晚期乳腺癌新发脑转移患者继续曲妥珠单抗治疗或更换TKI治疗的疗效和安全性比较

陈佳欣; 张会强; 周金妹; 吴雪雪; 张少华; 江泽飞; 王涛

doi:10.3969/j.issn.2095-5227.2023.05.007

晚期乳腺癌新发脑转移患者继续曲妥珠单抗治疗或更换TKI治疗的疗效和安全性比较

doi: 10.3969/j.issn.2095-5227.2023.05.007

陈佳欣^{1, 2,},
张会强²,
周金妹²,
吴雪雪²,
张少华²,
江泽飞²,
王涛^{1, 3, 4, ,}

1.
解放军医学院，北京　100853
2.
解放军总医院第五医学中心肿瘤医学部，北京　100071
3.
安徽医科大学，安徽合肥　230031
4.
南方医科大学，广东广州　510515

基金项目: 北京科创医学发展基金会(KC2022-ZZ-0091-7)

详细信息

作者简介:
陈佳欣，女，硕士。研究方向：恶性肿瘤的综合治疗。Email: amberchenjx@163.com

通讯作者:
王涛，女，博士，主任医师，病区负责人。Email: wangtao733073@163.com

中图分类号: R737.9
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出版历程
- 收稿日期: 2022-10-29
- 网络出版日期: 2023-05-09
- 刊出日期: 2023-05-28

Effect and safety of continuation of trastuzumab or switching to TKI therapy in patients with brain metastases

1.
Chinese PLA Medical School, Beijing 100853, China
2.
Department of Oncology, the Fifth Medical Center, Chinese PLA General Hospital, Beijing 100071, China
3.
Anhui Medical University, Hefei 230031, Anhui Province, China
4.
Southern Medical University, Guangzhou 510515, Guangdong Province, China

More Information

Corresponding author: WANG Tao. Email: wangtao733073@163.com

摘要

摘要: 背景随着医疗水平的进步，HER2阳性晚期乳腺癌患者生存时间显著延长，但有接近50%的患者会发生中枢神经系统转移。放疗是脑转移治疗的主要手段，但放疗的剂量和次数是有限的，药物治疗已成为近年来研究重点。目的比较接受曲妥珠单抗治疗颅外病灶有效的脑转移患者，继续曲妥珠单抗治疗或更换小分子酪氨酸激酶抑制剂(tyrosine kinase inhibitor，TKI)类药物治疗的疗效和安全性。方法本研究共纳入2007年5月 - 2021年12月就诊于解放军总医院第五医学中心的乳腺癌脑转移患者74例，患者既往接受曲妥珠单抗治疗有效，颅外病灶稳定，颅内病灶新发或进展，一组继续曲妥珠单抗治疗(A组)，另一组更换为TKI类药物治疗(B组)。主要研究终点为总生存期和颅内无进展生存期，次要研究终点为颅内客观反应率、颅内临床受益率和安全性。随访截至2022年4月。结果共纳入74例患者，其中曲妥珠单抗组38例，TKI组36例。两组患者均为女性，中位年龄分别为49.5岁和44岁，两组的中位无病生存期分别为17.0个月和16.0个月(P＞0.05)。曲妥珠单抗组和TKI组治疗脑转移患者中位颅内无进展生存期分别为9个月和8个月(P=0.400)，中位总生存分别为75个月和96个月(P=0.140)，颅内病灶临床缓解率为23.7%和41.7%(P=0.099)，颅内病灶临床获益率为63.2%和75.0%(P=0.271)。曲妥珠单抗组有34.2%(13/38)患者发生3级以上不良反应，TKI组有41.7%(15/36)患者发生3级以上不良反应，差异无统计学意义(P＞0.05)，两组均未发生治疗相关死亡事件。结论对于接受曲妥珠单抗治疗有效的脑转移患者， TKI类药物有延长脑转移患者总生存期的趋势，但无统计学意义。
- 乳腺癌 /
- 脑转移 /
- 人表皮生长因子受体2 /
- 吡咯替尼 /
- 拉帕替尼 /
- 曲妥珠单抗
Abstract: Background With the progress of medical technology, the survival time of advanced HER2-positive breast cancer patients is significantly prolonged, however, up to 50% of patients will eventually develop brain metastasis. Although radiotherapy is the mainstay treatment for brain metastasis, the dose and frequency of radiotherapy are limited, while drug therapy has become the focus of research in recent years. Objective To compare the efficacy and safety of the continuation of trastuzumab or switching to TKI therapy in patients with brain metastases for trastuzumab therapy, so as to provide references for clinical treatment and improve the survival of patients with brain metastasis of HER2-positive breast cancer. Methods A total of 74 breast cancer patients with brain metastases who were admitted to the Fifth Medical Center, Chinese PLA General Hospital from 2007 to 2021 were included in this study. Patients with brain metastasis who had previously received trastuzumab with stable extracranial lesions and new or progressive intracranial lesions were enrolled. One group of patients continued trastuzumab therapy (Cohort A), while the other group switched to TKI therapy (Cohort B). The primary endpoints were overall survival (OS) and intracranial progression-free survival (IC-PFS), and the secondary endpoints were intracranial objective response rate (ORR), intracranial clinical benefit rate (CBR), and safety. The follow-up ended in April 2022. Results We enrolled 74 breast cancer patients with brain metastases, including 38 patients in the trastuzumab group and 36 patients in the TKI group. All patients were female, with a median age of 49.5 years and 44 years, respectively. The median DFS was 17 months and 16 months in the two groups, respectively (P>0.05). The median intracranial progression-free survival was 9 months and 8 months (P=0.400), and the median overall survival was 75 months and 96 months (P=0.140) in trastuzumab group and TKI group. The clinical response rate (ORR) was 23.7% and 41.7% (P=0.099), and the clinical benefit rate (CBR) was 63.2% and 75.0% (P=0.271) in the two groups. The incidence of grade III-IV adverse reaction of the trastuzumab group was 34.2% (13/38), and it was 41.7% (15/36) in the TKI group, without significant difference (P>0.05). No treatment-related death occurred. Conclusion TKIs tend to prolong overall survival in patients with brain metastases who respond to trastuzumab, however, the difference is not significant.
- breast cancer /
- brain metastases /
- human epidermal growth factor receptor type 2 /
- pyrotinib /
- lapatinib /
- trastuzumab

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图 1 两组颅内无进展生存曲线

Figure 1. IC-PFS curves of the two groups

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图 2 两组总生存曲线

Figure 2. OS curves of the two groups

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图 3 TKI治疗组激素受体阳性和激素受体阴性患者颅内无进展生存曲线

Figure 3. IC-PFS curves of hormone receptor-positive and hormone receptor-negative patients in the TKI therapy group

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图 4 曲妥珠单抗治疗组激素受体阳性和激素受体阴性患者颅内无进展生存曲线

Figure 4. IC-PFS curves of hormone receptor-positive and hormone receptor-negative patients in the trastuzumab group

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表 1 乳腺癌脑转移患者基线信息

Table 1. Baseline characteristics of breast cancer patients with brain metastases

指标	A组(n=38)	B组(n=36)	χ²/Z值	P值
中位年龄/ 　[岁，Md(IQR)]	49.5(27.0，66.0)	44.0(24.0，70.0)	0.590	0.555
中位DFS/ 　[月，Md(IQR)]	17.0(0.0，74.0)	16.0(0.0，132.0)	0.856	0.392
既往曲妥珠单抗治疗　PFS/[月，Md(IQR)]	7.0(2.0，30.0)	8.0(3.0，50.0)	1.359	0.174
激素受体类型/(例，%)			0.000	0.990
HR阳性	18.0(47.4)	17.0(47.2)
HR阴性	20.0(52.6)	19.0(52.8)
TNM分期/(例，%)			1.810	0.613
Ⅰ	6.0(15.8)	3.0(8.3)
Ⅱ	18.0(47.4)	18.0(50.0)
Ⅲ	7.0(18.4)	5.0(13.9)
Ⅳ	7.0 (18.4)	10.0(27.8)
诊断时脑转移数目/ 　(例，%)			0.433	0.511
单发	11.0(28.9)	13.0(36.1)
多发	27.0(71.1)	23.0(63.9)
脑膜转移/(例，%)			0.006	0.940
有	3.0(7.9)	4.0(11.1)
无	35.0(92.1)	32.0(88.9)
诊断脑转移时有无　症状/(例，%)			2.933	0.087
有	7.0(18.4)	13.0(36.1)
无	31.0(81.6)	23.0(63.9)
是否接受脑部放疗/ 　(例，%)			0.004	0.948
是	24.0(63.2)	23.0(63.9)
否	14.0(36.8)	13.0(36.1)
颅外病灶/(例，%)
淋巴结转移	24.0(63.2)	26.0(72.2)	0.693	0.405
骨转移	16.0(42.1)	16.0(44.4)	0.041	0.839
肝转移	19.0(50.0)	18.0(50.0)	0.000	1.000
肺转移	24.0(63.2)	16.0(44.4)	2.607	0.106

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表 2 两组患者颅内疗效比较(例，%)

Table 2. Comparison of efficacy between the two groups (n, %)

疗效评价指标	A组(n=38)	B组(n=36)	χ²值	P值
CR	8.0(21.1)	2.0(5.6)	2.588	0.108
PR	1.0(2.6)	13.0(36.1)	13.508	＜0.001
SD	23.0(60.5)	19.0(52.8)	0.452	0.501
SD≥6个月	15.0(39.5)	12.0(33.3)	0.301	0.583
PD	6.0(15.8)	2.0(5.6)	1.087	0.297
ORR	9.0(23.7)	15.0(41.7)	2.728	0.099
CBR	24.0(63.2)	27.0(75.0)	1.210	0.271

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表 3 两组治疗相关不良反应比较(例，%)

Table 3. Comparison of treatment-related adverse reactions between the two groups (n, %)

不良反应	A组(n=38)		B组(n=36)
不良反应	全级别	≥3级	全级别	≥3级
急性脑水肿	0(0)	0(0)	0(0)	0(0)
认知功能障碍	0(0)	0(0)	0(0)	0(0)
腹泻	9.0(23.7)	3.0(7.9)	27.0(75.0)	4.0(11.1)
恶心	7.0(18.4)	2.0(5.3)	16.0(44.4)	3.0(8.3)
贫血	4.0(10.5)	0(0)	9.0(25.0)	0(0)
心脏毒性	0(0)	0(0)	0(0)	0(0)
手足综合征	5.0(13.2)	1.0(2.6)	12.0(33.3)	2.0(5.6)
呕吐	8.0(21.1)	2.0(5.3)	18.0(50.0)	3.0(8.3)
转氨酶升高	6.0(15.8)	1.0(2.6)	11.0(30.6)	0(0)
白细胞下降	8.0(21.1)	2.0(5.3)	10.0(27.8)	2.0(5.6)
中性粒细胞下降	7.0(18.4)	2.0(5.3)	9.0(25.0)	1.0(2.8)
血小板下降	5.0(13.2)	0(0)	6.0(16.7)	0(0)
疲劳	11.0(28.9)	0(0)	13.0(36.1)	0(0)
两组各指标比较均无统计学差异(P＞0.05)。

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