Letrozole-Oncology

• Breast Cancer (Hormone Receptor-Positive)
• Adjuvant Breast Cancer Treatment
• Aromatase Inhibitor Therapy
• Postmenopausal Breast Cancer

Letrozole is a nonsteroidal aromatase inhibitor used in the treatment of hormone receptor-positive breast cancer in postmenopausal women. This medication effectively reduces estrogen levels by inhibiting the aromatase enzyme, slowing the growth of estrogen-dependent tumors.

Mechanism of Action

Letrozole is a highly potent, nonsteroidal, competitive inhibitor of the aromatase enzyme (cytochrome P450-dependent enzyme that catalyzes the conversion of androgens to estrogens). In postmenopausal women, the primary source of circulating estrogen is the peripheral conversion of adrenal and ovarian androgens (primarily androstenedione and testosterone) to estrogens (estrone and estradiol) by aromatase in peripheral tissues. By inhibiting aromatase, letrozole reduces circulating estrogen levels to nearly undetectable concentrations, thereby depriving estrogen-dependent breast cancer cells of their growth stimulus.

Available Formulations

Letrozole is available as film-coated tablets containing 2.5 mg. The tablets can be taken with or without food. Generic formulations are widely available.

Medical Uses

Letrozole is FDA-approved for adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer, extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy, and first-line and second-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer. It is also used off-label for ovulation induction in infertility treatment.

Dosing Guidelines

The recommended dose is 2.5 mg once daily. For adjuvant treatment, the recommended duration is 5 years, or until tumor recurrence. For extended adjuvant therapy (after 5 years of tamoxifen), duration varies. For advanced disease, treatment continues until tumor progression. The medication should be taken at approximately the same time each day. No dose adjustment is needed for renal or mild to moderate hepatic impairment.

Important Safety Information

Letrozole can cause decreases in bone mineral density, increasing the risk of osteoporosis and fractures. Bone mineral density monitoring and consideration of bisphosphonate therapy may be appropriate. Elevations in serum cholesterol have been reported. Fatigue, dizziness, and somnolence may occur; patients should exercise caution when driving or operating machinery. Letrozole is contraindicated in premenopausal women. It may cause fetal harm and is contraindicated in pregnant women.

Drug Interactions

Tamoxifen significantly reduces letrozole plasma concentrations; do not administer together. CYP3A4 and CYP2A6 are involved in letrozole metabolism, but significant drug interactions have not been identified with CYP3A4 inhibitors or inducers at clinical doses. Letrozole does not significantly inhibit CYP enzymes at clinically relevant concentrations.

Special Populations

Letrozole is contraindicated in pregnancy due to potential for fetal harm. Women of reproductive potential should use effective contraception during treatment and for at least 3 weeks after the last dose. Verify pregnancy status before starting therapy. It is unknown whether letrozole is excreted in human breast milk; breastfeeding is not recommended. Letrozole is not indicated for use in pediatric patients. Clinical trials included patients up to age 96; no overall differences in safety or efficacy were observed in elderly patients. No dose adjustment is needed for renal impairment (CrCl ≥10 mL/min). No dose adjustment is needed for mild to moderate hepatic impairment; use with caution in severe hepatic impairment.