在所有实体瘤中，乳腺癌脑转移（BM）的发生率位列第二，仅次于非小细胞肺癌。由于很多大分子药物无法通过血脑屏障，脑转移的治疗存在障碍。近期，Cancer Treatment Reviews（IF=13.608）期刊发表题为“Epidemiology, clinical outcomes, and unmet needs of patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases: A systematic literature review”的综述文章[1]，全面概述了HER2+乳腺癌BM患者的流行病学、未满足的治疗需求和治疗前景。
HER2+乳腺癌BM患者的治疗现状
HER2靶向药物的临床结局
评估HER2+乳腺癌BM患者疗效的20项临床试验（24篇文章）的关键临床结局总结见表1。
表1 HER2+乳腺癌和BM相关关键研究的临床结局 (n = 24)
单克隆抗体
活动性BM：在 PATRICIA研究中，帕妥珠单抗和高剂量曲妥珠单抗在CNS 靶向放疗后进展的患者中产生了适度的颅内缓解 (CNS-ORR，11%) 和临床获益（CNS中的4个月和6个月临床获益率分别为68%和51%）[12]。在NCT01004172试验中，贝伐珠单抗联合卡铂（在HER2+乳腺癌患者中联合使用曲妥珠单抗）在BM患者中产生了较高的持久客观缓解率 (CNS-ORR，63%)[13]。
TKI
稳定BM：NALA研究表明，奈拉替尼+卡培他滨（CNS-ORR，26.3%；CNS-PFS，12.4个月）与拉帕替尼+卡培他滨（CNS-ORR，15.4%；CNS-PFS，8.3个月）相比，CNS结局改善[14]。NEfERT-T研究表明，与曲妥珠单抗联合紫杉醇相比，奈拉替尼联合紫杉醇可延迟症状性或进展性CNS复发的发生并降低发生频率[15]。在一项Ⅰb/Ⅱ期研究中，图卡替尼联合帕博西利和来曲唑治疗的中位CNS-PFS为8个月，3例患者(20%)的CNS-PFS≥1年[16]。
活动性BM：在 LANDSCAPE研究中，拉帕替尼+卡培他滨联合治疗在未接受过放疗的人群中表现出抗肿瘤活性(CNS-ORR，65.9%)[17]。在PERMEATE研究和TBCRC 022研究中，分别观察到吡咯替尼+卡培他滨和奈拉替尼+卡培他滨有前景的CNS-ORR结果[18,19]。
ADC
稳定性BM：在EMILIA研究中，T-DM1治疗与拉帕替尼-卡培他滨相比显著改善患者OS[20]。DESTINY-Breast01和KAMILLA研究的亚组/探索性分析表明，T-DXd(CNS-ORR，50%) 和T-DM1（脑靶病灶最大直径之和减少≥30%，42.9%）具有良好的抗肿瘤活性[21,22]。与 DESTINY-Breast03研究的主要结果一致，亚组分析观察到在BM患者中 T-DXd与T-DM1具有一致的PFS获益 (HR = 0.25) 和ORR获益[23]。
活动性BM：TUXEDO-1研究达到主要终点，T-DXd的颅内缓解率为73.3%[24]。
活动性和稳定性BM：在DEBBRAH研究中，T-DXd在队列A[稳定性BM患者；16周PFS，n = 7/8(87.5%)和队列C[活动性 BM 患者；CNS-ORR，n = 4/9(44.4%)]均达到了主要终点[25]。细胞周期蛋白依赖性激酶抑制剂：阿贝西利的 NCT02308020 试验未达到其HER2+乳腺癌患者队列的主要终点 (CNS-ORR，0%)[26]。哺乳动物雷帕霉素靶蛋白抑制剂：在 LCCC 1025中观察到依维莫司、曲妥珠单抗和长春瑞滨的CNS-ORR较低 (4%)[27]。
临床意义
随着HER2+乳腺癌BM患者的预期数量增加，该患者人群有效控制颅内疾病的标准治疗需求未得到满足。目前有许多评估HER2+乳腺癌BM患者结局的临床试验，表明近年来对该患者人群的关注增加。然而，在本综述中纳入的HER2+乳腺癌BM患者临床试验设计之间存在相当大的差异性。
未来展望
表2总结了正在进行的辅助治疗研究，这些研究可能有助于了解不同药物（例如 TKI 和ADC）对于预防HER2+乳腺癌患者脑转移的潜在作用。例如，CompassHER2 RD试验（NCT04457596）旨在评估T-DM1+图卡替尼与T-DM1单药相比无BM生存期的差别，并将其作为研究次要终点[28]。同样，DESTINY-Breast05 试验 (NCT04622319) 将评估新辅助治疗后没有达到pCR的高危HER2+乳腺癌患者接受T-DXd与T-DM1治疗后的无BM生存期[29,30]。
表2 正在进行的HER2+乳腺癌和BM患者的相关临床试验
目前ESMO和ASCO指南不建议对无BM症状患者进行常规筛查或脑成像监测[31,32]。但是，欧洲神经肿瘤学协会 ESMO 2021 建议指出，诊断时进行脑部筛查可能是合理的。正在进行的研究可能有助于提供早期主动监测所带来的潜在生存获益数据（表2）。此外，在转移性HER2+乳腺癌BM 患者中进行的不同联合治疗研究有望继续扩大该患者人群的治疗选择，对此，作者总结了正在进行的相关研究：Ⅲ期 HER2CLIMB-02(NCT03975647) 试验将PFS作为有或无基线BM（包括不需要局部治疗的稳定、进展或未经治疗的BM）患者接受图卡替尼或安慰剂联合T-DM1治疗的主要终点[33]。Ⅲb/Ⅳ期DESTINY-Breast12(NCT04739761) 试验将PFS作为接受T-DXd治疗的基线BM患者（包括稳定或进展的BM）的主要终点指标[34]。
结论
对HER2+乳腺癌BM患者进行有效颅内控制的全身性治疗药物的可用性正在增加，但相关临床试验设计存在显著差异。基于此，未来需要对HER2+乳腺癌BM患者的临床试验设计进行标准化，以帮助解释治疗效果，为治疗决策提供信息，并最终提高该患者人群有效治疗选择可及性。目前，一系列研究仍在进行中，包括常规脑筛查价值的研究（例如，NCT04030507、NCT03881605和NCT03617341），HER2+乳腺癌辅助治疗研究（例如，Com-HER2 passRD和DESTINY-Breast05）以及目前HER2+转移性乳腺癌治疗的新型组合研究（例如HER2CLIMB-02和DESTINY-Breast12）等，相信这些研究结果的公布有助于解决上述问题。
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