利用细胞周期蛋白依赖性激酶 4 和 6 抑制剂 (CDK4/6i) 与内分泌治疗 (ET) 的一线联合疗法显着影响了激素受体阳性 (HR )/人表皮生长因子受体 2 阴性 (HER2-) 的病程晚期乳腺癌（ABC）。然而，耐药性经常出现，导致分子上不同的疾病。雌激素受体一 (ESR1) 基因突变导致对芳香酶抑制剂 (AI) 产生耐药性，可能会指导氟维司群或新出现的口服选择性雌激素受体降解剂 (SERD)（如 elacestrant）的使用。 ESR1 突变的动态性质表明，对于进展后继续 CDK4/6i 治疗具有潜在指导作用。使用聚（ADP-核糖）聚合酶（PARP）抑制剂或 PI3K/AKT/mTOR 通路靶向乳腺癌基因 1 和 2 (BRCA 1/2) 等突变提供了治疗选择。曲妥珠单抗 deruxtecan (T-DXd) 等抗体药物偶联物 (ADC) 和针对滋养层细胞表面抗原 2 (Trop-2) 的新型药物的出现带来了进一步的复杂性，强调了针对转移性 BC 中特定基因组改变进行早期干预的必要性.版权所有 © 2024 Elsevier B.V. 保留所有权利。

The first-line combination therapies utilizing cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) with endocrine therapy (ET) have significantly impacted the course of hormone receptor positive (HR+)/Human Epidermal Growth Factor Receptor 2 negative (HER2-) advanced breast cancer (ABC). However, resistance often emerges, leading to a molecularly different disease. Estrogen receptor one (ESR1) gene mutations, driving resistance to aromatase inhibitors (AIs), may guide the use of fulvestrant or emerging oral selective estrogen receptor degraders (SERDs) like elacestrant. The dynamic nature of ESR1 mutations suggests potential guidance for continuing CDK4/6i therapy beyond progression. Targeting mutations like breast cancer gene 1 and 2 (BRCA 1/2) with Poly (ADP-ribose) polymerase (PARP) inhibitors or the PI3K/AKT/mTOR pathway provides therapeutic options. The advent of antibody-drug conjugates (ADCs) like trastuzumab deruxtecan (T-DXd) and novel agents targeting Trophoblast cell surface antigen-2 (Trop-2) introduces further complexity, underscoring the need for early intervention targeting specific genomic alterations in metastatic BC.Copyright © 2024 Elsevier B.V. All rights reserved.