骨恶性肿瘤RANKL表达分析及地舒单抗疗效观察  

The expression of RANKL in malignant bone tumor and the therapeutic outcomes of Denosumab

作　　者：王君[1] 鲍其远 彭程 温竣翔 沈宇辉[1] 张伟滨[1] 杨孝清 WANG Jun;BAO Qi-yuan;PENG Cheng;WEN Jun-xiang;SHEN Yu-hui;ZHANG Wei-bin;YANG Xiao-qing(Department of Orthopedics,Ruijin Hospital,Shanghai Jiaotong University School of Medicine.Shanghai,200025,China)

机构地区：[1]上海交通大学医学院附属瑞金医院骨科,上海市伤骨科研究所,200025 [2]上海交通大学医学院普胸外科,200025 [3]武汉市第三医院骨科,湖北430074

出　　处：《中国骨与关节杂志》2023年第5期337-344,共8页Chinese Journal of Bone and Joint

摘　　要：目的 观察核因子-κB受体活化因子配体(RANKL)在骨原发恶性肿瘤原发灶、转移灶中表达情况及其作为治疗靶点的潜在价值。方法 回顾分析2018年1月至2021年12月,在我院接受手术切除的骨原发恶性肿瘤肺转移标本31例,原发病灶标本8例;分析病灶内RANKL表达情况及其与年龄、性别、既往治疗线数、既往是否接受放射治疗、ECOG体能状态评分、肿瘤受累部位、病灶数量、病理类型等因素的相关性,同时随访接受RANKL抑制剂地舒单抗治疗的疾病无进展生存时间(progression-free survival rate,PFS)。结果 本研究纳入的39例患者标本,包括31例肺转移标本,8例原位肿瘤标本,男女比为27∶12,病理类型包括骨肉瘤34例,尤文肉瘤3例,骨未分化肉瘤2例。RANKL在正常肺和正常骨组织中不表达,在骨肿瘤原发病灶内呈较高表达,相较而言,RANKL在骨肿瘤肺转移标本中呈现总体低表达,少部分高表达趋势。肿瘤内RANKL表达水平与患者靶向治疗耐药、肿瘤相关巨噬细胞浸润及M2型巨噬细胞数量呈显著相关。通过随访14例骨肿瘤肺转移接受RANKL抑制剂治疗患者发现,其疗效在总人群中疗效有限(中位PFS仅2.8个月),而其中抗血管靶向药物耐药及病灶RANKL高表达的患者对于RANKL抑制剂治疗敏感度相对更佳。结论 本研究提示RANKL在骨肿瘤肺转移标本中呈现总体低表达,少部分高表达趋势。基于患者靶向治疗耐药情况及肿瘤RANKL表达水平进行个体化筛选,可能是进展期骨原发恶性肿瘤应用RANKL抑制剂的潜在治疗策略。Objective To examine the expression of receptor activator of nuclear factor kappa-B ligand(RANKL)in the primary and metastatic site of malignant bone tumor,and the therapeutic potential of RANKL.Methods We retrospectively included surgical samples of primary bone malignancy(n=8)and metastatic bone tumor(n=31).The tumoral expression of RANKL was correlated with the clinicopathological characteristics such as age,gender,prior lines of therapy,history of radiotherapy,ECOG performance status,tumor site,tumor number,histology type,etc.The progression-free survival(PFS)of patients who received RANKL inhibitor Denosumab was also followed up.Results Among the 31 metastatic and 8 primary tumor specimens,there were 27 males and 12 females with 34 osteosarcoma,3 Ewing sarcoma and 2 undifferentiated polymorphic sarcoma of bone.There were no expressions of RANKL in normal lung and bone,and high expressions of RANKL in primary site of the tumor.However,we found a generally low but heterogeneous expression of RANKL in lung metastatic lesions,with a minority even demonstrating a high expression of RANKL.The RANKL expression was observed to be correlated with resistance of anti-angiogenics,the infiltration of tumor associated macrophages(TAMs)and M2-subytpe of TAMs.Of the 14 patients with lung metastasis receiving Denosumab,there was a limited efficacy with a median PFS of 2.8 months.However,patients with resistance to anti-angiogenics or high tumoral expression of RANKL demonstrated a relative longer sensitivity of Denosumab.Conclusions Our study demonstrates an overall low but high expression of RANKL in a minority of lung metastatic samples of malignant bone tumor.An individual-based selection of RANKL blockade remains a potential strategy for advanced bone sarcoma.

关 键 词：骨肿瘤 肿瘤转移 分子靶向治疗 RANKL配体 生物标志物药理学 肺 

分 类 号：R738.1[医药卫生—肿瘤]