What is the recommended use and dosage of Letrozole (aromatase inhibitor) for breast cancer treatment?

Letrozole for Breast Cancer Treatment

Recommended Dosage

The standard dose of letrozole is 2.5 mg orally once daily, taken without regard to meals, and this dosing should be continued until tumor relapse in the adjuvant/extended adjuvant setting or until disease progression in metastatic disease. 1

• The 2.5 mg daily dose has been validated across all clinical settings and represents the FDA-approved dosing regimen 1
• Alternative dosing schedules (intermittent or lower doses) achieve similar estrogen suppression but offer no advantage in tolerability, so standard dosing should be maintained 2

Clinical Indications and Treatment Settings

Adjuvant Treatment (Early Breast Cancer)

Letrozole is indicated as adjuvant treatment for postmenopausal women with hormone receptor-positive early breast cancer, and should be incorporated as initial therapy, sequential therapy after 2-3 years of tamoxifen, or as extended therapy after completing 5 years of tamoxifen. 3, 1

• The NCCN guidelines find no compelling evidence that anastrozole, letrozole, and exemestane have meaningful differences in efficacy or toxicity, making any third-generation aromatase inhibitor an appropriate choice 3
• When used as initial adjuvant therapy, letrozole significantly prolongs disease-free survival compared to tamoxifen (median follow-up 25.8 months) 4
• Sequential therapy (switching from tamoxifen to letrozole after 2-3 years) improves disease-free survival with a hazard ratio of 0.60 (95% CI 0.44-0.81, P=0.0009) 3

Extended Adjuvant Treatment

For postmenopausal women who have completed 5 years of tamoxifen therapy, extended adjuvant letrozole should be offered, particularly to those with node-positive disease where a survival benefit has been demonstrated. 3, 1

• The MA-17 trial demonstrated that extended letrozole reduces recurrences with HR 0.58 (95% CI 0.45-0.76, P<0.001) 3
• A survival advantage was specifically seen in node-positive patients (HR 0.61,95% CI 0.38-0.98, P=0.04) 3
• The optimal duration is unknown, but treatment in clinical trials was planned for 5 years with median treatment duration of 60 months 1
• ASCO 2019 guidelines recommend that many women with node-negative breast cancer may also be offered extended therapy for up to 10 years total of adjuvant endocrine treatment based on recurrence risk 3

First-Line Metastatic Disease

Letrozole is recommended as first-line treatment for postmenopausal women with hormone receptor-positive or unknown locally advanced or metastatic breast cancer, demonstrating superior efficacy to tamoxifen. 3, 1, 5

• Letrozole showed superior time to progression (9.9 months vs 6.2 months, P=0.0001) and objective response rate (32% vs 21%, P=0.0003) compared to tamoxifen 5
• The Annals of Oncology consensus recommends third-generation aromatase inhibitors as first-line treatment based on more favorable toxicity profile, though tamoxifen remains a valuable option 3
• Treatment should continue until tumor progression is evident 1

Second-Line Metastatic Disease

Following tamoxifen failure, letrozole is recommended as second-line endocrine therapy for postmenopausal women with hormone receptor-positive metastatic breast cancer. 3, 1

• Letrozole demonstrated superiority over older agents (megestrol acetate and aminoglutethimide) in second-line settings 5
• The 2.5 mg dose was superior to 0.5 mg dose and megestrol acetate with response rates of 24%, 13%, and 16% respectively 5

Critical Eligibility Requirements

Menopausal Status Verification

Letrozole must only be used in confirmed postmenopausal women, as it does not adequately suppress ovarian estrogen synthesis in premenopausal women with functioning ovaries. 3

• Serial assessment of luteinizing hormone, follicle-stimulating hormone, and estradiol is mandatory in women who become amenorrheic with chemotherapy before considering aromatase inhibitor therapy 3
• Premenopausal women should not receive aromatase inhibitor therapy outside clinical trials 3
• If aromatase inhibitors are used in premenopausal women, they must be combined with ovarian function suppression (LHRH agonists) 3

Dose Modifications

Hepatic Impairment

For patients with cirrhosis and severe hepatic dysfunction, reduce the letrozole dose by 50% to 2.5 mg every other day. 1

• No dose adjustment is needed for mild to moderate hepatic impairment 1
• The effect of hepatic impairment in non-cirrhotic patients with elevated bilirubin has not been determined 1

Renal Impairment

No dose adjustment is required for renal impairment if creatinine clearance is ≥10 mL/min. 1

Key Safety Monitoring

Bone Health

Bone mineral density monitoring should be considered, as letrozole causes significant decreases in BMD with a median decrease of 4.1% in lumbar spine at 24 months compared to 0.3% increase with tamoxifen (P<0.0001). 1

• At 2 years in extended adjuvant setting, patients had a median decrease of 3.8% in hip BMD 1
• This represents a consistent adverse effect across all aromatase inhibitors 3

Lipid Monitoring

Total cholesterol monitoring should be considered, as increases may occur with letrozole therapy. 1

Quality of Life Considerations

While quality of life is reasonably preserved during extended endocrine therapy, patients should be counseled about ongoing menopausal symptoms and potential bone mineral density loss. 3

• Fatigue, dizziness, and somnolence may occur; caution should be exercised when operating machinery 1
• The most common adverse reactions (>20%) include hot flashes, arthralgia, flushing, asthenia, edema, headache, dizziness, hypercholesterolemia, increased sweating, and bone pain 1

Contraindications

Letrozole is contraindicated in pregnancy (can cause fetal harm) and in patients with known hypersensitivity to the active substance or excipients. 1

• Pregnancy testing should be obtained in females of reproductive potential 1
• Females of reproductive potential should use effective contraception 1
• Breastfeeding should be avoided 1

Mechanism and Pharmacology

Letrozole is a highly selective nonsteroidal aromatase inhibitor that decreases plasma estradiol, estrone, and estrone sulfate by 75-95% from baseline, with maximal suppression achieved within 2-3 days. 5, 6

• Letrozole binds to the heme component of the cytochrome P450 subunit of aromatase, inhibiting estrogen biosynthesis throughout the body 4
• At clinically used dosages, letrozole does not impair adrenal synthesis of glucocorticoids or aldosterone 5
• Suppression is dose-related, with doses ≥0.5 mg giving estrone and estrone sulfate values often below assay detection limits 5