早期乳腺癌女性患者的骨健康管理中国专家共识（2022年版）

doi:10.19401/j.cnki.1007-3639.2022.03.011

摘要/Abstract

摘要：

早期乳腺癌女性患者的骨健康管理包括骨丢失的管理和骨转移的预防。随着早期乳腺癌患者生存期不断延长,这些患者的骨健康问题受到广泛关注,但目前临床上尚无系统的管理方案及诊疗措施。因此,中国抗癌协会乳腺癌专业委员会和长江学术带乳腺联盟组织相关专家,基于国内外指南及循证医学证据,深入探讨并制定了《早期乳腺癌女性患者的骨健康管理中国专家共识（2022年版）》,希望通过本共识规范早期乳腺癌患者的骨健康管理。

关键词: 乳腺癌, 骨健康, 肿瘤治疗引起的骨丢失, 骨转移

Abstract:

The management of bone health in female patients with early breast cancer includes managing bone loss and preventing bone metastasis. As the overall survival of patients with early breast cancer continues to increase, bone health is getting extensive attention. However, there is no specific consensus in China on the methods and strategies of management and treatment. Based on the guideline and the substantial evidence based medicine (EBM), the Society of Breast Cancer of China Anti-Cancer Association and Breast Cancer Study Group Along Yangtze River thoroughly discussed and formulated the Chinese expert consensus recommendations for management of bone health in female patients with early breast cancer (2022 edition), in order to further standardize the management of patient’s bone health.

Key words: Breast cancer, Bone health, Cancer treatment-induced bone loss, Bone metastasis

中图分类号:

R737.9

中国抗癌协会乳腺癌专业委员会, 长江学术带乳腺联盟. 早期乳腺癌女性患者的骨健康管理中国专家共识（2022年版）[J]. 中国癌症杂志, 2022, 32(3): 274-286.

The Society of Breast Cancer of China Anti-Cancer Association, Breast Cancer Study Group Along Yangtze River. Chinese expert consensus recommendations for management of bone health in female patients with early breast cancer (2022 edition)[J]. China Oncology, 2022, 32(3): 274-286.

图/表 5

图1

表1

表2

骨改良药物对乳腺癌患者BMD的影响"

研究名称	研究类型	入组人群	治疗方案	骨改良药物干预时机	治疗时间/年	结论
ABCSG-12研究^[31,32]	随机、开放Ⅲ期临床试验	1 800例绝经前HR⁺早期乳腺癌患者	内分泌治疗+唑来膦酸（4 mg/6个月） vs 内分泌治疗	内分泌治疗的同时立即接受唑来膦酸治疗	3	① 内分泌治疗（OFS+AI/TAM）会引起严重的骨丢失（-13.6%,平均差为-0.141 g/cm,95% CI：-0.179~-0.102 vs -9.0%,平均差为-0.95 g/cm,95% CI：-0.134~-0.570,P<0.000 1）,且OFS+AI治疗引起的骨丢失更严重;② 唑来膦酸联合内分泌治疗（OFS+TAM/AI）可有效防止内分泌治疗带来的骨丢失（+0.4%,平均差为0.004 g/ cm,95% CI：-0.024~0.032）,并且治疗结束后2年对患者的BMD仍有改善（4.0%,平均差为0.039 g/cm²,95% CI：0.005~0.075,P=0.02）
HOBOE研究^[18]	多中心、随机、对照Ⅲ期临床试验	483例HR⁺早期乳腺癌患者	绝经前：OFS + TAM vs OFS+AI vs OFS+AI+唑来膦酸（4 mg/6个月）;绝经后：TAM vs AI vs AI +唑来膦酸（4 mg/6个月）	内分泌治疗的同时立即接受唑来膦酸治疗	5	① 联合唑来膦酸组（AI+唑来膦酸）比非联合唑来膦酸组（AI）BMD得到有效改善（0.60,95% CI：0.46~0.77,P<0.000 1）,并且绝经前与绝经后患者结果相似;② 内分泌治疗（AI/OFS+AI）会引起骨丢失,而唑来膦酸可预防内分泌治疗引起的骨丢失
ARIBON研究^[33,34]	双盲、随机、安慰剂对照Ⅲ期临床研究	131例绝经后ER⁺早期乳腺癌患者	AI+口服伊班膦酸（150 mg/个月） vs AI+安慰剂	内分泌治疗的同时接受口服伊班膦酸治疗	5	2年后,口服伊班膦酸组椎骨和髋关节BMD分别增加2.98%（-8.9~19.9）和0.60%（-9.0~6.9）,安慰剂组腰椎BMD降低3.22%（-16.0~4.3）,髋关节BMD降低3.90%（-12.3~7.2）。两个治疗组在两个部位的差异均有统计学意义（P<0.01）。根据治疗2年后的BMD情况,T值<-2.5的患者继续接受口服伊班膦酸治疗直至5年。5年后,口服伊班膦酸组椎骨BMD增加9.65%,髋关节BMD增加2.72%
ABCSG-18研究^[35]	随机、双盲、安慰剂对照Ⅲ期临床研究	3 420例绝经后早期HR⁺乳腺癌患者	AI+地舒单抗（60 mg/6个月） vs AI + 安慰剂	内分泌治疗的同时接受地舒单抗治疗	3	① AI联合地舒单抗组首次发生骨折的临床时间明显延迟（风险比为0.50,95% CI：0.39~0.65,P<0.000 1）;② AI联合地舒单抗组骨折总数低于安慰剂组,无论是基线T值≥-1亚组（风险比为0.44,95% CI：0.31~0.64,P<0.000 1）还是基线T值<-1亚组（风险比为0.57,95% CI：0.40~0.82,P=0.002）
HALT-BC研究^[36]	随机、双盲、安慰剂对照Ⅲ期临床试验	252例HR⁺乳腺癌患者	AI+地舒单抗（60 mg/6个月） vs AI + 安慰剂	内分泌治疗的同时接受地舒单抗治疗	2	12和24个月时,地舒单抗组与安慰剂组相比腰椎BMD分别增加了5.5%（P<0.001）和7.6%（P<0.001）

表2

表3

双膦酸盐对早期乳腺癌患者生存获益的影响"

研究名称	研究类型	入组人群	治疗方案	双膦酸盐干预时机	治疗时间/年	中位随访时间	DFS	OS
ABCSG-12研究^[52]	随机、开放Ⅲ期临床试验	1 800例绝经前HR⁺早期乳腺癌患者	OFS+TAM/AI+唑来膦（4 mg/6个月）vs OFS+TAM/AI	内分泌治疗的同时立即接受唑来膦酸治疗	3	94.4个月	联合唑来膦酸组与单独内分泌治疗相比,DFS率增长3.4%（88.4% vs 85.0%）,复发风险降低23%（风险比为0.77,95% CI：0.60~0.99,P=0.042）	联合唑来膦酸组与无唑来膦酸组相比OS率更高（96.7% vs 94.5%）,死亡风险绝对值降低2.2%
HOBOE2研究^[53]	多中心、随机、对照Ⅲ期临床试验	1 065例绝经前HR⁺早期乳腺癌患者	OFS+TAM vs OFS+AI vs OFS + AI+唑来膦酸（4 mg/6个月）	内分泌治疗的同时立即接受唑来膦酸治疗	治疗5年或治疗至患者55岁	64.0个月	OFS+TAM的5年DFS率为96.9%,OFS+AI的5年DFS率为98.4%,OFS+AI+唑来膦酸的5年DFS率为99.7%（P=0.008）;OFS+AI+唑来膦酸 vs OFS+TAM：风险比为0.52（95% CI：0.34~0.80,P=0.003）;OFS+AI+唑来膦酸 vs OFS+AI：风险比为0.70（95% CI：0.44~1.12,P=0.22）	OFS+TAM的5年OS率为96.9%（95% CI：94.1~98.4）,OFS+AI的5年OS率为98.4%（95% CI：96.2~99.3）,OFS+AI+唑来膦酸的5年OS率为99.7%（95% CI：97.9~100.0）
AZURE研究^[51]	多中心、随机、开放、平行对照Ⅲ期临床试验	3 360例女性乳腺癌患者（HR⁺、HER2⁺、三阴性）	系统治疗# vs 系统治疗+唑来膦酸（4 mg/6个月）	系统治疗的同时立即接受唑来膦酸治疗	5	117.0个月	① 绝经后患者：系统治疗联合唑来膦酸可降低18%的疾病复发风险（风险比为0.82,95% CI：0.67~1.00）,降低22%的侵袭性疾病发生风险（风险比为0.78,95% CI：0.64~0.94）;② MAF基因^*阴性（拷贝数<2.5）的患者：系统治疗联合唑来膦酸可降低25%的侵袭性疾病发生风险（风险比为0.75,95% CI：0.58~0.97,P=0.026）	MAF基因阴性（拷贝数<2.5）的患者：系统治疗联合唑来膦酸可降低31%的死亡风险（风险比为0.69,95% CI：0.50~0.94,P=0.019）
SUCCESS A试验^[54]	多中心、随机、开放Ⅲ期临床试验	3 754例有淋巴结阳性或高风险淋巴结阴性（以下至少1种：肿瘤大小≥p_T2,组织学分级3级,HR阴性,年龄≤35岁）的原发性浸润性乳腺癌患者	化疗后,患者分别接受5年唑来膦酸治疗（4 mg/3个月,持续2年,随后4 mg/6个月,持续3年）和2年唑来膦酸治疗（4 mg/3个月,持续2年）	患者接受6个周期的化疗后,立即接受唑来膦酸治疗	5 vs 2	唑来膦酸治疗2年后开始测量生存时间	5年DFS率 vs 2年DFS率：风险比为0.97（95% CI：0.75~1.25,P=0.81） 5年无远处转移生存率 vs 2年无远处转移生存率：风险比为0.87（95% CI：0.65~1.18,P=0.38）	风险比为0.98,95% CI：0.67~1.42,P=0.90
EBCTCG/meta分析^[55]	纳入26项随机、对照临床试验	18 766例早期HR⁺乳腺癌患者（其中使用唑来膦酸的患者有9 290例）	内分泌治疗方案 vs 内分泌治疗方案+双膦酸盐	内分泌治疗的同时立即接受双膦酸盐治疗	/	/	联合双膦酸盐在降低绝经后患者疾病复发率（风险比为0.86,95% CI：0.78~0.94,P=0.002 0）、远处复发率（风险比为0.82,95% CI：0.74~0.92,P=0.000 3）和骨转移发生率（风险比为0.72,95% CI：0.60~0.86,P=0.000 2）方面均有获益;	联合双膦酸盐在降低绝经后患者死亡率（风险比为0.82,95% CI：0.73~0.93,P=0.002 0）方面有明显获益
Meta分析1^[56]	纳入8项随机对照研究	7 730例早期HR⁺乳腺癌患者	内分泌治疗方案 vs 内分泌治疗方案+唑来膦酸	内分泌治疗的同时立即接受唑来膦酸治疗	/	/	联合唑来膦酸可使患者的5年DFS率有改善趋势（RR=0.90,95% CI：0.81~1.00,P=0.06）	联合唑来膦酸可使患者的5年OS率显著改善（RR=0.86,95% CI：0.75~0.99,P=0.03）
Meta分析2^[57]	纳入7项随机对照研究	3 969例早期HR⁺乳腺癌患者	内分泌治疗方案 vs 内分泌治疗方案+唑来膦酸	内分泌治疗的同时立即接受唑来膦酸治疗	/	/	联合唑来膦酸治疗使患者的DFS有改善趋势（风险比为0.75,95% CI：0.52~1.08,P=0.121）	联合唑来膦酸治疗可显著延长乳腺癌患者的OS（风险比为0.85,95% CI：0.73~1.00,P=0.047）

表3

表4

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风险分级	风险分级影响因素
低危	T值≥-1.0
中危	-2.0<T值<-1.0
高危	T值≤-2.0,或-2.0<T值<-1.0同时存在任意两个风险因素（年龄>65岁、T值<-1.5、现在吸烟及有吸烟史、BMI<24、髋骨骨折家族史、 50岁以上脆性骨折个人史、口服糖皮质激素 >6个月）

研究名称	研究类型	入组人群	治疗方案	地舒单抗干预时机	治疗时间/年	中位随访时间	DFS	OS
ABCSG-18研究 ^[58]	多中心、前瞻性、双盲、安慰剂对照Ⅲ期临床试验	3 425例绝经后早期HR⁺乳腺癌患者	AI+地舒单抗（60 mg/6个月） vs AI+安慰剂	内分泌治疗的同时接受地舒单抗治疗	3	73个月	地舒单抗组的DFS率显著提高（风险比为0.82,95% CI：0.69~0.98,多因素比例风险回归模型分析,P=0.026 0;描述性统计学分析,未控制多重性）;地舒单抗组的5年DFS率为89.2%（95% CI：87.6~90.8）,8年DFS率为80.6%（95% CI：78.1~83.1）,而安慰剂组5年DFS率为87.3%（95% CI：85.7~89.0）,8年DFS率为77.5%（95% CI：74.8-80.2）	/
D-CARE研究 ^[59]	国际、双盲、随机、安慰剂对照Ⅲ期临床试验	4 509例乳腺癌患者（HR⁺、HER2⁺）	系统治疗+安慰剂 vs 系统治疗+地舒单抗（120 mg/3~4周,持续6个月,120 mg/12周）	新辅助和辅助化疗的同时接受地舒单抗治疗	5	67个月	① 无骨转移生存率：地舒单抗组与安慰剂组无明显差异（风险比为0.97,95% CI：0.82~1.14,P=0.70）,各亚组中两组均无差异均无统计学意义;② DFS：地舒单抗组与安慰剂组无明显差异（风险比为1.04,95% CI：0.91~1.19,P=0.57）,各亚组中差异均无统计学意义	/