University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA
Memorial Sloan Kettering Cancer Center, New York City, New York, USA.
Oncologist. 2018 May;23(5):528-539. doi: 10.1634/theoncologist.2017-0423. Epub 2018 Jan 19.
Advancements in molecular profiling and endocrine therapy (ET) have led to more focused clinical attention on precision medicine. These advances have expanded our understanding of breast cancer (BC) pathogenesis and hold promising implications for the future of therapy. The estrogen receptor-α is a predominant endocrine regulatory protein in the breast and in estrogen-induced BC. Successful targeting of proteins and genes within estrogen receptor (ER) nuclear and nonnuclear pathways remains a clinical goal. Several classes of antiestrogenic agents are available for patients with early, advanced, or metastatic BC, including selective ER modulators, aromatase inhibitors, and a selective ER degrader. Clinical development is focused upon characterizing the efficacy and tolerability of inhibitors that target the phosphatidylinositol 3 kinase (PI3K)/akt murine thymoma viral oncogene (AKT)/mammalian target of rapamycin inhibitor (mTOR) signaling pathway or the cyclin-dependent kinase 4/6 (CDK4/6) cell cycle pathway in women with hormone receptor-positive, human epidermal growth receptor 2-negative BC who have demonstrated disease recurrence or progression. De novo and acquired resistance remain a major challenge for women with BC receiving antiestrogenic therapy. Therefore, sequential combination of targeted ET is preferred in these patients, and the ever-increasing understanding of resistance mechanisms may better inform the selection of future therapy. This review describes the intricate roles of the PI3K/AKT/mTOR and CDK4/6 pathways in intracellular signaling and the use of endocrine and endocrine-based combination therapy in BC.
The foundational strategy for treating hormone receptor-positive, human epidermal growth receptor 2-negative, advanced breast cancer includes the use of endocrine therapy either alone or in combination with targeted agents. The use of combination therapy aims to downregulate cell-signaling pathways with the intent of minimizing cellular "crosstalk," which can otherwise result in continued tumorigenesis or progression through redundant pathways. This review provides the clinician with the molecular rationale and clinical evidence for these treatments and refers to evidence-based guidelines to inform the decision-making process.
分子谱分析和内分泌治疗 (ET) 的进步使临床更加关注精准医学。这些进展扩大了我们对乳腺癌 (BC) 发病机制的理解，并为未来的治疗带来了希望。雌激素受体-α是乳腺和雌激素诱导的 BC 中主要的内分泌调节蛋白。成功靶向雌激素受体 (ER) 核和非核途径中的蛋白质和基因仍然是临床目标。有几种类别的抗雌激素药物可用于早期、晚期或转移性 BC 患者，包括选择性雌激素受体调节剂、芳香酶抑制剂和选择性 ER 降解剂。临床开发的重点是描述针对磷脂酰肌醇 3 激酶 (PI3K)/akt 鼠胸腺瘤病毒癌基因 (AKT)/哺乳动物雷帕霉素靶蛋白抑制剂 (mTOR) 信号通路或细胞周期蛋白依赖性激酶 4/6 (CDK4/6) 细胞周期通路的抑制剂在激素受体阳性、人表皮生长因子受体 2 阴性 BC 女性中的疗效和耐受性，这些女性已经出现疾病复发或进展。新出现和获得性耐药仍然是接受抗雌激素治疗的 BC 女性的主要挑战。因此，这些患者首选靶向 ET 的序贯联合治疗，并且对耐药机制的不断深入理解可能更好地为未来治疗的选择提供信息。本综述描述了 PI3K/AKT/mTOR 和 CDK4/6 通路在细胞内信号转导中的复杂作用以及内分泌和基于内分泌的联合治疗在 BC 中的应用。
治疗激素受体阳性、人表皮生长因子受体 2 阴性、晚期乳腺癌的基础策略包括单独使用内分泌治疗或联合使用靶向药物。联合治疗的目的是下调细胞信号通路，旨在最小化细胞“串扰”，否则可能通过冗余通路导致持续的肿瘤发生或进展。本综述为临床医生提供了这些治疗方法的分子基础和临床证据，并参考循证指南为决策过程提供信息。
