Aromatase Inhibitors in Oncology

Aromatase inhibitors block conversion of androgens to oestrogens in peripheral fat, liver and tumour tissue, lowering oestrogen by more than 95 percent. They work only when ovarian production has stopped, so they are used in postmenopausal women or with ovarian suppression. They are the preferred adjuvant and first-line metastatic endocrine drugs in postmenopausal oestrogen receptor-positive breast cancer.

Classification. Non-steroidal reversible inhibitors (anastrozole, letrozole) and the steroidal irreversible inhibitor (exemestane).

Pharmacokinetics. Hepatic metabolism; half life about 40 to 48 hours (anastrozole), 2 days (letrozole), 24 hours (exemestane).

• Anastrozole 1 mg orally once daily.
• Letrozole 2.5 mg orally once daily.
• Exemestane 25 mg orally once daily after food (with everolimus in metastatic disease).
• Duration: 5 years, or extended to 7 to 10 years in high-risk disease, or after 2 to 3 years of tamoxifen to complete 5 years.

Differences. The three have similar efficacy; exemestane has mild androgenic effects, and switching between them is used when one is not tolerated.

• Adjuvant treatment, postmenopausal: an aromatase inhibitor for 5 years (or sequenced with tamoxifen).
• Premenopausal women: an aromatase inhibitor only with ovarian suppression (a GnRH agonist, oophorectomy or ovarian irradiation), usually in higher-risk disease; confirm suppression by oestradiol levels.
• Metastatic disease: aromatase inhibitor with a CDK4 and CDK6 inhibitor as first-line therapy.
• Defining menopause: bilateral oophorectomy, age 60 or more, or age under 60 with amenorrhoea for 12 months and follicle-stimulating hormone and oestradiol in the postmenopausal range (repeat testing in women taking tamoxifen or after chemotherapy).
• Bone protection: assess bone density at baseline; give calcium (1,000 to 1,200 mg daily from diet and supplement) and vitamin D (800 to 2,000 IU daily); add a bisphosphonate or denosumab when T-score is under minus 2.0 or there are fragility fractures.

Selection. Choose by tolerance and cost; generic anastrozole and letrozole are widely available and inexpensive.

Contraindications. Premenopausal status without ovarian suppression; pregnancy; severe liver impairment.

Adverse effects. Arthralgia and myalgia (up to half of patients; often cause of non-adherence), hot flushes, vaginal dryness, bone loss and fractures, fatigue, hypercholesterolaemia, mild cardiovascular risk, and carpal tunnel syndrome.

Interactions. Tamoxifen lowers anastrozole and letrozole levels; oestrogen-containing products oppose action; CYP3A4 inducers lower exemestane.

Special groups.

• Pregnancy: contraindicated.
• Breastfeeding: avoid.
• Older adults: monitor bone density and falls.
• Kidney impairment: no adjustment.
• Liver impairment: no adjustment in mild to moderate disease; avoid in severe.

Monitoring. DEXA at baseline and every 1 to 2 years, lipids, symptom review, and adherence. For joint pain, use exercise, paracetamol or NSAIDs, duloxetine, or switch to another aromatase inhibitor.

Referral and escalation. Fragility fracture, severe arthralgia that persists after switching, or any suspicion of incomplete ovarian suppression in premenopausal women need specialist review.