The trastuzumab era: current and upcoming targeted HER2+ breast cancer therapies.
The trastuzumab era: current and upcoming targeted HER2+ breast cancer therapies.
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发表时间：
2020-04
影响因子：
5.3
通讯作者：
Jordyn Kreutzfeldt;Brett J. Rozeboom;N. Dey;P. De
中科院分区：
文献类型：
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作者：
Jordyn Kreutzfeldt;Brett J. Rozeboom;N. Dey;P. De
人表皮生长因子受体 2 阳性乳腺癌 (HER2+ BC) 的定义是 ERBB2/neu 癌基因扩增增加和/或其相关 HER2 跨膜受体蛋白过度表达。 HER2+ BC 约占乳腺癌的 15-20%，它与更高级别、更具侵袭性的表型和更差的预后独立相关。随着曲妥珠单抗的出现，HER2+ BC 患者的预后状况已大大改善。然而，曲妥珠单抗的从头耐药性和获得性耐药性仍然是许多患者的重大障碍，需要新的疗法才能获得进一步的临床益处。在过去的二十年里，HER2+ BC 治疗方案的开发取得了非凡的进展，并通过 NCI-MATCH 精准医学试验计划 (NCT02465060) 扩展到 HER2 扩增的胃食管交界癌。根据国家综合癌症网络 (NCCN) 指南，曲妥珠单抗、帕妥珠单抗、T-DM1 和拉帕替尼通常被推荐作为单药（与化疗一起）或抗 HER2 药物联合用于新辅助、辅助和转移治疗。目前，曲妥珠单抗、帕妥珠单抗和紫杉烷联合化疗是治疗 HER2+/HR- 转移性乳腺癌的一线疗法，曲妥珠单抗-deruxtecan (DS-8201a)、margetuximab 和 tucatinib (ONT-380) 等潜在突破性疗法即将出现。此外，最近的临床试验证明了激素受体状态、PAM-50 管腔内在亚型、PD-L1 和 TIL 作为 HER2+ 治疗反应的预测生物标志物的潜在用途。我们简单介绍了HER2的起源、曲妥珠单抗的发明以及HER2+ BC的分类。然后通过适应症、作用机制和相关临床试验介绍每种 HER2 靶向疗法，并在临床环境中进行后续阐述和背景化，最后列出用于 HER2+ BC 临床使用的潜在未来生物标志物。我们总结了与 HER2+ BC 管理相关的临床实践中最重要和最新的研究，并重点介绍了即将推出的抗 HER2 药物以及与抗 HER2 药物联合使用的免疫治疗药物的临床状况。
Human Epidermal Growth Factor Receptor 2-positive breast cancer (HER2+ BC) is defined by increased amplification of the ERBB2/neu oncogene and/or overexpression of its associated HER2 transmembrane receptor protein. HER2+ BC represents approximately 15-20% of breast cancer, and it is independently associated with a higher grade, more aggressive phenotype, and worse prognosis. With the advent of trastuzumab, the prognostic landscape for HER2+ BC patients has considerably improved. However, both de novo and acquired resistance to trastuzumab remain a significant obstacle for many patients, requiring novel therapies for further clinical benefit. Over the last two decades, there has been extraordinary progress in the development of HER2+ BC treatment regimens, with extensions into HER2-amplified gastroesophageal junction cancer via the NCI-MATCH precision medicine trial program (NCT02465060). Trastuzumab, pertuzumab, T-DM1, and lapatinib are commonly recommended as a single agent (along with chemotherapy) or in combinations of anti-HER2 agents in neoadjuvant, adjuvant and metastatic settings according to National Comprehensive Cancer Network (NCCN) guidelines. Currently, the combination of trastuzumab, pertuzumab, and taxane chemotherapy are first-line for HER2+/HR- metastatic breast cancer with potential breakthrough therapies such as trastuzumab-deruxtecan (DS-8201a), margetuximab and tucatinib (ONT-380) on the horizon. Furthermore, recent clinical trials have demonstrated the potential utility of hormone receptor status, PAM-50 luminal intrinsic subtype, PD-L1, and TIL as predictive biomarkers for response to HER2+ therapies. We briefly introduce the origin of HER2, the invention of trastuzumab, and the classification of HER2+ BC. Each HER2-targeted therapy is then presented by indication, mechanism of action, and relevant clinical trials with subsequent elaboration and contextualization within clinical settings with an epilogue of potential future biomarkers for clinical use in HER2+ BC. We summarize the most significant and updated research in clinical practice relevant to HER2+ BC management and highlight the clinical status of upcoming anti-HER2 agents as well as immunotherapy drugs in combination with anti-HER2 agents.