Alec Vi

Background: Breast cancer is a common cancer diagnosed in women worldwide and serves to be the leading cause of death of women by cancer.^1,2 Breast cancer is typically caused by a mutation found in Breast Cancer Associated gene 1 or 2 (BRCA1/2) that normally functions to regulate DNA repair and cell cycle checkpoints and can then be separated into multiple molecular profiles such as estrogen receptor positive (ER+) which constitutes 60-70% of all breast cancers.^1,3,4 In ER+ breast cancer, current therapy involves the use of antiestrogens, CDK4/6 inhibitors, mTOR inhibitors, or PI3K inhibitors.^1-4 However, in several ER+ breast cancer cases, endocrine therapy resistance can develop which necessitates the development newer therapies to provide improved outcomes or alternative treatment to current methods.^1,3,4

Objective: The purpose of this study is to look at the literature for ER+ breast cancer therapy development of proteolysis targeting chimera (PROTAC).

Search Methods: An online search in the PubMed database was conducted from 2019 to 2025 using the following keywords: “breast cancer”, “ARV-471”, “proteolysis targeting chimera”, “vepdegstrant”, “breast cancer”, “ESR1 mutations”.

Results: Studies have shown that vepdegstrant works by directly binding onto estrogen receptors in the cell and using its own E3-ligase for ubiquitination of the receptor to mark it for degradation by the proteasome. It was shown to be stable under several conditions when administered in vitro and in vivo, however it was unstable in pH testing during in vitro testing.⁵ The administration of vepdegestrant through oral and IV routes was done in both male and female rats and plasma concentration was measured afterwards which showed similar concentrations when dosage was equalized between routes.⁶ Vepdegestrant showed no toxic metabolites when administered in vitro and was primarily excreted through urine and feces.^6,7 The breakdown of vepdegestrant was done through the processes of glucuronidation, oxidation, N-dealkylation, and hydrolysis.⁷ When administered in rats no changes in uterine weights were found while at the time ER+ receptors were found to be decreased.⁸ In vivo studies of rats and mice demonstrated greater tumor growth inhibitions when administered with vepdegstrant in comparison to fulvestrant.⁸ In phase 1 clinical studies, it was shown that oral vepdegestrant was capable in treating advanced breast cancer in Japanese patients who had undergone several previous therapies with minimal adverse events and the most common being fatigue.⁹

Conclusion: Studies have shown that vepdegestrant is a viable option for patients undergoing therapy for ER+ breast cancer since it has shown to have greater therapeutic outcomes than current medications such as fulvestrant in monotherapy and in polytherapy combinations. Furthermore, it is less difficult to administer as it can be given orally which is much easier for patients to follow in comparison to fulvestrant which is done by intramuscular injection.

Works Cited:

1. Clusan L, Ferrière F, Flouriot G, Pakdel F. A Basic Review on Estrogen Receptor Signaling Pathways in Breast Cancer. Int J Mol Sci. 2023;24(7):6834. Published 2023 Apr 6. doi:10.3390/ijms24076834
2. Katsura C, Ogunmwonyi I, Kankam HK, Saha S. Breast cancer: presentation, investigation and management. Br J Hosp Med (Lond). 2022;83(2):1-7. doi:10.12968/hmed.2021.0459
3. Raheem F, Karikalan SA, Batalini F, El Masry A, Mina L. Metastatic ER+ Breast Cancer: Mechanisms of Resistance and Future Therapeutic Approaches. Int J Mol Sci. 2023;24(22):16198. Published 2023 Nov 11. doi:10.3390/ijms242216198
4. Dustin D, Gu G, Fuqua SAW. ESR1 mutations in breast cancer. Cancer. 2019;125(21):3714-3728. doi:10.1002/cncr.32345
5. Choi HI, Choi J, Kim JW, Lee YH, Cho KH, Koo TS. Stability Evaluation and  Pharmacokinetic Profiling of Vepdegestrant in Rodents Using Liquid Chromatography-Tandem Mass Spectrometry. Molecules. 2024 Aug 27;29(17):4048. doi: 10.3390/molecules29174048. PMID: 39274896; PMCID: PMC11396746.
6. He Y, Zhu C, Lei P, et al. Characterization of preclinical radio ADME properties of  ARV-471 for predicting human PK using PBPK modeling. Journal of Pharmaceutical Analysis. Published online December 28, 2024:101175. doi:https://doi.org/10.1016/j.jpha.2024.101175
7. He Y, Hou P, Long Z, et al. Application of Electro-Activated Dissociation Fragmentation Technique to Identifying Glucuronidation and Oxidative Metabolism Sites of Vepdegestrant by Liquid Chromatography-High Resolution Mass Spectrometry. Drug Metab Dispos. 2024;52(7):634-643. Published 2024 Jun 17. doi:10.1124/dmd.124.001661
8. Gough SM, Flanagan JJ, Teh J, et al. Oral Estrogen Receptor PROTAC Vepdegestrant (ARV-471) Is Highly Efficacious as Monotherapy and in Combination with CDK4/6 or PI3K/mTOR Pathway Inhibitors in Preclinical ER+ Breast Cancer Models. Clin Cancer Res. 2024;30(16):3549-3563. doi:10.1158/1078-0432.CCR-23-3465
9. Iwata H, Naito Y, Hattori M, et al. Safety and pharmacokinetics of vepdegestrant in Japanese patients with ER+ advanced breast cancer: a phase 1 study. Int J Clin Oncol. 2025;30(1):72-82. doi:10.1007/s10147-024-02648-3