Letrozole: Third-Generation Aromatase Inhibitor for Breast Cancer
Letrozole (Femara) is a non-steroidal, competitive inhibitor of aromatase (CYP19A1), the enzyme that converts androgens to oestrogens. By suppressing oestrogen synthesis, it deprives oestrogen-receptor-positive (ER+) breast cancer cells of their growth stimulus.
First-line and adjuvant treatment for postmenopausal women with hormone receptor-positive (HR+) breast cancer. Also used off-label as ovulation induction in infertility (superior to clomiphene in PCOS patients).
Mechanism of Action
Competitively inhibits aromatase in peripheral tissues (fat, muscle, liver, breast tissue), reducing oestradiol, oestrone, and oestrone sulphate by >99% in postmenopausal women. Does not affect adrenal steroid synthesis (unlike aminoglutethimide).
Indications & Use
HR+ breast cancer: adjuvant (5 years postoperatively), extended adjuvant (after 5 years of tamoxifen), first-line advanced/metastatic disease. Combined with CDK4/6 inhibitors (palbociclib, ribociclib) for advanced disease. Off-label: ovulation induction (2.5–7.5 mg/day, day 3–7 of cycle).
Dosage
Breast cancer: 2.5 mg once daily (continuous). No dose adjustment for mild-moderate renal impairment. Severe hepatic impairment: use with caution (dose halving may be necessary). Ovulation induction: 2.5–5 mg/day for 5 days.
Side Effects
Oestrogen deprivation effects: hot flushes, arthralgia/myalgia (most common — affects 20–30%, can cause treatment discontinuation), bone loss (osteoporosis/fractures — monitor BMD, supplement vitamin D and calcium), fatigue. Cognitive effects: mild memory/concentration impairment. Hypercholesterolaemia.
Drug Interactions
Tamoxifen: reduces letrozole levels — avoid concurrent use. Strong CYP2A6 inhibitors: may increase letrozole levels. CDK4/6 inhibitors: pharmacodynamic combination — approved for advanced HR+ disease.
Contraindications
Premenopausal women (endogenous oestrogen production not suppressed by letrozole alone), pregnancy, breastfeeding, hypersensitivity.
Frequently Asked Questions
Why is letrozole only effective in postmenopausal women for breast cancer?
In premenopausal women, the ovaries produce oestrogen in a feedback-controlled manner — letrozole inhibition of peripheral aromatase triggers a compensatory increase in ovarian oestrogen production. In postmenopausal women, the ovaries are inactive and peripheral aromatase is the main oestrogen source — letrozole suppresses this effectively.
What is the main difference between letrozole and tamoxifen?
Tamoxifen is an oestrogen receptor (ER) antagonist — it blocks ER signalling. Letrozole is an aromatase inhibitor — it reduces oestrogen production. For postmenopausal patients, aromatase inhibitors (letrozole, anastrozole) have superior efficacy and are preferred over tamoxifen.
Can letrozole be used for fertility treatment?
Yes. Letrozole (2.5–5 mg/day for 5 days starting day 2–5 of cycle) is used off-label as first-line ovulation induction in PCOS — meta-analyses show higher live birth rates than clomiphene. It is now recommended by major fertility guidelines as first-line in PCOS.
References
- EMA Femara SPC 2023
- ASCO Breast Cancer Adjuvant Guideline 2023
- Legro RS et al. NEJM 2014 (PCOS fertility)
Medical Disclaimer: This information is for educational purposes only and does not replace professional medical advice.