Selective Estrogen Receptor Modulators in Oncology

Selective oestrogen receptor modulators bind the oestrogen receptor and act as antagonists in breast tissue and partial agonists in bone, liver and endometrium. In oncology they are used in oestrogen receptor-positive breast cancer for adjuvant treatment, metastatic disease and risk reduction.

Classification. Tamoxifen, toremifene, raloxifene (risk reduction and bone use). Fulvestrant, a pure receptor antagonist and degrader, and elacestrant, an oral degrader, act by a different mechanism and are used in endocrine-resistant disease.

Pharmacokinetics. Tamoxifen is a prodrug activated by CYP2D6 (mainly to endoxifen) and CYP3A4; the half life is 5 to 7 days, so steady state takes about 4 weeks.

• Tamoxifen 20 mg orally once daily, for 5 years or extended to 10 years in selected patients.
• Toremifene 60 mg orally once daily (metastatic disease, postmenopausal); it prolongs the QT interval.
• Raloxifene 60 mg orally once daily for risk reduction in postmenopausal women; it does not protect against endometrial cancer but also does not cause it.
• Fulvestrant 500 mg intramuscularly on days 1, 15 and 29, then every 28 days.

Differences. Tamoxifen works before and after menopause but increases thromboembolism and endometrial cancer risk; raloxifene has less uterine effect and is used only after menopause.

• Premenopausal breast cancer (oestrogen receptor-positive): tamoxifen for 5 to 10 years, with or without ovarian suppression.
• Postmenopausal breast cancer: an aromatase inhibitor is usually preferred; tamoxifen when an aromatase inhibitor is not tolerated or contraindicated, or in sequence after 2 to 3 years.
• Ductal carcinoma in situ: tamoxifen 20 mg daily for 5 years after local treatment when receptor-positive.
• Risk reduction: tamoxifen 20 mg daily for 5 years (or raloxifene) in high-risk women, with counselling on thromboembolic risk.
• Male breast cancer: tamoxifen 20 mg daily.
• Avoid CYP2D6 inhibitors: paroxetine and fluoxetine (strong inhibitors) reduce endoxifen; use sertraline, venlafaxine or citalopram instead.

Selection. Confirm oestrogen receptor status before starting; stress adherence, because stopping early shortens survival.

Contraindications. Pregnancy; history of venous thromboembolism or stroke (relative; avoid when risk exceeds benefit); undiagnosed vaginal bleeding; concurrent warfarin without close monitoring.

Adverse effects. Hot flushes, vaginal discharge, menstrual irregularity, venous thromboembolism (2 to 3 times the baseline risk), endometrial hyperplasia and cancer, uterine sarcoma, cataracts, mood change, liver steatosis, and QT prolongation (toremifene).

Interactions. Strong CYP2D6 inhibitors lower efficacy; rifampicin and phenytoin lower tamoxifen levels; warfarin effect rises sharply; avoid combination with ribociclib because of QT prolongation.

Special groups.

• Pregnancy: contraindicated; use non-hormonal contraception.
• Breastfeeding: avoid.
• Children: not used.
• Older adults: higher thromboembolic risk; consider an aromatase inhibitor.
• Kidney impairment: no adjustment.
• Liver impairment: avoid in severe disease.

Monitoring. Annual gynaecological symptom review with prompt investigation of abnormal bleeding (pelvic ultrasound and endometrial sampling), blood pressure, liver enzymes and lipids, and adherence at each visit.

Referral and escalation. Postmenopausal bleeding, calf swelling, chest pain, dyspnoea, sudden visual loss or severe headache need urgent assessment.