Sex hormone antagonists for breast cancer

Key examples

• Tamoxifen (SERM)
• Anastrozole (aromatase inhibitor)
• Letrozole (aromatase inhibitor)

 

Common indications

1. Early and locally advanced estrogen-receptor positive (ER-positive) breast cancer, as an adjuvant treatment option (i.e. after surgery) to reduce the risk of recurrent disease.
2. Advanced ER-positive positive breast cancer, to slow disease progression. Hormonal therapy is given as a first-line treatment if the tumour does not express human epidermal growth factor receptor 2 (HER2-negative). Other options are available in HER2-positive disease. 
• Aromatase inhibitors are used in post-menopausal women only. 
• Tamoxifen is used in pre-menopausal women and in post-menopausal women who cannot take an aromatase inhibitor.

 

Mechanisms of action

• Approximately two-thirds of breast cancers express oestrogen receptors (ER-positive). Oestrogen binds to these and stimulates cell proliferation. 
• Sex hormone antagonists reduce tumour cell proliferation by blocking the effects of oestrogen. 
• Tamoxifen is a selective estrogen (oestrogen) receptor modulator (SERM), which acts to prevent oestrogen binding to its receptor. 
• Aromatase inhibitors interfere with synthesis of oestrogens outside the ovary (e.g. in fat and muscle) by inhibiting the enzyme (aromatase) that converts androgens to oestrogens. 
• Aromatase inhibitors are superior to tamoxifen for ER-positive breast cancer in post-menopausal women, but ineffective in pre-menopausal women with functioning ovaries. This is because they have relatively little effect on ovarian oestrogen synthesis, which may even rise in response to aromatase inhibition. 
• Antioestrogen therapies are ineffective if the tumour does not express oestrogen receptors.

 

Important adverse effects

• The most common adverse effects of tamoxifen and aromatase inhibitors are symptoms of oestrogen depletion, including vaginal dryness, hot flushes and loss of bone density. 
• Tamoxifen increases the risk of venous thromboembolism and endometrial cancer, so any unusual vaginal discharge or menstrual irregularity must be investigated. 
• Other side effects include gastrointestinal upset and headache. 
• Rarely, tamoxifen and aromatase inhibitors can cause agranulocytosis and liver failure.

 

Warnings

• Tamoxifen may increase the risk of miscarriage and is contraindicated in pregnancy, and is secreted in breast milk so should be avoided in lactation. 
• Aromatase inhibitors should not be used in pre-menopausal women unless ovarian function is suppressed or ablated (e.g. by oophorectomy).

 

Important interactions

• Tamoxifen inhibits a cytochrome P450 enzyme (CYP2C9) responsible for metabolising warfarin, increasing the risk of bleeding. 
• The SSRIs fluoxetine and paroxetine inhibit hepatic activation of tamoxifen. 
• Aromatase inhibitors do not have clinically important drug interactions.