Pegram Mark, Pietras Richard, Dang Chau T, Murthy Rashmi, Bachelot Thomas, Janni Wolfgang, Sharma Priyanka, Hamilton Erika, Saura Cristina
Stanford Comprehensive Cancer Institute, Stanford University School of Medicine, Lorry Lokey Building/SIM 1, 265 Campus Drive, Ste G2103, Stanford, CA 94305-5456, USA.
Division of Hematology-Oncology, Department of Medicine, UCLA David Geffen School of Medicine, Los Angeles, CA, USA.
Ther Adv Med Oncol. 2023 Aug 11;15:17588359231187201. doi: 10.1177/17588359231187201. eCollection 2023.
Breast cancer (BC) with expression of the estrogen receptor (ER) and/or progesterone receptor (PR) protein and with overexpression/amplification of the human epidermal growth factor receptor 2 (HER2), termed hormone receptor-positive (HR+)/HER2+ BC, represents ∼10% of all BCs in the United States. HR+/HER2+ BC includes HER2+ BCs that are ER+, PR+, or both ER+ and PR+ (triple-positive BC). Although the current guideline-recommended treatment combination of anti-HER2 monoclonal antibodies plus chemotherapy is an effective first-line therapy for many patients with HER2+ advanced disease, intratumoral heterogeneity within the HR+/HER2+ subtype and differences between the HR+/HER2+ subtype and the HR-/HER2+ subtype suggest that other targeted combinations could be investigated in randomized clinical trials for patients with HR+/HER2+ BC. In addition, published data indicate that crosstalk between HRs and HER2 can lead to treatment resistance. Dual HR and HER2 pathway targeting has been shown to be a rational approach to effective and well-tolerated therapy for patients with tumors driven by HER2 and HR, as it may prevent development of resistance by blocking receptor pathway crosstalk. However, clinical trial data for such approaches are limited. Treatments to attenuate other signaling pathways involved in receptor crosstalk are also under investigation for inclusion in dual receptor targeting regimens. These include cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, based on the rationale that association of CDK4/6 with cyclin D1 may play a role in resistance to HER2-directed therapies, and others such as phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway inhibitors. Herein, we will review the scientific and clinical rationale for combined receptor blockade targeting HER2 and ER for patients with advanced-stage HR+/HER2+ disease.
雌激素受体（ER）和/或孕激素受体（PR）蛋白表达阳性且人表皮生长因子受体2（HER2）过表达/扩增的乳腺癌（BC），即激素受体阳性（HR+）/HER2+ BC，在美国所有乳腺癌中占比约10%。HR+/HER2+ BC包括ER+、PR+或ER+和PR+均阳性（三阳性BC）的HER2+ BC。尽管目前指南推荐的抗HER2单克隆抗体联合化疗是许多HER2+晚期疾病患者的有效一线治疗方案，但HR+/HER2+亚型内的肿瘤内异质性以及HR+/HER2+亚型与HR-/HER2+亚型之间的差异表明，其他靶向联合方案可在HR+/HER2+ BC患者的随机临床试验中进行研究。此外，已发表的数据表明，HRs与HER2之间的相互作用可导致治疗耐药。针对HR和HER2双途径靶向已被证明是一种针对由HER2和HR驱动的肿瘤患者进行有效且耐受性良好治疗的合理方法，因为它可能通过阻断受体途径相互作用来预防耐药的发生。然而，此类方法的临床试验数据有限。针对受体相互作用中涉及的其他信号通路的减毒治疗也在研究中，以纳入双受体靶向治疗方案。这些包括细胞周期蛋白依赖性激酶4和6（CDK4/6）抑制剂，其依据是CDK4/6与细胞周期蛋白D1的结合可能在对HER2导向治疗的耐药中起作用，以及其他如磷脂酰肌醇-3-激酶（PI3K）/蛋白激酶B（AKT）/雷帕霉素靶蛋白（mTOR）途径抑制剂。在此，我们将综述针对晚期HR+/HER2+疾病患者联合靶向HER2和ER进行受体阻断的科学和临床依据。
