Letrozole — Drug Monograph

Brand names: Femara

Drug class: Hormonal Agent

Mechanism of Action

Third-generation, highly selective, non-steroidal aromatase inhibitor (AI). Letrozole competitively and reversibly inhibits the aromatase enzyme (cytochrome P450 19A1, CYP19A1), which catalyzes the final and rate-limiting step in estrogen biosynthesis — the conversion of androgens (androstenedione, testosterone) to estrogens (estrone, estradiol) in peripheral tissues including fat, liver, breast tissue, and intratumorally. In postmenopausal women, peripheral aromatization is the dominant estrogen source, and letrozole suppresses circulating estradiol by >98%. The resulting profound estrogen…

FDA Indications

• Postmenopausal women with HR-positive, HER2-negative early breast cancer — adjuvant therapy after completing 5 years of tamoxifen (extended adjuvant; MA.17 trial: 42% reduction in distant recurrence)
• Postmenopausal women with HR-positive advanced or metastatic breast cancer — first-line (P025 trial) or after antiestrogen failure
• HR-positive, HER2-negative advanced breast cancer in combination with ribociclib (MONALEESA-2: PFS HR 0.56, median OS improvement ~23 months vs placebo + letrozole)
• HR-positive, HER2-negative advanced breast cancer in combination with palbociclib (PALOMA-2: PFS HR 0.58; first-line)
• HR-positive, HER2-negative advanced breast cancer in combination with abemaciclib (MONARCH-3: PFS HR 0.54; first-line)

Common Side Effects

• Arthralgia / arthritis (20–35% — major adherence issue)
• Hot flashes (20–30%)
• Fatigue (20%)
• Bone pain
• Peripheral edema
• Nausea (17%)
• Osteoporosis / bone loss (progressive ~2–3% reduction in bone density per year)
• Headache (20%)
• Dyslipidemia (elevated cholesterol)
• Night sweats

Clinical Pearl

Letrozole is the most widely used backbone for CDK4/6 inhibitor combinations in postmenopausal HR+ MBC. The MONALEESA-2 trial (ribociclib + letrozole) demonstrated a median OS benefit of ~23 months — one of the largest OS improvements ever reported in first-line HR+ MBC. Arthralgias are the primary adherence barrier; switching to exemestane or anastrozole within the AI class can sometimes improve tolerability. Extended adjuvant use after tamoxifen (MA.17) significantly reduces late distant…

Related Therapies & Mechanisms

• Anastrozole (Arimidex) — Hormonal Agent · Breast
• Exemestane (Aromasin) — Hormonal Agent · Breast
• Fulvestrant (Faslodex) — Hormonal Agent · Breast
• Goserelin (Zoladex) — Hormonal Agent · Breast