人表皮生长因子受体2阳性晚期乳腺癌靶向治疗耐药与预后关系的真实世界研究

A real world study on the relationship between drug resistance of targeted therapy and prognosis of HER-2-positive advanced breast cancer

目的探讨抗人表皮生长因子受体2(HER-2)原发耐药与继发耐药对HER-2阳性晚期乳腺癌患者预后的影响。方法选取1998—2018年于中国医学科学院肿瘤医院接受治疗的HER-2阳性晚期乳腺癌患者, 分析其新辅助或辅助及晚期三线化疗的治疗情况。抗HER-2靶向治疗药物包括曲妥珠单抗、帕妥珠单抗、T-DM1、RC48-ADC、拉帕替尼、吡咯替尼、艾力替尼、西帕替尼、塞拉替尼。基于患者对抗HER-2治疗获益的持续时间, 将患者分为原发抗HER-2耐药(原发耐药)组和继发抗HER-2耐药(继发耐药)组。以总生存时间(OS)为主要研究终点, 生存分析采用Kaplan-Meier法。结果全组284例患者发生复发转移时的中位年龄为48岁, 激素受体阳性155例(54.6%), 阴性129例(45.4%);绝经前128例(45.1%), 绝经后156例(54.9%)。初次确诊复发转移时美国东部肿瘤协作组(ECOG)功能状态(PS)评分0~1分277例(97.5%), ECOG PS评分≥2分7例(2.5%)。原发耐药组103例(36.3%), 继发耐药组181例(63.7%), 两组患者中位OS分别为24.9和40.4个月, 差异有统计学意义(P<0.001)。结论抗HER-2原发耐药为HER-2阳性乳腺癌预后不良的因素之一, 其机制有待进一步探索。

Objective To explore the effect of primary and acquired resistance to anti-human epidermal growth factor receptor 2(HER-2)on the overall survival of patients with HER-2 positive advanced breast cancer.Methods The clinical characteristics of HER-2 positive patients with advanced breast cancer admitted to Cancer Hospital of Chinese Academy of Medical Sciences from January 1998 to December 2018 were collected,and their neoadjuvant/adjuvant and advanced three-line chemotherapy were summarized.Among them,targeted drugs for HER-2 included trastuzumab,pertuzumab,T-DM1,RC48-ADC,lapatinib,pyrotinib,allitinib,sipatinib,seratinib.Based on the duration of benefit from anti HER-2 treatment,the patients were divided into two groups:primary anti HER-2 resistance group and acquired anti HER-2 resistance group.In this study,the overall survival(OS)was used as the main end point.Kaplan-Meier analysis and Cox proportional risk regression model were used to analyze the effects of different drug resistance mechanisms on the overall survival.Results The whole group of 284 patients were included.The median age of recurrence and metastasis was 48 years old,155(54.6%)were hormone receptor(HR)positive and 129(45.4%)were HR negative,128 cases(45.1%)were premenopausal and 156 cases(54.9%)were postmenopausal,277 cases(97.5%)had a score of 0-1 in ECoG PS and 7 cases(2.5%)had a score of more than 2 in the first diagnosis of relapse and metastasis.There were 103 cases(36.3%)in the primary drug resistance group and 181 cases(63.7%)in the secondary drug resistance group.The median overall survival time of the two groups was 24.9 months and 40.4 months,respectively,with statistical significance(P<0.001).Conclusion Primary resistance to HER-2 is one of the factors of poor prognosis in HER-2 positive breast cancer,and its mechanism needs to be further explored.