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对于HER2阳性晚期乳腺癌，即使接受曲妥珠单抗治疗，仍有大约30%～50%的患者发生脑转移，而且目前针对脑转移的有效治疗选择很少。虽然局部治疗仍然是脑转移的主要治疗方法，包括手术切除、立体定向放疗或全脑放疗，但是6～12个月复发内仍很常见，并且这些局部治疗方法存在神经认知障碍风险，给脑转移的管理带来了巨大挑战。全身治疗的优点之一为药物如果有效，可同时控制颅内和颅外转移病变。化疗药物治疗脑转移患者的中位总生存大约11个月，大分子单克隆抗体（曲妥珠单抗和帕妥珠单抗）难以穿过血脑屏障，治疗脑转移患者的结局不如人意。HER2酪氨酸激酶可逆抑制剂图卡替尼可将曲妥珠单抗＋卡培他滨治疗脑转移的中位无进展生存由4.2个月延长至9.9个月、进展或死亡风险减少68%、中位总生存由12.0个月延长至18.1个月、总死亡风险减少42%，颅内客观缓解率由20.0%提高至47.3%，创造了历史纪录。不过，图卡替尼至今仍未进入中国大陆内陆。中国原创的HER1、HER2、HER4酪氨酸激酶不可逆抑制剂吡咯替尼已被前瞻研究PHOEBE和PHENIX证实对HER2阳性晚期乳腺癌有效，两项真实世界回顾研究表明吡咯替尼对HER2阳性晚期乳腺癌脑转移有效。 2022年1月24日，英国《柳叶刀》肿瘤学分册在线发表郑州大学附属肿瘤医院（河南省肿瘤医院）闫敏、牛李敏、刘真真、张梦玮、律慧敏、陈秀春、乔江华、湖南省肿瘤医院（湘雅医学院附属肿瘤医院）欧阳取长、刘莉萍、杨小红、肖华伍、中国医科大学附属肿瘤医院（辽宁省肿瘤医院）孙涛、高志超、李晓睿、董方圆、西安交通大学第一附属医院杨谨、山东大学齐鲁医院黎莉、青岛大学附属医院宋玉华、天津医科大学肿瘤医院郝春芳、中国科学院大学附属肿瘤医院（浙江省肿瘤医院）陈占红、新乡市中心医院张桂芳等学者的PERMEATE研究报告，首次前瞻调查了吡咯替尼＋卡培他滨对HER2阳性晚期乳腺癌脑转移患者的有效性和安全性。该研究由中国癌症基金会攀登基金和江苏恒瑞医药有限公司资助。 PERMEATE (NCT03691051): Pyrotinib Plus Capecitabine in Patients With Brain Metastases From HER2-positive Metastatic Breast Cancer: a Single-arm, Open-label, Ahead Study 该多中心非盲单组双队列二期临床研究于2019年1月29日～2020年7月10日从中国八家三级医院入组年龄≥18岁女性、美国东部肿瘤协作组体力状态评分为0～2的HER2阳性晚期乳腺癌脑转移患者78例，分为两个队列： 
全部患者每天一次口服吡咯替尼400毫克，同时每天两次口服卡培他滨1000毫克/平方米体表面积，连续服用14天后停用7天，每3周为1个周期，直至疾病进展或出现无法耐受的毒性反应。主要研究终点为经确认的颅内客观缓解率，由研究者根据实体瘤疗效评价标准1.1版本进行评估。至少接受过一次研究药物治疗的患者进入有效性和安全性分析。 结果，中位随访15.7个月（四分位9.7～19.0），队列A与队列B相比： 
因此，该小样本前瞻非对照研究结果表明，吡咯替尼＋卡培他滨对HER2阳性晚期乳腺癌脑转移患者的有效性和安全性令人鼓舞，尤其对于未经局部放疗患者，颅内客观缓解率甚至打破了图卡替尼创造的历史纪录，故有必要进一步开展大样本随机对照研究进行验证。 对此，法国尼斯癌症中心和里昂癌症中心发表同期评论：活动性乳腺癌脑转移的药物治疗。 相关链接 Lancet Oncol. 2022 Jan 24. Online ahead of print.
Pyrotinib plus capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases (PERMEATE): a multicentre, single-arm, two-cohort, phase 2 trial. Min Yan, Quchang Ouyang, Tao Sun, Limin Niu, Jin Yang, Li Li, Yuhua Song, Chunfang Hao, Zhanhong Chen, Armando Orlandi, Naohiro Ishii, Kazuaki Takabe, Gianluca Franceschini, Francesco Ricci, Claire Verschraegen, Zhenzhen Liu, Mengwei Zhang, Huimin Lv, Liping Liu, Xiaohong Yang, Huawu Xiao, Zhichao Gao, Xiaorui Li, Fangyuan Dong, Xiuchun Chen, Jianghua Qiao, Guifang Zhang. The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China; Hunan Cancer Hospital, the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China; Cancer Hospital of China Medical University, Liaoning Cancer Hospital, Shenyang, China; The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; Qilu Hospital of Shandong University, Jinan, China; The Affiliated Hospital of Qingdao University, Qingdao, China; Tianjin Medical University Cancer Institute & Hospital, Tianjin, China; Cancer Hospital of the University of Chinese Academy of Sciences, Hangzhou, China; Fondazione Policlinico Universitario A Gemelli IRCCS, Roma, Italy; International University of Health and Welfare Hospital, Tochigi, Japan; Roswell Park Comprehensive Cancer Centre, Buffalo, NY, USA; Clinique Croix du Sud, Quint-Fonsegrives, France; Ohio State University Comprehensive Cancer Centre, Columbus, OH, USA; Xinxiang Central Hospital, Xinxiang, China. BACKGROUND: Patients with HER2-positive metastatic breast cancer have a high risk of developing brain metastases. Efficacious treatment options are scarce. We investigated the activity and safety of pyrotinib plus capecitabine in patients with HER2-positive metastatic breast cancer and brain metastases. METHODS: We did a multicentre, single-arm, two-cohort, phase 2 trial in eight tertiary hospitals in China. Patients aged 18 years or older who had radiotherapy-naive HER2-positive brain metastases (cohort A) or progressive disease after radiotherapy (cohort B), with an Eastern Cooperative Oncology Group performance status of 0-2, received pyrotinib 400 mg orally once daily, and capecitabine 1000 mg/m2 orally twice daily for 14 days, followed by 7 days off every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was confirmed intracranial objective response rate by investigator assessment according to the Response Evaluation Criteria In Solid Tumours (version 1.1). Activity and safety were analysed in patients with at least one dose of study drug. The study is ongoing, but recruitment is complete. The study is registered with ClinicalTrials.gov, NCT03691051. FINDINGS: Between Jan 29, 2019, and July 10, 2020, we enrolled 78 women: 51 (86%) of 59 patients in cohort A and 18 (95%) of 19 patients in cohort B had previous exposure to trastuzumab. Median follow-up duration was 15.7 months (IQR 9.7-19.0). The intracranial objective response rate was 74.6% (95% CI 61.6-85.0; 44 of 59 patients) in cohort A and 42.1% (20.3-66.5; eight of 19 patients) in cohort B. The most common grade 3 or worse treatment-emergent adverse event was diarrhoea (14 [24%] in cohort A and four [21%] in cohort B). Two (3%) patients in cohort A and three (16%) in cohort B had treatment-related serious adverse events. No treatment-related deaths occurred. INTERPRETATION: To our knowledge, this is the first prospective study showing the activity and safety of pyrotinib plus capecitabine in patients with HER2-positive breast cancer and brain metastases, especially in radiotherapy-naive population. This combination deserves further validation in a randomised, controlled trial. FUNDING: National Cancer Centre Climbing Foundation Key Project of China, Jiangsu Hengrui Pharmaceuticals. DOI: 10.1016/S1470-2045(21)00716-6 Lancet Oncol. 2022 Jan 24. Online ahead of print.
Medical treatment for active breast cancer brain metastases. Caroline Bailleux, Thomas Bachelot. Centre Antoine Lacassagne, Nice, France; Centre Léon Bérard, Lyon, France. Metastatic breast cancer is the second most common cause of brain metastases. In the ESME cohort, the risk of developing brain metastases during metastatic disease was 34% for patients with ER-positive and HER2-positive breast cancer and 49% for patients with ER-negative and HER2-positive breast cancer. Brain metastases are associated with decreased quality of life and overall survival. Current recommendations principally rely on surgery and radiotherapy for control of brain metastases, with medical treatment mostly considered after failure of such interventions. DOI: 10.1016/S1470-2045(22)00022-5 
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