Tamoxifen, a Selective Estrogen Receptor Modulator (SERM), serves as a foundational endocrine therapy for patients diagnosed with hormone-receptor-positive breast cancer. This medication works by blocking estrogen from binding to receptors on cancer cells, thereby slowing tumor growth. While highly effective, patients may require alternative treatments due to intolerance to side effects, specific health risks like blood clots, or the eventual development of resistance by the cancer cells. The strategies for finding an alternative focus on either blocking the production of estrogen entirely or employing a different mechanism to attack the estrogen receptor.
Aromatase Inhibitors
Aromatase inhibitors (AIs) represent the most common alternative to Tamoxifen, particularly for postmenopausal women whose primary source of estrogen is no longer the ovaries. This class of drugs acts by suppressing the final step of estrogen synthesis in non-ovarian tissues like fat and muscle. The drug targets the aromatase enzyme, which is responsible for converting androgen hormones into estrogen. By inhibiting this enzyme, AIs can reduce the amount of circulating estrogen in the body by up to 95%.
Three third-generation AIs are commonly used: anastrozole, letrozole, and exemestane. Anastrozole and letrozole are non-steroidal inhibitors that bind reversibly to the aromatase enzyme, competitively occupying the active site.
Exemestane is classified as a steroidal AI and functions through a distinct mechanism. It is an irreversible inhibitor, permanently deactivating the aromatase enzyme once it binds. This difference in mechanism is why a patient might switch from a non-steroidal AI to exemestane if resistance develops. AIs are generally preferred over Tamoxifen for postmenopausal women because they have demonstrated a slight increase in preventing recurrence.
Strategies for Premenopausal Patients
The treatment approach for premenopausal patients requires a unique strategy because their ovaries are the main source of estrogen production. Aromatase inhibitors alone are ineffective, as the body’s feedback loop causes the ovaries to increase estrogen output in response to suppressed peripheral production. The primary alternative strategy involves combining an endocrine therapy with Ovarian Function Suppression (OFS). OFS effectively shuts down the ovaries, rendering the patient functionally postmenopausal, which allows AIs to be used effectively.
Ovarian function can be suppressed using temporary or permanent methods. Temporary suppression is achieved with Luteinizing Hormone-Releasing Hormone (LHRH) agonists (e.g., goserelin or leuprolide). These injectable medications block pituitary signals that stimulate the ovaries to produce estrogen. This method is reversible, offering flexibility for women who may wish to preserve their fertility options after treatment.
Permanent suppression involves either the surgical removal of the ovaries, known as bilateral oophorectomy, or ovarian ablation using radiation. Once ovarian function is suppressed, the patient can be treated with Tamoxifen or an AI, such as exemestane, in combination with the OFS agent. Studies have demonstrated that using an AI combined with OFS can lower the risk of cancer recurrence more than Tamoxifen alone in premenopausal women with a high-risk diagnosis.
Selective Estrogen Receptor Degraders (SERDs)
Selective Estrogen Receptor Degraders (SERDs) offer a distinct mechanism compared to Tamoxifen (a SERM). While Tamoxifen modulates the receptor’s activity, a SERD actively binds to the estrogen receptor (ER) and induces its degradation. This process causes the physical destruction and downregulation of the receptor protein, leading to a complete interruption of estrogen signaling.
The first approved drug in this class is fulvestrant, administered as an intramuscular injection. Fulvestrant is often reserved for patients whose cancer has progressed after receiving other anti-estrogen therapies like Tamoxifen or AIs. Its ability to destabilize the ER and act as a pure antagonist makes it effective against tumors that have developed resistance to earlier treatments.
Newer, oral SERDs are now being developed to improve patient convenience and address the poor bioavailability of fulvestrant. The oral SERD elacestrant has been approved for patients with advanced or metastatic disease that harbors a specific mutation in the estrogen receptor gene, ESR1. The development of these oral agents, such as elacestrant and camizestrant, offers a more convenient and potentially more potent alternative for tackling endocrine-resistant cancer.
Targeted Therapies Used in Combination
When cancer cells become resistant to standard endocrine monotherapy (Tamoxifen or an AI), the strategy shifts to combination treatment involving targeted therapies. These therapies are designed to overcome resistance by disrupting alternative growth pathways within the cell. They are always administered concurrently with an endocrine drug, such as an AI or fulvestrant, to achieve a synergistic effect.
The most widely used class of these combination agents is the Cyclin-Dependent Kinase 4/6 (CDK4/6) inhibitors, which include drugs like palbociclib, ribociclib, and abemaciclib. CDK4/6 inhibitors stall the cell division cycle, preventing the cancer cells from multiplying. Combining these inhibitors with an endocrine agent significantly improves progression-free survival in advanced hormone-receptor-positive breast cancer.
Other targeted therapies address different resistance pathways, such as the PI3K/AKT/mTOR signaling cascade. The mTOR inhibitor everolimus is combined with an AI to overcome resistance by blocking a downstream growth signal. The PI3K inhibitor alpelisib is used in combination with an endocrine agent for tumors that have a PIK3CA gene mutation, a common resistance mechanism. These combination strategies are reserved for advanced disease or high-risk early-stage disease where the cancer has proven difficult to control.