Introduction
Letrozole is a potent, third-generation nonsteroidal aromatase inhibitor used primarily in the treatment of hormone receptor-positive breast cancer in postmenopausal women. As a selective estrogen deprivation agent, it has become a cornerstone in both adjuvant and metastatic breast cancer therapy since its FDA approval in 1997.
Mechanism of Action
Letrozole works through competitive, reversible inhibition of the aromatase enzyme complex. This enzyme system, located primarily in adipose tissue, muscle, liver, and breast tissue, is responsible for converting androgens (androstenedione and testosterone) to estrogens (estrone and estradiol). By inhibiting this conversion, letrozole dramatically reduces circulating estrogen levels by 97-99%, creating an estrogen-deprived environment that slows or stops the growth of estrogen-dependent breast cancer cells.
Indications
- Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
- Extended adjuvant treatment of early breast cancer following 5 years of tamoxifen therapy
- First-line treatment of postmenopausal women with hormone receptor-positive or unknown, locally advanced or metastatic breast cancer
- Treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy
- Off-label uses: ovulation induction in anovulatory women, treatment of endometriosis
Dosage and Administration
Standard adult dosage: 2.5 mg orally once daily, with or without food Special populations:- Renal impairment: No dosage adjustment necessary for mild to moderate impairment (CrCl ≥30 mL/min)
- Hepatic impairment: No dosage adjustment necessary for mild to moderate impairment (Child-Pugh A and B)
- Geriatric patients: No dosage adjustment required
- Pediatric patients: Safety and effectiveness not established
Pharmacokinetics
Absorption: Rapidly and completely absorbed after oral administration; bioavailability 99.9%; time to peak concentration: 1-2 hours; food reduces rate but not extent of absorption Distribution: Volume of distribution: 1.87 ± 0.47 L/kg; plasma protein binding: approximately 60% (primarily to albumin) Metabolism: Extensively metabolized in the liver via CYP3A4 and CYP2A6 to an inactive carbinol metabolite Elimination: Terminal half-life: approximately 2-4 days; excretion: primarily renal (90% as metabolites, <5% unchanged); clearance: 2.1 ± 0.6 L/hContraindications
- Premenopausal women (unless combined with ovarian suppression)
- Pregnancy or women who may become pregnant
- Known hypersensitivity to letrozole or any component of the formulation
- Patients with severe hepatic impairment (Child-Pugh C) not recommended
Warnings and Precautions
Bone effects: Significant reduction in bone mineral density may occur; monitor bone density and consider bone-protective agents Cardiovascular: Increased incidence of hypercholesterolemia; monitor lipid profiles periodically CNS effects: May cause dizziness, fatigue; caution patients about driving or operating machinery Hepatic impairment: Use with caution in patients with severe hepatic impairment Pregnancy: Category D - can cause fetal harm; exclude pregnancy before initiationDrug Interactions
Strong CYP3A4 inducers (rifampin, carbamazepine, phenytoin): May decrease letrozole concentrations; consider alternative agents or monitor efficacy Tamoxifen: Concurrent use may reduce letrozole efficacy; avoid combination therapy Estrogen-containing therapies: May interfere with pharmacological action; contraindicated Medications that prolong QT interval: Theoretical risk of additive effects; monitor ECG if coadministeredAdverse Effects
Very common (>10%):- Hot flashes (20-35%)
- Arthralgia (15-25%)
- Fatigue (10-20%)
- Headache (10-15%)
- Hypercholesterolemia (15-20%)
- Nausea (5-10%)
- Sweating (5-10%)
- Edema (5-10%)
- Weight increase (5-10%)
- Bone pain (5-10%)
- Depression (5-10%)
- Cardiovascular events (myocardial infarction, angina)
- Osteoporosis and fractures
- Thromboembolic events
- Hepatic toxicity
- Visual disturbances
Monitoring Parameters
Baseline:- Pregnancy test in women of childbearing potential
- Bone mineral density (DEXA scan)
- Lipid profile
- Liver function tests
- Complete blood count
- Bone mineral density annually
- Lipid profile every 3-6 months
- Liver function tests every 3-6 months
- Regular assessment of treatment response and disease status
- Monitoring for signs of disease progression
- Assessment of musculoskeletal symptoms
- Cardiovascular risk assessment
- Ongoing bone health evaluation
- Quality of life assessment
Patient Education
- Take medication exactly as prescribed at the same time each day
- Do not stop taking without consulting your oncologist
- Report any new or worsening symptoms, especially bone pain, joint stiffness, or hot flashes
- Use effective non-hormonal contraception if premenopausal with ovarian suppression
- Maintain regular follow-up appointments for monitoring
- Discuss bone health strategies with your healthcare provider
- Report any signs of cardiovascular issues (chest pain, shortness of breath)
- Inform all healthcare providers about letrozole therapy
- Store at room temperature away from moisture and heat
References
1. FDA Prescribing Information: Femara (letrozole) tablets. Revised 2022. 2. Early Breast Cancer Trialists' Collaborative Group. Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015;386(10001):1341-1352. 3. Mouridsen H, et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol. 2003;21(11):2101-2109. 4. Coombes RC, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350(11):1081-1092. 5. National Comprehensive Cancer Network. Breast Cancer Guidelines Version 3.2023. 6. Micromedex Solutions. Letrozole Drug Monograph. Truven Health Analytics. Updated 2023. 7. The American Society of Clinical Oncology. Management of Aromatase Inhibitor-Associated Bone Loss in Postmenopausal Women With Breast Cancer. J Clin Oncol. 2022;40(15):1709-1719.