Oral SERD, a Novel Endocrine Therapy for Estrogen Receptor-Positive Breast Cancer

Abstract

Breast cancer is the most common cancer among women worldwide, and estrogen receptor-positive (ER+) breast cancer accounts for a significant proportion of cases. While various treatments are available, endocrine therapies are often the first-line treatment for this type of breast cancer. However, the development of drug resistance poses a significant challenge in managing this disease. ESR1 mutations have been identified as a common mechanism of endocrine therapy resistance in ER+ breast cancer. The first-generation selective estrogen receptor degrader (SERD) fulvestrant has shown some activity against ESR1 mutant tumors. However, due to its poor bioavailability and need for intramuscular injection, it may not be the optimal therapy for patients. Second-generation SERDs were developed to overcome these limitations. These newer drugs have improved oral bioavailability and pharmacokinetics, making them more convenient and effective for patients. Several oral SERDs are now in phase III trials for early and advanced ER+ breast cancer. This review summarizes the background of oral SERD development, the current status, and future perspectives.

Keywords: SERDs; breast cancer; endocrine therapies; estrogen receptor-positive; oral; resistance; selective estrogen receptor degraders.

Figure 1

(A) Common pathway for estrogen in breast cancer. (B) Metastatic breast cancer patients may experience resistance mechanisms to endocrine therapy. A mutation of estrogen receptor 1 (ESR1) causes constant ER activity and enhanced transcription of ER-dependent genes without hormones, resulting in resistance to estrogen deprivation and aromatase inhibitor therapy. (C) SERDs bind to the estrogen receptor; then, E3 ubiquitin ligases and ubiquitinates the ER, marking it for degradation by the proteasome. The proteasome eventually degrades the ubiquitinated ER. Created with BioRender.com (accessed on 8 June 2023).