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HER2阳性乳腺癌的侵袭性强、脑转移率高，三分之二的HER2阳性乳腺癌脑转移由于PI3K/mTOR通路激活而对HER2靶向疗法耐药。依维莫司属于mTOR抑制剂，而且可以穿过血脑屏障。 2018年6月25日，施普林格·自然旗下《乳腺癌研究与治疗》在线发表美国北卡罗来纳大学（UNC）莱恩伯格综合癌症中心（LCCC）、德克萨斯大学MD安德森癌症中心奥兰多医院、阿拉巴马大学、芝加哥大学、弗吉尼亚大学、范德比大学、田纳西大学的II期研究（LCCC 1025）报告，初步评价了依维莫司＋曲妥珠单抗＋长春瑞滨治疗HER2阳性乳腺癌脑转移患者的有效性和安全性。 该非盲单组II期研究（LCCC 1025）于2011～2016年入组32例进行性HER2阳性乳腺癌脑转移患者接受依维莫司＋曲妥珠单抗＋长春瑞滨治疗。主要终点为颅内缓解率；次要目标为中枢神经系统临床获益率、颅外缓解率、进展时间、总生存、入组患者肿瘤靶向测序。根据历史对照，预设两阶段颅内缓解率5%比20%。 最后，32例患者可评估毒性反应，26例可评估疗效。 颅内缓解率4%（部分缓解1例）。3、6个月时中枢神经系统临床获益率65%、27%；颅内进展时间中位3.9个月（95%置信区间：2.2～5）。总生存中位12.2个月（95%置信区间：0.6～20.2）。 3～4级毒性反应包括中性粒细胞减少（41%）贫血（16%）口腔炎（16%）。 TP53和PIK3CA突变常见于乳腺癌脑转移。PI3K/mTOR通路突变与疗效无关。乳腺癌脑转移与乳腺癌原发灶相比，ERBB2扩增率较高；乳腺癌原发灶ERBB2扩增患者的总生存较差。 因此，虽然依维莫司＋曲妥珠单抗＋长春瑞滨治疗HER2阳性乳腺癌脑转移患者的颅内缓解率低，但是中枢神经系统临床获益率将近三分之一；进展时间、总生存、毒性反应与历史对照相似。有必要进一步分析乳腺癌脑转移的基因组机制，确定能够预测疗效和/或结局的生物标志。 相关阅读 Breast Cancer Res Treat. 2018 Jun 25. LCCC 1025: a phase II study of everolimus, trastuzumab, and vinorelbine to treat progressive HER2-positive breast cancer brain metastases. Amanda E. D. Van Swearingen, Marni B. Siegel, Allison M. Deal, Maria J. Sambade, Alan Hoyle, D. Neil Hayes, Heejoon Jo, Paul Little, Elizabeth Claire Dees, Hyman Muss, Trevor Jolly, Timothy M. Zagar, Nirali Patel, C. Ryan Miller, Joel S. Parker, J. Keith Smith, Julie Fisher, Nikita Shah, Lisle Nabell, Rita Nanda, Patrick Dillon, Vandana Abramson, Lisa A. Carey, Carey K. Anders. University of North Carolina at Chapel Hill, Chapel Hill, USA Carolinas Medical Center, Charlotte, USA; MD Anderson Orlando, Orlando, USA; University of Alabama, Birmingham, USA; University of Chicago, Chicago, USA; University of Virginia, Charlottesville, USA; Vanderbilt University, Nashville, USA; University of Tennessee, Knoxville, USA. PURPOSE: HER2+ breast cancer (BC) is an aggressive subtype with high rates of brain metastases (BCBM). Two-thirds of HER2+ BCBM demonstrate activation of the PI3K/mTOR pathway driving resistance to anti-HER2 therapy. This phase II study evaluated everolimus (E), a brain-permeable mTOR inhibitor, trastuzumab (T), and vinorelbine (V) in patients with HER2+ BCBM. PATIENTS AND METHODS: Eligible patients had progressive HER2+ BCBM. The primary endpoint was intracranial response rate (RR); secondary objectives were CNS clinical benefit rate (CBR), extracranial RR, time to progression (TTP), overall survival (OS), and targeted sequencing of tumors from enrolled patients. A two-stage design distinguished intracranial RR of 5% versus 20%. RESULTS: 32 patients were evaluable for toxicity, 26 for efficacy. Intracranial RR was 4% (1 PR). CNS CBR at 6 mos was 27%; at 3 mos 65%. Median intracranial TTP was 3.9 mos (95% CI 2.2-5). OS was 12.2 mos (95% CI 0.6-20.2). Grade 3-4 toxicities included neutropenia (41%), anemia (16%), and stomatitis (16%). Mutations in TP53 and PIK3CA were common in BCBM. Mutations in the PI3K/mTOR pathway were not associated with response. ERBB2 amplification was higher in BCBM compared to primary BC; ERBB2 amplification in the primary BC trended toward worse OS. CONCLUSION: While intracranial RR to ETV was low in HER2+ BCBM patients, one-third achieved CNS CBR; TTP/OS was similar to historical control. No new toxicity signals were observed. Further analysis of the genomic underpinnings of BCBM to identify tractable prognostic and/or predictive biomarkers is warranted. CLINICAL TRIAL: NCT01305941. KEYWORDS: Breast cancer; Brain metastases; Metastases; PI3K, MEK Targeted therapy DOI: 10.1007/s10549-018-4852-5
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