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Accelerating drug development in breast cancer: New frontiers for ER inhibition

      Highlights

      • New ER inhibitors show improved pharmacokinetics and pharmacodynamics compared to fulvestrant.
      • Composition of the side chain of oral SERDs affects their efficacy for efficacy.
      • Five oral SERDs are in phase III trials in the advanced setting and two in the adjuvant setting.
      • New ER inhibitors/degraders under investigation: SERCA, CERAN, PROTAC, and SERM/SERD hybrid.
      • Oral route and potency render the agents ideal endocrine backbone for combination therapies.

      Abstract

      The estrogen receptor (ER) is an important driver in the proliferation, tumorigenesis, and progression of breast cancers, and targeting ER signaling at different levels is a successful strategy in the control of hormone receptor positive (HR+) breast cancer. Endocrine therapy has been the treatment of choice for HR+ breast cancer in the early and advanced stages with multiple agents, including selective estrogen receptor modulators (SERMS), selective estrogen receptor degraders (SERDs), and aromatase inhibitors (AIs), which vary in their mechanisms of action and pharmacokinetics. Combination strategies also employ cyclin dependent kinase 4 and 6 and phosphatidylinositol 3-kinase to maximize the benefits of endocrine therapy. This paper reviews the clinical development of SERDs and other novel ER inhibitors, as well as combination strategies to overcome mechanisms of ER pathway escape. It also assesses the advantages of newer oral ER inhibitors with increased bioavailability, improved therapeutic index, better administration, and increased efficacy, as well as discussing future directions in the field.

      Keywords

      Abbreviations:

      AI: (Aromatase Inhibitor), AF-1 and AF2: (Activation Fuctions 1 and 2 regions of ER), CDK4/6: (Cyclin Dependent Kinase 4 and 6), CERAN: (Complete ER ANtagonists), cfDNA: (cell free DNA), DCIS: (Ductal Carcinoma In Situ), EMA: (European Medicine Agency), ESR1: (Estrogen Receptor 1), FDA: (Food and Drug Administration), HER2- : (Human Epidermal growth factor Receptor 2 negative), HR+ : (Hormone Receptors positive), OS: (Overall Survival), PFS: (Progression-Free Survival), PI3K: (Phosphatidylinositol 3-kinase), PK: (Pharmacokinetics), PROTAC: (PROteolysis TArgeting Chimera), SERCA: (Selective Estrogen Receptor Covalent Antagonist), SERD: (Selective Estrogen Receptor Degrader), SERM: (Selective Estrogen Receptor Modulator)
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