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.

中文翻译：

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HR+/HER2+ 转移性乳腺癌治疗的观点不断变化。

表达雌激素受体 (ER) 和/或孕激素受体 (PR) 蛋白以及过度表达/扩增人表皮生长因子受体 2 (HER2) 的乳腺癌 (BC)，称为激素受体阳性 (HR+)/HER2+ BC 省占美国所有 BC 省的 10%。HR+/HER2+ BC 包括 ER+、PR+ 或同时为 ER+ 和 PR+ 的 HER2+ BC（三阳性 BC）。尽管目前指南推荐的抗 HER2 单克隆抗体联合化疗的治疗组合对于许多 HER2+ 晚期疾病患者来说是有效的一线治疗，但 HR+/HER2+ 亚型内的瘤内异质性以及 HR+/HER2+ 亚型与 HR 之间的差异-/HER2+ 亚型表明，可以在针对 HR+/HER2+ BC 患者的随机临床试验中研究其他靶向组合。此外，已发表的数据表明 HR 和 HER2 之间的串扰可导致治疗耐药。HR 和 HER2 通路双重靶向已被证明是对 HER2 和 HR 驱动的肿瘤患者进行有效且耐受性良好的治疗的合理方法，因为它可以通过阻断受体通路串扰来防止耐药性的发展。然而，此类方法的临床试验数据有限。减弱与受体串扰有关的其他信号通路的治疗也在研究中，以纳入双受体靶向治疗方案中。其中包括细胞周期蛋白依赖性激酶 4 和 6 (CDK4/6) 抑制剂，其原理是 CDK4/6 与细胞周期蛋白 D1 的关联可能在 HER2 导向疗法的耐药性中发挥作用，以及其他药物，例如磷脂酰肌醇 3 激酶(PI3K)/蛋白激酶 B (AKT)/哺乳动物雷帕霉素靶点 (mTOR) 通路抑制剂。在此，我们将回顾针对晚期 HR+/HER2+ 疾病患者针对 HER2 和 ER 的联合受体阻断的科学和临床原理。