In metastatic hormone receptor-positive breast cancer, ESR1 mutations are a common cause of acquired resistance to the backbone of therapy, estrogen deprivation by aromatase inhibition. How these mutations affect tumor sensitivity to established and novel therapies are active areas of research. These therapies include estrogen receptor-targeting agents, such as selective estrogen receptor modulators, covalent antagonists, and degraders (including tamoxifen, fulvestrant, and novel agents), and combination therapies, such as endocrine therapy plus CDK4/6, PI3K, or mTORC1 inhibition. In this review, we summarize existing knowledge surrounding the mechanisms of action of ESR1 mutations and roles in resistance to aromatase inhibition. We then analyze the recent literature on how ESR1 mutations affect outcomes in estrogen receptor-targeting and combination therapies. For estrogen receptor-targeting therapies such as tamoxifen and fulvestrant, ESR1 mutations cause relative resistance in vitro but do not clearly lead to resistance in patients, making novel agents in this category promising. Regarding combination therapies, ESR1 mutations nullify any aromatase inhibitor component of the combination. Thus, combinations using endocrine alternatives to aromatase inhibition, or combinations where the non-endocrine component is efficacious as monotherapy, are still effective against ESR1 mutations. These results emphasize the importance of investigating combinatorial resistance, challenging as these efforts are. We also discuss future directions and open questions, such as studying the differences among distinct ESR1 mutations, asking how to adjust clinical decisions based on molecular surveillance testing, and developing novel therapies that are effective against ESR1 mutations.

中文翻译：

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ESR1 突变作为转移性激素受体阳性乳腺癌的新兴临床生物标志物

在转移性激素受体阳性乳腺癌中，ESR1 突变是对主要疗法（芳香酶抑制导致的雌激素剥夺）产生获得性耐药的常见原因。这些突变如何影响肿瘤对现有疗法和新型疗法的敏感性是活跃的研究领域。这些疗法包括雌激素受体靶向药物，如选择性雌激素受体调节剂、共价拮抗剂和降解剂（包括他莫昔芬、氟维司群和新型药物），以及联合疗法，如内分泌治疗加 CDK4/6、PI3K 或 mTORC1 抑制。在这篇综述中，我们总结了有关 ESR1 突变的作用机制以及在抵抗芳香酶抑制中的作用的现有知识。然后，我们分析了有关 ESR1 突变如何影响雌激素受体靶向和联合治疗结果的最新文献。对于雌激素受体靶向疗法，如他莫昔芬和氟维司群，ESR1 突变在体外会引起相对耐药性，但不会明显导致患者产生耐药性，这使得此类新药前景广阔。对于联合疗法，ESR1 突变会使联合疗法中的任何芳香酶抑制剂成分失效。因此，使用内分泌替代品替代芳香酶抑制的组合，或非内分泌成分作为单一疗法有效的组合，仍然能有效对抗ESR1突变。这些结果强调了研究组合阻力的重要性，尽管这些努力具有挑战性。我们还讨论了未来的方向和悬而未决的问题，例如研究不同 ESR1 突变之间的差异，询问如何根据分子监测测试调整临床决策，以及开发有效对抗 ESR1 突变的新疗法。