Hormonal Therapy in Cancer
Hormonal therapies exploit hormone receptor dependence in breast and prostate cancers by reducing hormone levels or blocking receptor signaling.
## Overview
Many cancers retain dependence on steroid hormones for growth and survival. Hormonal therapies block this dependence by reducing circulating hormone levels, blocking hormone receptors, or degrading receptors. These are among the most effective and well-tolerated systemic therapies in oncology.
## Estrogen Receptor-Positive Breast Cancer
**Selective Estrogen Receptor Modulators (SERMs)**: Tamoxifen binds ER with high affinity, acting as an antagonist in breast tissue (blocking proliferation) but agonist in bone (preserving density) and endometrium (increasing endometrial cancer risk ~2-3x). Metabolized by CYP2D6 to active metabolite endoxifen; CYP2D6 poor metabolizers may have reduced benefit. Used for premenopausal and postmenopausal ER+ breast cancer; 5-10 years of adjuvant therapy.
**Aromatase Inhibitors (AIs)**: Anastrozole, letrozole (non-steroidal, reversible), and exemestane (steroidal, irreversible) block aromatase, which converts androgens to estrogens in peripheral tissues. Effective only in postmenopausal women (ovarian estrogen production is not suppressed). Superior to tamoxifen in postmenopausal adjuvant setting. Toxicities: arthralgia, bone loss (bisphosphonate co-treatment), hot flashes.
**SERDs**: Fulvestrant is a pure ER antagonist/degrader with no agonist activity. Given as IM injection. Elacestrant is an oral SERD approved for ESR1-mutated breast cancer.
**CDK4/6 inhibitors** (palbociclib, ribociclib, abemaciclib) are combined with AIs or fulvestrant in metastatic HR+/HER2- breast cancer.
## Prostate Cancer: Androgen Deprivation Therapy
Prostate cancer depends on androgen receptor (AR) signaling. ADT suppresses testosterone to castrate levels (<50 ng/dL).
**GnRH agonists** (leuprolide, goserelin) cause initial testosterone surge (flare) followed by sustained suppression; anti-androgen co-treatment for 4 weeks prevents flare in patients with bone metastases.
**GnRH antagonists** (degarelix, relugolix) suppress testosterone rapidly without flare. Relugolix (oral) is preferred in patients with cardiovascular risk.
**Anti-androgens**: Enzalutamide and apalutamide block AR ligand binding, nuclear translocation, and DNA binding. Active in metastatic CRPC. Darolutamide has reduced CNS penetration, lowering seizure and CNS side effect risk.
**CYP17A1 inhibitors**: Abiraterone blocks adrenal and intratumoral androgen synthesis; requires prednisone co-administration to prevent mineralocorticoid excess.
## Key Takeaways
- Tamoxifen acts as ER antagonist in breast and agonist in endometrium; CYP2D6 metabolism affects efficacy
- Aromatase inhibitors reduce peripheral estrogen production; active only in postmenopausal women
- ADT suppresses testosterone; GnRH antagonists avoid the testosterone flare seen with agonists
- Enzalutamide and abiraterone are standard in CRPC with complementary mechanisms