cells in vivo. Our data support early intervention with anti‐resorptive therapy in a low‐oestrogen environment to prevent development of bone metastases.     

Increased expression and serum levels of the stromal cell‐secreted protein periostin in breast cancer bone metastases

Periostin, a matricellular protein, is overexpressed in the stroma of several cancers. The aim of our study was to investigate more specifically whether periostin expression is associated with bone metastases from breast cancer and to determine its source in the affected bone. Nude mice were inoculated with human MDA‐B02 breast cancer cells. Bone metastases‐bearing mice were treated with zoledronic acid—an antiresorptive drug—or vehicle. Bone metastases were examined for tumor‐ and stroma‐derived periostin expression by quantitative polymerase chain reaction with human‐ and mouse‐specific primers and immunohistochemistry. Serum periostin and conventional bone turnover markers were also measured. MDA‐B02 cells did not express periostin both in vitro and in vivo. However, mouse‐derived periostin was markedly overexpressed (eightfold) in metastatic legs compared to noninoculated mice. Serum periostin levels were also markedly increased in metastatic mice and correlated with in situ expression levels. Immunostaining showed that periostin derived from the environing stromal cells of bone metastasis. Bone turnover blockade by zoledronic acid markedly decreased osteolytic lesions but only slightly modulated serum periostin levels. Bone metastases from breast cancer induce overexpression of periostin by surrounding stromal cells. Periostin could be a biochemical marker of the early stromal response associated to breast cancer bone metastasis formation.     

Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases.

BACKGROUND: This phase III study compared the efficacy of the new potent bisphosphonate, ibandronate, with placebo as intravenous (i.v.) therapy in metastatic bone disease due to breast cancer. PATIENTS AND METHODS: A total of 466 patients were randomised to receive placebo (n = 158), or 2 mg (n = 154) or 6 mg (n = 154) ibandronate every 3-4 weeks for up to 2 years. The primary efficacy parameter was the number of 12-week periods with new bone complications, expressed as the skeletal morbidity period rate (SMPR). Bone pain, analgesic use and safety were evaluated monthly. Results SMPR was lower in both ibandronate groups compared with the placebo group; the difference was statistically significant for the ibandronate 6 mg group (P = 0.004 versus placebo). Consistent with the SMPR, ibandronate 6 mg significantly reduced the number of new bone events (by 38%) and increased time to first new bone event. Patients on ibandronate 6 mg also experienced decreased bone pain scores and analgesic use. Treatment with ibandronate was well tolerated. CONCLUSIONS: These results indicate that 6 mg i.v. ibandronate is effective and safe in the treatment of bone metastases from breast cancer.     

Changes of bone turnover markers and serum PTH after night or morning administration of zoledronic acid in breast cancer patients with bone metastases

Persistent circadian rhythm of bone turnover in bone metastatic breast cancer suggests greater skeletal retention of bisphosphonates if administered in the night. We assessed differential effects of night vs morning administration of zoledronic acid (ZA) on bone turnover. Forty-four breast cancer patients with bone metastases were randomised to receive intravenous ZA (4 mg) at 1100 or 2300 hours every 28 days for four times. Urinary concentration N-telopeptide of type-I collagen (NTX) and deoxypyridinolines, and serum C-telopeptide of type-I collagen (CTX), bone alkaline phosphatase (ALP), osteocalcin and Parathyroid hormone (PTH) was measured in the morning at baseline and after 4, 7, 14, 28, 56 and 84 days. Urinary ZA concentration was also measured. Zoledronic acid caused significant decreases of NTX and CTX (P<0.001), without any difference in percent changes between night and morning arms. Bone ALP and osteocalcin were also significantly affected by ZA (P=0.001), without any difference between arms. Parathyroid hormone significantly increased in both the arms; PTH increase was lower in the night arm (P=0.001). From the second administration onwards, urinary ZA level was significantly higher in the night arm (P<0.01). Administration of ZA at two opposite phases of the circadian cycle causes similar changes of bone-turnover marker levels, but has differential effects on the level of serum PTH.     

Site-specific human breast cancer (MDA-MB-231) metastases in nude rats: model characterisation and in vivo effects of ibandronate on tumour growth

Animal models are important tools to study the development of bone metastases and to evaluate strategies for their prevention and treatment. We here describe a new model in which tumour inoculation is achieved by injection of cancer cells into the femoral artery. This approach results in the development of multiple osteolytic lesions in the distal femora and proximal tibiae within 18 days after inoculation, with a success rate of 95-100% and no additional comorbidity. In untreated animals, osteolyses expanded continuously at a growth rate of 4.7-8.2 mm(2)/4 days, causing extensive destruction of resident bone structures by the tumour, significant loss of tibial bone density and a transient rise in urinary bone resorption markers. Continuous daily treatment with ibandronate (10 microg/kg) inhibited further growth of fully established metastases and reduced the mean osteolytic growth rate to 0.03 mm(2)/4 days. In lesions <6 mm bisphosphonate treatment resulted in a negative growth rate (-0.33 to -0.81 mm(2)/4 days). When ibandronate was started 3 days prior to tumour cell inoculation, the development of osteolytic lesions was substantially reduced (take rate only 17%) and bone density and structure were mostly preserved. We conclude that the intra-arterial approach used in this new model of metastatic bone disease results in site-specific osteolytic lesions with high take rates, steady tumour growth and no additional morbidity. While serial bone marker assessments did not prove useful to monitor osteolytic growth, our studies provide in vivo evidence that ibandronate treatment induces tumour remission by reversal of tumour growth.     

Disruption of the blood brain barrier by brain metastases of triple‐negative and basal‐type breast cancer but not HER2/neu‐positive breast cancer

BACKGROUND:

Generally, the blood‐brain barrier (BBB) of brain metastasis was thought to be disrupted.

METHODS:

We retrospectively performed immunohistochemical staining for glucose transporter 1 (GLUT1) and breast cancer resistance protein (BCRP) to evaluate the status of the BBB in resected brain metastases. Associations between expression of GLUT1 and/or BCRP and the immunohistochemical profiles of breast cancers, such as the statuses of hormone receptors, human epidermal growth factor receptor 2 (HER2/neu), and a basal‐type marker (cytokeratin 5/6, HER1), were also analyzed.

RESULTS:

The study included 29 breast cancer patients with brain metastasis who had undergone brain tumor resections. Among the 29 patients, there was no expression of GLUT1 and BCRP in the intratumor microvessels of 9 (32%) and 11 (38%) patients, respectively. There was no expression of both GLUT1 and BCRP in 8 patients (28%). The expression of GLUT1 was significantly associated with that of BCRP (P < .001). A positive correlation was observed between the expression of GLUT1 and/or BCRP and brain metastases of HER2/neu‐positive breast cancer (P = .012), while a negative correlation was observed between the expression of GLUT1 and/or BCRP and brain metastases of triple negative or basal‐type breast cancer (P = .014 and P = .003 for triple negative and basal‐type, respectively).

CONCLUSIONS:

Brain metastases of triple negative or basal‐type breast cancers may often disrupt the BBB, whereas brain metastases of HER2/neu‐positive breast cancer tend to preserve the BBB. Cancer 2010. © 2010 American Cancer Society.     

A phase 2 trial of whole-brain radiotherapy combined with intravenous chemotherapy in patients with brain metastases from breast cancer

BACKGROUND

A study was conducted to determine the efficacy, tolerability, and safety of concurrent cisplatin and vinorelbine chemotherapy and radiotherapy in patients with previously untreated brain metastases from breast cancer.

METHODS

Twenty‐five patients with untreated brain metastases from breast cancer were treated with cisplatin (at a dose of 20 mg/m²/day, Days 1‐5) and vinorelbine (6‐mg/m² bolus on Day 1 and 6 mg/m²/day continuous infusion on Days 1‐5) chemotherapy combined with concurrent 30‐gray fractionated external‐beam radiotherapy. Chemotherapy was given at 3‐week intervals for a total of 4 cycles. Primary endpoint was the rate of radiologic response of brain metastases.

RESULTS

Complete response in the brain was observed in 3 patients, and partial response was noted in 16 patients, yielding a 76% response rate in the brain. The overall systemic response rate was 44%. Progression‐free and overall survival were 3.7 months and 6.5 months, respectively. Overall toxicity was acceptable; nonhematologic grade 3‐4 events were noted in 5 (20%) patients, and there were no toxic deaths.

CONCLUSIONS

Concurrent chemoradiation with cisplatin and vinorelbine for brain metastases from breast cancer appears to be active and well tolerated. Cancer 2008. © 2008 American Cancer Society.     

Comparative effects of 1,25(OH)2D3 and EB1089 on cell cycle kinetics and apoptosis in MCF-7 breast cancer cells

1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], the active metabolite of vitamin D, inhibits breast cancer cell growth both in vivo and in vitro. In addition to its anti-proliferative effects, 1,25(OH)₂D₃ induces morphological and biochemical markers of apoptosis in MCF-7 cells. In the studies reported here, we compared the effects of 1,25(OH)₂D₃ and EB1089, a low calcemic vitamin D analog, on cell cycle kinetics and apoptosis in MCF-7 cells. Both vitamin D compounds reduced viable MCF-7 cell number in a time and dose dependent manner, with EB1089 approximately 50 fold more potent than 1,25(OH)₂D₃. Flow cytometric analysis indicated that both agents induced cell cycle arrest in G₀/G₁ which was associated with accumulation of the hypophosphorylated form of the retinoblastoma (Rb) protein. MCF-7 cells treated with either 1,25(OH)₂D₃ or EB1089 for 48 h exhibited characteristics of apoptosis, including cytoplasmic condensation, pyknotic nuclei, condensed chromatin and DNA fragmentation. Cells treated with either agent exhibited up regulation of proteins associated with mammary gland regression (clusterin and cathepsin B) and down regulation of the anti-apoptotic protein bcl-2. These studies demonstrate that, despite its lower calcemic activity in vivo, the vitamin D analog EB1089 induces effects that are indistinguishable from those of 1,25(OH)₂D₃ on cell number, cell cycle and indices of apoptosis in MCF-7 cells in vitro. In addition, since both agents rapidly down regulate estrogen receptor, disruption of estrogen dependent signalling may play a role in the induction of apoptosis by vitamin D compounds in MCF-7 cells.