双磷酸盐乳腺癌中的应用研究进展

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1、双膦酸盐在乳腺癌中的应用及研究进展 双膦酸盐在乳腺癌骨转移中的应用 双膦酸盐在乳腺癌治疗相关骨丢失的研究进展 双磷酸盐在乳腺癌探索领域正在进行中的临床双膦酸盐在乳腺癌骨转移中的应用骨转移是常见疾病全球5年的 患病人数 1000 1肿瘤患者 骨转移发生率 2中位 生存时间 月2-5疾病1. Ferlay J, et al. IARC GLOBOCAN 2002. Cancer Incidence, Mortality, and Prevalence Worldwide. 2. Coleman RE. Cancer Treat Rev. 2001;27:165-176. 3. Coleman RE

2、. Cancer. 1997;80(suppl):1588-1594. 4. Zekri J, et al. Int J Oncol. 2001;19:379-382. 5. Hussain M, et al. J Clin Oncol. 2001;19:2527-2533.骨髓瘤 18370 - 956 - 54 乳腺癌4,40665 - 7519 - 25 前列腺癌2,36965 - 7512 - 53 肺癌 1,36230 - 406 - 7黑色素瘤 64314 - 456膀胱癌 1,1104015肾癌 58620 - 2512约70%的乳腺癌患者发生骨转移 4050%的患者第1个复发部

3、位 症状：骨痛、高钙血症、骨折仅20%发生骨转移的乳腺癌患者存 活5年乳腺癌骨转移骨转移及骨相关事件可带来严重的后果骨转移如不经治疗，SRE将十分常见SRE = Skeletal-related event; NSCLC = Non-small cell lung cancer. *PLACEBO ARM FROM ZOLEDRONIC ACID AND PAMIDRONATE TRIALS; ALL PATIENTS RECEIVED STANDARD ANTINEOPLASTIC THERAPIES.1. Kohno N, et al. J Clin Oncol. 2005;23:3314

4、-3321; 2. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882; 3. Berenson JR, et al. J Clin Oncol. 1998;16:593-602; 4. Rosen LS, et al. Cancer. 2004;100:2613-2621.Placebo arm*50%49%51% 46%010203040506070Breastcancer1 Prostatecancer2Multiplemyeloma3NSCLC and OST 4Patients with an SRE, %Data are from

5、placebo-control arms of bisphosphonate trials. 1. Lipton A, et al. Cancer. 2000;88:1082-1090; 2. Rosen LS, et al. Cancer. 2004;100:2613-2621; 3. Berenson JR, et al. J Clin Oncol. 1998;16:593-602; 4. Saad F, et al. J Natl Cancer Inst. 2004;96:879-882.2.712.203.701.470.01.02.03.04.0Mean SREs/yearBreas

6、t cancer1Lung cancer and other solid tumors2Multiple myeloma3Prostate cancer4Patients with cancer乳腺癌患者每年可能发生多次骨相关事件乳腺癌中骨相关事件的发生率Lipton A, et al. Cancer, 2000;88:1082-1090; *总SREs中不包含高钙血症乳腺癌骨相关事件（SREs）发生率病理性骨折可降低生存 病理性骨折与死亡风险增加显著相关1,2 乳腺癌 1.52 (1.28, 1.81) P 1 or between 1 and 2 )Z-FAST: 唑来膦酸早期治疗 可增加

7、腰椎和髋关节BMD （36个月结果）SEM = Standard error of the mean; BMD = Bone mineral density; ZOL = Zoledronic acid. *P values correspond to intergroup comparisons. Adapted from Brufsky A, et al. Presented at: 29th Annual SABCS; December 14-17, 2006; San Antonio, TX. Abstract 5060. Adapted from Brufsky A, et al.

8、Presented at: 30th Annual SABCS; December 13-16, 2007; San Antonio, TX.Month 24Lumbar spineTotal hipMean (SEM) % change BMD P -1BMD T-score between -1 and -2.5BMD T-score 65 yearsLow BMI ( 6 monthsSmoking (current or history of)T-score 2.0, No risk factors Monitor risk status and BMD every 1 to 2 ye

9、ars*Zoledronic acid (4 mg / 6 months) calcium and vitamin D supplementsMonitor BMD every 2 yearsCalcium and vitamin D supplements* 5% drop in BMD should trigger zoledronic acid treatment (4 mg / 6 months). Use lowest T-score from 3 sites.Hadji P, et al. Presented at: SABCS 2007. Abstract 504. Data f

10、or oral bisphosphonates are emerging Evidence from 4 clinical trials indicate that zoledronic acid prevents AI-associated bone loss开始芳香化酶抑制剂治疗的乳腺癌妇女的推荐双磷酸盐在乳腺癌探索领域正在进行的临床研究骨标志物在乳腺癌骨转移领域临床研究进展多数肿瘤骨转移病人基线NTX 升高NTX levels (nmol/mmol creatinine): Low .2; E-E = Patients whose NTX levels remained elevated

11、 at 3 months. Lipton A, et al. Presented at ESMO 2006. Abstract 870P.First SREBreast cancer0Death490.5050.4730.821Risk reduction, %53.002P value.00248.0020.51.01.52.0Increased risk versus E-EDecreased risk versus E-E1st Fracture/Bone surgeryBone lesion progression 0.517NS唑来膦酸可延长NTX正常化乳腺癌患者生存E-NE-E10

12、08060402003691215182124Proportion deceased, % patientsTime on study, months (starting at month 3)NTX = N-telopeptide of type I collagen; E-E = Patients whose NTX levels remained elevated at 3 months; E-N = Patients whose NTX levels normalized at 3 months from elevated baseline levels. Lipton A, et a

13、l. Presented at ESMO 2006. Abstract 870P.Breast cancerP = .0017唑来膦酸治疗后NTX正常化组可获与基线NTX正常组相似生存NTX = N-telopeptide of type I collagen; E-E = Persistently elevated NTX; E-N = Elevated baseline NTX that normalized at 3 months; N-N = Normal NTX at baseline and 3 months. Lipton A, et al. Presented at SABCS

14、 2005. Abstract 3015.60801004020003691215182124N-N (132 at risk, 49 events)E-N (160 at risk, 79 events)E-E (36 at risk, 27 events)Time since randomization, monthsPatients who died, %小结 唑来膦酸治疗3个月使大多数NTX升高的乳腺癌 患者NTX水平下降至正常，同时在这些患者中 ： 显著降低首次SRE的发生风险 显著降低死亡风险 下一步应进行前瞻性、随机临床试验以进一步 证实上述结果NTX = N-telopepti

15、de of type I collagen; BC = Breast cancer; HRPC = Hormone-refractory prostate cancer; NSCLC = Non-small cell lung cancer; OST = Other solid tumors. 双磷酸盐在乳腺癌预防骨转移领域正在进行的临床研究唑来膦酸预防乳腺癌骨转移：AZURE试验主要终点: 无病生存期 次要重点: 无骨转移生存期, SREs, 总生存, 副反应, 预测性的生物标志物 第一次中期分析时间：2008Standard TherapyStandard TherapyZoledroni

16、c acid 4 mg6 doses (q 3-4 wk) 8 doses (q 3 months) 5 doses (q 6 months)3,360 patientsBC stage II/III Stratification: N+/N- T Stage ER Status Chemotherapy type Pre-/ Postmenopausal StatinsRFollow-up without treatment: 5 years for recurrence and survivalTreatment duration 5 yearsPI: Rob ColemanSREs = Skeletal-related events; BC = Breast cancer; ER = Estrogen receptor.Accrual completed February 2006唑来