Most breast cancers are Estrogen Receptor-positive (ER+), meaning the cancer cells rely on estrogen to fuel their growth. The Estrogen Receptor (ER) is a protein inside these cells that, when bound by estrogen, initiates signals promoting tumor progression. Therapeutic strategies for ER+ cancers interfere with this signaling pathway by targeting the ER. Two distinct drug classes, Selective Estrogen Receptor Modulators (SERMs) and Selective Estrogen Receptor Degraders (SERDs), block ER activity using fundamentally different molecular mechanisms.
Selective Estrogen Receptor Modulators (SERMs)
Selective Estrogen Receptor Modulators (SERMs) engage with the ER but exert effects that vary depending on the specific tissue. This is known as “modulation,” where the drug acts as an estrogen agonist (activator) in some tissues and an antagonist (blocker) in others. SERMs bind to the ER protein, changing its shape, which determines whether the receptor recruits co-activator proteins to turn on gene transcription or co-repressor proteins to shut it down.
Tamoxifen, a well-known SERM, acts as an antagonist in breast tissue, blocking the proliferative signal to cancer cells. Conversely, in tissues like bone, Tamoxifen and Raloxifene act as agonists, helping maintain bone density in postmenopausal women. This tissue-specific activity makes SERMs valuable for treating early-stage ER+ breast cancer and for chemoprevention.
Selective Estrogen Receptor Degraders (SERDs)
Selective Estrogen Receptor Degraders (SERDs) employ an aggressive approach to blocking ER signaling. Instead of modulating the receptor’s function, SERDs induce the physical destruction and removal of the ER protein from the cell. When a SERD binds to the Estrogen Receptor, it causes a conformational change that tags the receptor for degradation.
This tagging involves ubiquitination, where cellular machinery attaches ubiquitin molecules to the misfolded receptor. The ubiquitinated ER protein is then targeted to the proteasome, the cell’s protein disposal system, leading to rapid breakdown. This mechanism, known as downregulation, results in a near-total loss of the ER population, suppressing tumor growth signals. SERDs act as pure antagonists, meaning they do not exhibit estrogen-like agonist activity in any tissue, unlike SERMs.
Distinctions in Clinical Use and Administration
The clinical application of SERMs and SERDs differs significantly due to their distinct mechanisms and properties. Historically, the first-generation SERD, Fulvestrant, required intramuscular injection due to poor oral bioavailability. This contrasted with SERMs like Tamoxifen and Raloxifene, which are convenient oral tablets. The recent development of next-generation oral SERDs, such as Elacestrant, offers the potent degradation mechanism in a patient-friendly oral formulation.
SERMs are frequently used for primary and adjuvant therapy in early-stage breast cancer and for risk reduction. Their dual agonist/antagonist nature contributes to specific side effects. Agonist activity in the uterus can increase the risk of endometrial thickening and, rarely, cancer, while agonism on clotting factors can raise the risk of venous thromboembolism.
SERDs were traditionally reserved for treating advanced or metastatic ER+ breast cancer, often after progression on other endocrine therapies. Because SERDs are pure antagonists, they avoid the uterine and thromboembolic risks associated with SERMs. SERMs are generally preferred for long-term adjuvant use, while SERDs are utilized in later-line settings for more aggressive or resistant disease.
Addressing Hormone Therapy Resistance
A significant challenge in treating ER+ breast cancer is the development of acquired resistance to endocrine therapies, often occurring during treatment with SERMs or aromatase inhibitors. A common mechanism involves activating mutations in the ESR1 gene, which encodes the Estrogen Receptor. While rare in primary tumors, these mutations are found in many metastatic cancers that progress after initial endocrine therapy.
The mutation alters the receptor’s structure, causing it to become constitutively active, signaling for cell growth even without estrogen or a SERM. SERMs are ineffective against these mutated receptors because they cannot overcome this constant activity. SERDs become the preferred therapeutic option because their mechanism is to physically destroy the receptor protein. By degrading the total population of ER proteins, including the mutated, constitutively active ones, SERDs remove the source of the uncontrolled growth signal. The approval of oral SERDs for use in patients whose tumors harbor ESR1 mutations underscores their utility in overcoming this common form of resistance.