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Purpose <p>The management of hormone receptor-positive (HR +) breast cancer (BC) relies on endocrine therapy (ET), with a primary focus on disrupting estrogen receptor (ER) signaling due to its critical role in BC tumorigenesis and progression. While effective for both early-stage and advanced breast cancers, ET frequently encounters resistance mechanisms, including both ligand-dependent and ligand-independent trajectories, ultimately leading to disease progression.</p> Methods <p>We searched PubMed, EMBASE and Scopus databases&#xa0;to review the current evidence on&#xa0;the use of novel&#xa0;oral selective estrogen receptor degraders (SERDs)&#xa0;for the treatment of HR+ BC.</p> Conclusions <p>Somatic activating mutations of the <i>estrogen receptor 1 (ESR1)</i> gene are known to sustain ER activity, boost ER-dependent gene transcription, and foster resistance to ET. The most significant gap remains after treatment failure with ET and cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, where fulvestrant monotherapy typically results in a median progression-free survival of 2–3&#xa0;months. Novel compounds, including oral SERDs, have been explored for their potential to overcome therapeutic resistance, both as monotherapy and in combination with other targeted therapies. Herein, we provide an overview on the latest findings on oral SERDs, examining their mechanism of action, safety data, and pharmacokinetics and pharmacodynamics profiles.</p>

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Oral selective estrogen receptor degraders for breast cancer treatment: focus on pharmacological differences

  • 期刊论文

  • 发表日期：

    2025年1月8日

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  • Roberta Scafetta,
  • Paola Zagami,
  • Marzia Del Re,
  • Carmen Criscitiello,
  • Antonio Marra,
  • Giuseppe Curigliano

摘要

Purpose

The management of hormone receptor-positive (HR +) breast cancer (BC) relies on endocrine therapy (ET), with a primary focus on disrupting estrogen receptor (ER) signaling due to its critical role in BC tumorigenesis and progression. While effective for both early-stage and advanced breast cancers, ET frequently encounters resistance mechanisms, including both ligand-dependent and ligand-independent trajectories, ultimately leading to disease progression.

Methods

We searched PubMed, EMBASE and Scopus databases to review the current evidence on the use of novel oral selective estrogen receptor degraders (SERDs) for the treatment of HR+ BC.

Conclusions

Somatic activating mutations of the estrogen receptor 1 (ESR1) gene are known to sustain ER activity, boost ER-dependent gene transcription, and foster resistance to ET. The most significant gap remains after treatment failure with ET and cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, where fulvestrant monotherapy typically results in a median progression-free survival of 2–3 months. Novel compounds, including oral SERDs, have been explored for their potential to overcome therapeutic resistance, both as monotherapy and in combination with other targeted therapies. Herein, we provide an overview on the latest findings on oral SERDs, examining their mechanism of action, safety data, and pharmacokinetics and pharmacodynamics profiles.