Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Gynecological Oncology Section, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Cancer Treat Rev. 2024 Feb;123:102670. doi: 10.1016/j.ctrv.2023.102670. Epub 2023 Dec 9.
In the past decade, significant progress was made in treating hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC), but many clinical questions remain. Cyclin-dependent kinase 4/6 inhibitors are now widely used in combination with endocrine therapy (ET) as standard of care, having demonstrated significant progression-free survival versus ET, and also significant overall survival benefits in the metastatic setting. Inhibition of the PI3K/AKT/mTOR intracellular signaling pathway coupled with ET typically follows first-line therapies. Novel endocrine options including oral selective estrogen receptor down-regulators (SERDs) are in late phases of development, with elacestrant being the first oral SERD to be approved for ESR1-mutant mBC. However, endocrine-refractory disease is inevitable in most patients and represents an area of unmet need, with current recommended options offering poor efficacy, undesirable toxicity, and reduced quality of life. Breakthrough advances in the metastatic setting came via the development of antibody-drug conjugates, which have the advantage of delivering cytotoxic payloads to tumor cells with higher tumor selectivity. Trastuzumab deruxtecan offers a novel therapeutic option for patients with HR+/HER2-low mBC and sacituzumab govitecan is a novel therapeutic option for patients with HR+/HER2- mBC, including those with unmet treatment need in the later-line endocrine-refractory setting. Data gaps still exist regarding optimal sequencing of these novel agents; additional studies into mechanisms of resistance in the metastatic setting would provide further insights. Herein, we describe the current treatment options for HR+/HER2- mBC, including the latest practice-impacting data, and provide commentary on future directions.
在过去的十年中，激素受体阳性（HR+）、人表皮生长因子受体 2 阴性（HER2-）转移性乳腺癌（mBC）的治疗取得了重大进展，但仍存在许多临床问题。细胞周期蛋白依赖性激酶 4/6 抑制剂（CDK4/6i）现已广泛与内分泌治疗（ET）联合用于标准治疗，与 ET 相比，CDK4/6i 显著改善了无进展生存期（PFS），在转移性环境中也显著改善了总生存期（OS）获益。抑制 PI3K/AKT/mTOR 细胞内信号通路与 ET 联合应用通常作为一线治疗。新型内分泌治疗选择包括口服选择性雌激素受体降解剂（SERD），处于开发后期，Elacestrant 是首个获批用于 ESR1 突变 mBC 的口服 SERD。然而，大多数患者最终都会发生内分泌难治性疾病，这是一个尚未满足的需求领域，目前推荐的治疗方案疗效不佳、毒性不可接受，且生活质量降低。在转移性环境中，抗体药物偶联物（ADC）的开发带来了突破性进展，其具有将细胞毒性有效载荷递送至肿瘤细胞的优势，而肿瘤细胞的选择性更高。Trastuzumab deruxtecan 为 HR+/HER2-low mBC 患者提供了一种新的治疗选择，sacituzumab govitecan 为 HR+/HER2-mBC 患者提供了一种新的治疗选择，包括那些在后线内分泌难治性环境中具有未满足治疗需求的患者。关于这些新型药物的最佳序贯应用，仍存在数据空白；进一步研究转移性环境中的耐药机制将提供更多的见解。本文描述了 HR+/HER2- mBC 的当前治疗选择，包括最新的具有临床实践影响的数据，并对未来的方向进行了评论。
