抑制破骨细胞或可改善乳腺癌生存
对于激素受体阳性早期乳腺癌绝经后女性，芳香酶抑制剂辅助治疗是术后标准治疗药物，但是骨质疏松和骨折的风险增加。2015年，英国《柳叶刀》正刊发表奥地利乳腺结直肠癌研究协作组（ABCSG）的随机双盲安慰剂对照三期研究（ABCSG-18）初步结果表明，破骨细胞核转录因子κB（NFκB）受体激活蛋白配体（RANKL）抑制剂狄诺塞麦（又称地诺单抗、地舒单抗、迪诺舒单抗、狄诺塞单抗）可以显著减少芳香酶抑制剂辅助治疗期间的临床骨折，不过当时尚未报告无病生存结果。
2019年2月19日，英国《柳叶刀》肿瘤学分册在线发表奥地利维也纳医科大学、因斯布鲁克医科大学、帕拉塞尔斯医科大学、萨尔茨堡癌症研究所、林茨慈善姊妹医院、格兰河畔圣法伊特乳腺中心、格拉茨医科大学、弗克拉布鲁克医院、沃尔夫斯堡医院、维也纳席津医院、ABCSG的狄诺塞麦辅助治疗激素受体阳性早期乳腺癌绝经后女性患者随机双盲安慰剂对照三期研究（ABCSG-18）无病生存结果。
该多中心前瞻双盲安慰剂随机对照三期研究于2006年12月18日～2013年7月22日从奥地利和瑞典的58个研究中心入组激素受体阳性早期非转移性乳腺癌已经完成初始辅助治疗（手术、放疗或化疗或联合）并且正在接受芳香酶抑制剂辅助治疗的绝经后患者3420例，通过区组分层随机化（区组大小2×4，按既往芳香酶抑制剂用药、入组时全腰椎骨矿物质密度评分、研究中心类型进行分层）按1∶1分组，芳香酶抑制剂治疗期间每6个月皮下注射狄诺塞麦60毫克（1711例）或匹配安慰剂（1709例）。主要终点为随机化至首次临床骨折的时间。次要终点为无病生存（定义为意向治疗人群随机化至首次局部或远处转移或对侧乳腺癌或其他癌或任何原因所致死亡的时间）。该研究由美国安进提供资助，欧盟临床研究登记编号：2005-005275-15，美国临床研究登记编号：NCT00556374，目前正在进行长期随访。
结果，中位随访73个月（四分位：58～95个月）后，狄诺塞麦组与安慰剂组相比：
无病生存事件发生风险较低：14.0%比16.8%（风险比：0.82，95%置信区间：0.69～0.98；多因素比例风险回归模型分析，P=0.0260；描述性统计学分析，未控制多重性）
随访五年时无病生存率较高：89.2%比87.3%（95%置信区间：87.6～90.8、85.7～89.0）
随访八年时无病生存率较高：80.6%比77.5%（95%置信区间：78.1～83.1、74.8～80.2）
所有不良事件：1367例比1339例
严重不良事件：521例比515例
严重骨关节炎：62例比58例（3.6%比3.4%）
严重半月板损伤：23例比24例（1.3%比1.4%）
严重白内障：16例比28例（0.9%比1.7%）
治疗相关死亡：1例（<0.1%）发生于狄诺塞麦组（由于肺炎、脓毒性肾衰竭、心脏失代偿）
因此，该研究结果表明，对于接受芳香酶抑制剂治疗的激素受体阳性早期乳腺癌绝经后患者，狄诺塞麦可以提供安全有效的辅助治疗。
对此，美国乔治城大学癌症中心发表同期评论：狄诺塞麦辅助治疗激素受体阳性乳腺癌绝经后患者。
相关阅读
Lancet Oncol. 2019 Feb 19. [Epub ahead of print]
Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial.
Michael Gnant, Georg Pfeiler, Günther G Steger, Daniel Egle, Richard Greil, Florian Fitzal, Viktor Wette, Marija Balic, Ferdinand Haslbauer, Elisabeth Melbinger-Zeinitzer, Vesna Bjelic-Radisic, Raimund Jakesz, Christian Marth, Paul Sevelda, Brigitte Mlineritsch, Ruth Exner, Christian Fesl, Sophie Frantal, Christian F Singeron; Austrian Breast and Colorectal Cancer Study Group.
Medical University of Vienna, Vienna, Austria; Medical University Innsbruck, Innsbruck, Austria; Paracelsus Medical University Salzburg, Salzburg Cancer Research Institute, Salzburg, Austria; Hospital of Sisters of Mercy Linz, Linz, Austria; Sankt Veit an der Glan, Austria; Medical University Graz, Graz, Austria; Hospital Voecklabruck, Voecklabruck, Austria; Hospital Wolfsberg, Wolfsberg, Austria; Hospital Hietzing, Vienna, Austria; Austrian Breast & Colorectal Cancer Study Group, Vienna, Austria.
BACKGROUND: In postmenopausal women with hormone receptor-positive, early-stage breast cancer, treatment with adjuvant aromatase inhibitors is the standard of care, but it increases risk for osteoporosis and fractures. Results from the ABCSG-18 trial showed that use of denosumab as an adjuvant to aromatase inhibitor therapy significantly reduced clinical fractures. Disease-free survival outcomes from ABCSG-18 have not yet been reported.
METHODS: Postmenopausal patients with early, hormone receptor-positive, non-metastatic adenocarcinoma of the breast, who had completed their initial adjuvant treatment pathway (surgery, radiotherapy, or chemotherapy, or a combination) and were receiving adjuvant aromatase inhibitors, were enrolled at 58 trial centres in Austria and Sweden into this prospective, double-blind, placebo-controlled, phase 3 trial. With permuted block randomisation (block sizes 2 and 4, stratified by previous aromatase inhibitor use, total lumbar spine bone mineral density score at baseline, and type of centre), patients were assigned (1:1) to receive subcutaneous denosumab (60 mg) or matching placebo every 6 months during aromatase inhibitor therapy. The primary endpoint (previously reported) was the time to first clinical fracture after randomisation. The secondary endpoint reported here is disease-free survival (defined as time from randomisation to first evidence of local or distant metastasis, contralateral breast cancer, secondary carcinoma, or death from any cause) in the intention-to-treat population. This study is registered with EudraCT (number 2005-005275-15) and ClinicalTrials.gov (number NCT00556374), and is ongoing for long-term follow-up.
FINDINGS: Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled and randomly assigned; 1711 to the denosumab group and 1709 to the placebo group (with five others withdrawing consent). After a median follow-up of 73 months (IQR 58-95), 240 (14.0%) patients in the denosumab and 287 (16.8%) in the placebo group had disease-free survival events. Disease-free survival was significantly improved in the denosumab group versus the placebo group (hazard ratio 0.82, 95% CI 0.69-0.98, Cox p=0.0260; descriptive analysis, without controlling for multiplicity). In the denosumab group, disease-free survival was 89.2% (95% CI 87.6-90.8) at 5 years and 80.6% (78.1-83.1) at 8 years of follow-up, compared with 87.3% (85.7-89.0) at 5 years and 77.5% (74.8-80.2) and 8 years in the placebo group. No independently adjudicated cases of osteonecrosis of the jaw or confirmed atypical femoral fractures were recorded. The total number of adverse events was similar in the denosumab group (1367 [including 521 serious] adverse events) and the placebo group (1339 [515 serious]). The most common serious adverse events were osteoarthritis (62 [3.6%] of 1709 in the denosumab group vs 58 [3.4%] of 1690 in the placebo group), meniscus injury (23 [1.3%] vs 24 [1.4%]), and cataract (16 [0.9%] vs 28 [1.7%]). One (<0.1%) treatment-related death (due to pneumonia, septic kidney failure, and cardiac decompensation) occurred in the denosumab group.
INTERPRETATION: Denosumab constitutes an effective and safe adjuvant treatment for patients with postmenopausal hormone receptor-positive early breast cancer receiving aromatase inhibitor therapy.
FUNDING: Amgen.
DOI: 10.1016/S1470-2045(18)30862-3
Lancet Oncol. 2019 Feb 19. [Epub ahead of print]
Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer.
Marc Lippman.
Georgetown University, Washington DC, USA.
DOI: 10.1016/S1470-2045(18)30913-6
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