目的针对激素受体阳性（HR⁺）和人表皮生长因子受体2阴性（HER2^-）晚期乳腺癌一线细胞周期蛋白依赖性激酶4/6抑制剂（CDK4/6抑制剂）联合内分泌治疗后发生原发耐药的患者，探讨二线的治疗模式、疗效及影响因素。方法回顾性收集2022年3月1日9—2024年12月31日在天津医科大学肿瘤医院就诊的176例一线CDK4/6抑制剂联合内分泌治疗后6个月内出现疾病进展的患者资料。采用R 4.6.0软件进行统计分析，双侧检验，P＜0.05为差异有统计学意义。采用Kaplan-Meier法绘制生存曲线，并用Log-rank检验进行组间比较。采用Cox比例风险模型筛选混杂因素，分析影响真实世界无进展生存期2（rwPFS2）的独立因素，并评估预设亚组内相对疗效。结果 176例原发耐药患者中，真实世界二线治疗方案占比依次为化疗联合/不联合靶向/免疫治疗组（化疗组，109例，61.9%），内分泌联合/不联合靶向治疗组（内分泌组，36例，20.5%），抗体药物偶联物（ADC）治疗（21例，11.9%），其他治疗（10例，5.7%）。生存分析显示化疗组中位rwPFS2为4.0个月，内分泌组中位rwPFS2为6.0个月，ADC组中位rwPFS2为5.0个月，组间存在显著差异（P＝0.001）。单/多因素Cox分析提示内分泌组的疾病进展风险较化疗组显著降低42%[合并风险比（HR） ＝0.58，P＝0.037]，ADC组降低61%（HR＝0.39，P＝0.001）。一线内分泌使用选择性雌激素受体降解剂（SERD）/调节剂（SERM）（HR＝2.03，P＜0.001）以及转移数目≥3个（HR＝2.03，P＝0.001）均与较短的rwPFS2相关。预设亚组分析显示无肝转移（HR＝0.38，P＝0.001）、转移灶数目1～2个（HR＝0.51，P＝0.03）、初治IV期（HR＝0.35，P＝0.046）的患者选择内分泌联合/不联合靶向，与化疗组相比，rwPFS2进展风险显著降低。结论真实世界研究发现HR⁺/HER2^-晚期乳腺癌一线CDK4/6抑制剂联合内分泌治疗后发生原发耐药的患者，二线治疗仍以化疗为主，但疗效并不优于内分泌联合/不联合靶向及ADC类药物。肝转移、转移灶数目等临床特征在缺乏生物标志物的背景下将有助于指导二线治疗的选择。

Objective To explore the treatment strategies, efficacy, and influencing factors for patients with HR⁺/HER2^- advanced breast cancer who develop primary resistance to first-line CDK4/6 inhibitors combined with endocrine therapy. Methods Retrospective data were collected from 176 patients treated at the Tianjin Medical University Cancer Hospital between March 1, 2022 and December 31, 2024, who experienced disease progression within six months after first-line CDK4/6 inhibitor combined with endocrine therapy. Statistical analysis was performed using R 4.6.0 software with two-sided tests; P < 0.05 was considered statistically significant. Kaplan-Meier curves were used to plot survival data, and intergroup comparisons were conducted using the log-rank test. A Cox proportional hazards model was applied to adjust for confounding factors, identify independent predictors of rwPFS2, and evaluate relative efficacy within pre-specified subgroups. Results Among 176 patients with primary resistance, the real-world secondline treatment regimens were distributed as follows: Chemotherapy group with/without combination of targeted/immunotherapy (109 cases, 61.9%), endocrine combination/non-combination targeted therapy group (36 cases, 20.5%), ADC therapy (21 cases, 11.9%), and other treatments (10 cases, 5.7%). Survival analysis showed that the median rwPFS2 was 4.0 months in the chemotherapy group, 6.0 months in the endocrine group, and 5.0 months in the ADC group, with significant differences among groups (P = 0.001). Univariate and multivariate Cox analyses indicated that the risk of disease progression was significantly lower in the endocrine group compared to the chemotherapy group by 42% (HR = 0.58, P = 0.037), and by 61% in the ADC group (HR = 0.39, P = 0.001). Use of SERD/SERM in first-line endocrine therapy (HR = 2.03, P < 0.001) and ≥ 3 metastatic sites (HR = 2.03, P = 0.001) were both associated with shorter rwPFS2. Prespecified subgroup analysis revealed that patients without liver metastasis (HR = 0.38, P = 0.001), those with 1–2 metastatic lesions (HR = 0.51, P = 0.03), and those with newly diagnosed stage IV disease (HR = 0.35, P = 0.046) who received endocrine with/without targeted therapy had a significantly lower risk of rwPFS2 progression compared to those treated with chemotherapy with/without targeted/immunotherapy. Conclusion Real-world studies have found that patients with HR⁺/HER2^- advanced breast cancer who develop primary resistance to first-line CDK4/6 inhibitors combined with endocrine therapy still primarily receive chemotherapy as second-line treatment, although its efficacy is no better than endocrine therapy alone or in combination with targeted agents and ADCs. In the absence of biomarkers, clinical features such as liver metastasis and number of metastatic lesions may help guide second-line treatment selection.

R979.1

国家自然科学基金青年项目（82202971）；天津市医学重点学科建设资助（ TJYXZDXK-3-003A）