【作者】 李凤娟；

【导师】 宋艳秋；

【作者基本信息】 吉林大学 ， 临床医学硕士（内科学）（专业学位）， 2022， 硕士

【摘要】 目的:总结抗血管新生TKI类药物阿帕替尼及安罗替尼在难治性乳腺癌治疗中的疗效、安全性,探讨不同治疗方案、剂量、肿瘤特征对疗效的影响,为指导临床实践提供参考。方法:采用回顾性分析的方法,收集2017年1月至2021年10月在我中心接受阿帕替尼或安罗替尼治疗的晚期乳腺癌患者名单,收集患者的各项资料,包括年龄、性别、基础疾病等基本资料,肿瘤复发后的分子分型、转移部位、治疗线数、用药方案、药物剂量、生存时间等临床资料及不良反应发生情况。应用SPSS 26.0软件分析患者的客观缓解率、临床获益率、无进展生存时间、总生存时间以及不良反应的发生情况。结果:1.按照入组标准和排除标准筛选符合条件的患者共有58例,入组患者多为后线治疗、病情较重,伴有多重耐药的特点。2.TKI类抗血管药物治疗难治性晚期乳腺癌,客观缓解率(ORR)为19.0%,临床获益率(CBR)为77.6%。中位无进展生存时间(PFS)为4.0个月(0.6～27.6个月),中位总生存时间(OS)为20.1个月(1.0～40.3个月)。3.疗效亚组分析提示:(1)≤2线与≥3线治疗患者的ORR、CBR、PFS、OS的差异均无统计学意义;(2)不同分子分型之间ORR、CBR、和PFS差异无统计学意义,非三阴性乳腺癌OS较三阴性乳腺癌更长(P=0.008);(3)TKI联合双药化疗对比联合单药化疗ORR更高(P=0.044),但PFS更短(P=0.042),两组间CBR和OS差异无统计学意义;(4)用药剂量上,足量用药患者ORR和CBR更高(P=0.026),但不同用药剂量患者的PFS和OS之间的差异无统计学意义;(5)脑转移患者与非脑转移患者的ORR、CBR和PFS的差异无统计学意义,脑转移患者的OS较非脑转移患者更短(P=0.014)。(6)ECOG评分越高者,CBR越低,而不同ECOG评分患者的ORR和PFS差异无统计学意义。4.单因素和多因素分析提示肝转移和用药方案是PFS的独立预后因素。5.不良反应分析提示本研究中TKI类抗血管药物相关不良反应发生率为86.2%,常见的不良反应有乏力、食欲不振、皮肤黏膜溃疡和手足综合征,且不良反应程度多为1～2度。6.不良反应亚组分析提示阿帕替尼和安罗替尼之间不良反应的种类和严重程度无明显差异,但安罗替尼的足量耐受性更好;药物剂量与不良反应发生率存在正相关,但不同用药剂量之间不良反应的严重程度的差异无统计学意义(P>0.05)。结论:1.TKI类小分子抗血管药物对晚期乳腺癌尤其是多线治疗失败后的难治性乳腺癌是一种安全有效的治疗选择。2.TKI类抗血管药物的应用不局限于三阴性乳腺癌,非三阴性乳腺癌患者也可获益,且对缩小脑转移病灶、改善脑水肿有效。3.用药方案的选择上TKI联合单药化疗优于联合双药化疗。4.药物剂量的选择上推荐在患者可耐受的前提下给予足量用药,同时密切监测不良反应,及时调整用药剂量。5.ECOG评分不影响TKI类抗血管药物的选择。更多还原

【Abstract】 Objective:Summarize the efficacy and safety of TKI antiangiogenic drugs including apatinib and anlotinib in the treatment of refractory breast cancer.Explore the effects of different treatment regimens,doses and tumor characteristics on the efficacy,so as to provide reference for clinical practice.Method:A retrospective analysis was conducted.Collect the list of patients with advanced breast cancer who received apatinib or anlotinib treatment in our center from January 2017 to October 2021.Collect data of the patients,including age,gender,underlying diseases and other basic information.When the tumor recurrence,collect information of molecular classification,metastatic site,number of therapy lines,drug regimen,dose and other clinical data as well as the occurrence of adverse reactions.SPSS 26.0 software was used to analyze the objective response rate,clinical benefit rate,progression free survival time,overall survival time and the occurrence of adverse reactions.Result:1.A total of 58 eligible patients were screened according to the inclusion criteria and exclusion criteria.Most of the enrolled patients were treated in the back line,with severe conditions and accompanied by multiple drug resistance.2.Objective response rate(ORR)of refractory advanced breast cancer treated with TKI antiangiogenic drugs was 19.0%.Clinical benefit rate(CBR)was 77.6%.Median progression free survival(PFS)was 4.0 months(0.6～27.6 months),and median overall survival(OS)was 10.5 months(1.0～40.3 months).3.Subgroup analysis of efficacy indicated that:(1)There was no significant statistical difference in ORR、CBR、PFS、OS between more than or equal to third-line therapy patients and less than three-line therapy patients.(2)There was no significant statistical difference in ORR,CBR and PFS among different molecular types,and the OS of non-triple negative breast cancer was longer than that of triple negative breast cancer(P=0.008).(3)ORR in patients treated with TKI combined with double-drug chemotherapy was higher than that in patients treated with TKI combined with single-drug chemotherapy(P=0.044),but the PFS was shorter(P=0.042)in the former.There was no significant statistical difference in CBR and OS between the two groups.(4)In terms of dose,the higher the dose,the higher ORR and CBR(P=0.026),but there was no significant statistical difference in PFS and OS among patients using different dose;(5)There was no significant statistical difference in ORR,CBR and PFS between patients with and without brain metastases.OS of patients with brain metastases was shorter than that in patients without brain metastases(P=0.014).(6)The higher the ECOG score,the lower CBR,while there was no statistical significance in ORR and PFS of patients with different ECOG scores.4.Univariate and multivariate analyses suggested that liver metastasis and medication regimen were independent predictors of PFS.5.Analysis of adverse reactions suggested that in this study,the incidence rate of adverse reactions associated with TKI antiangiogenic drugs was 86.2%,and the common adverse reactions were fatigue,anorexia,skin and mucous ulcer and hand and foot syndrome,and the degree of most of adverse reactions was 1～2 degree.6.Subgroup analysis of adverse reactions suggested that even though there was no significant difference in the category and severity of adverse reactions between apatinib and anlotinib,but adequate tolerability of anlotinib was better.There was a positive correlation between drug dose and the incidence of adverse reactions.There was no significant statistical difference in the severity of adverse reactions between different drug doses(P>0.05).Conclusion:1.For patients with advanced breast cancer,especially refractory ones with the failure of multi-line therapy,TKI antiangiogenic drug is a safe and effective treatment option.2.The application of TKI antiangiogenic drugs is not limited to triple negative breast cancer,non-triple negative breast cancer patients can also benefit from the therapy.In addition,the drug is effective in reducing brain metastasis sites and alleviating cerebral edema.3.TKI combined with single-drug chemotherapy is superior to combined with double-drug chemotherapy in terms of the choice of medication regimen.4.In terms of the selection of drug dose,it is recommended to give sufficient medication under the premise that patients can tolerate it.At the same time,close monitoring of adverse reactions and timely adjustment of drug dosage are necessary.5.ECOG score was not a factor limiting the application of TKI antivascular drugs.更多还原