Nearly 80% of all breast
cancers are
estrogen receptor positive (ER+) and require the activity of this
transcription factor for
tumor growth and survival. Thus, endocrine
therapies, which target the
estrogen signaling axis, have and will continue to be the cornerstone of
therapy for patients diagnosed with ER+ disease. Several inhibitors of ER activity exist, including
aromatase inhibitors (AIs),
selective estrogen receptor modulators (
SERMs), selective
estrogen receptor degraders/down-regulators (SERDs), and ER
proteolysis-targeting chimeras (ER
PROTACs); drugs which differ in the mechanism(s) by which they inhibit this signaling pathway. Notwithstanding their significant impact on the management of this
disease, resistance to existing endocrine
therapies remains a major impediment to durable clinical responses. Although the mechanisms of resistance are complex and varied, dependence on ER is typically retained after progression on
SERMs and AIs, suggesting that ER remains a bona fide therapeutic target. The discovery and development of orally bioavailable drugs that eliminate ER expression (SERDs and ER
PROTACs) will likely aid in treating this growing patient population. All of the existing endocrine
therapies were developed with the intent of inhibiting the
cancer cell intrinsic actions of ER and/or with the objective of achieving extreme
estrogen deprivation and most achieve that goal. A longstanding question that remains to be addressed, however, is how actions of existing interventions extrinsic to the
cancer cells influence
tumor biology. We believe that these issues need to be addressed in the development of strategies to develop the next generation of ER-modulators optimized for positive activities in both
cancer cells and other cells within the tumor microenvironment (TME).