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

Letrozole for Breast Cancer Treatment

Recommended Dosage

Letrozole is administered at 2.5 mg orally once daily, without regard to meals, across all breast cancer treatment settings. 1

• Dose modifications: In patients with cirrhosis and severe hepatic dysfunction, reduce the dose to 2.5 mg every other day 1
• No dose adjustment is required for mild to moderate hepatic impairment or renal impairment (creatinine clearance ≥10 mL/min) 1

Clinical Indications and Treatment Duration

Adjuvant Treatment (Early-Stage Breast Cancer)

Letrozole is recommended as first-line adjuvant therapy for postmenopausal women with hormone receptor-positive early breast cancer for 5 years. 2, 3, 1

• Third-generation aromatase inhibitors (letrozole, anastrozole, exemestane) are preferred over tamoxifen based on superior efficacy and more favorable toxicity profiles 2
• Letrozole demonstrated significantly longer disease-free survival compared to tamoxifen in the BIG 1-98 trial 4
• Treatment should be discontinued at relapse 1

Extended Adjuvant Treatment

For patients at higher risk of recurrence who have completed 5 years of endocrine therapy (tamoxifen or aromatase inhibitor), extending letrozole for an additional 5 years (total 10 years) should be offered, particularly for node-positive disease. 2, 3, 5

Algorithm for Extended Therapy Decision:

• Node-positive disease: Offer extended therapy up to 10 years total 3, 5
• High-risk node-negative disease: Consider extended therapy based on established prognostic factors 3, 5
• Low-risk node-negative disease: Do not routinely offer extended therapy, as absolute benefits may not justify ongoing toxicity 5
• Prerequisites for extension: Good tolerance of initial 5 years, no significant bone density loss or cardiovascular issues 3

The MA.17R trial demonstrated that extending letrozole to 10 years improved disease-free survival (95% vs 91% at 5 years) 3. However, extended therapy does not improve overall survival but prevents distant recurrence and contralateral breast cancers 5.

Maximum duration: Do not extend beyond 10 years total, as there is no evidence supporting benefit beyond this duration. 5

First-Line Treatment (Advanced/Metastatic Breast Cancer)

Letrozole is recommended as first-line treatment for postmenopausal women with hormone receptor-positive or unknown locally advanced or metastatic breast cancer. 2, 1, 6

• Letrozole demonstrated superior time to progression (9.4-9.9 months vs 6.0-6.2 months) and objective response rate (32% vs 21%) compared to tamoxifen 2, 6
• Treatment should continue until tumor progression is evident 1

Second-Line Treatment (Advanced Breast Cancer)

Following tamoxifen failure, letrozole is recommended as second-line therapy for postmenopausal women with hormone receptor-positive metastatic breast cancer. 2, 1

• Letrozole achieved objective response rates of 19.5-24% with median response duration of 24-33 months in second-line settings 7
• Letrozole showed equivalent efficacy to anastrozole and superior or similar efficacy to megestrol acetate 2, 8

Critical Monitoring and Safety Considerations

Bone Health

Regular bone mineral density monitoring is essential, as letrozole causes significant BMD decreases. 3, 5, 1

• At 24 months, letrozole caused a median 4.1% decrease in lumbar spine BMD compared to 0.3% increase with tamoxifen (difference 4.4%, P<0.0001) 1
• Extended therapy increases fracture risk and osteoporosis 3, 5
• Proactive bone health management is required 5

Cardiovascular Monitoring

Monitor cardiovascular risk factors, particularly with extended therapy, as there is a trend toward increased cardiovascular events (odds ratio 1.18). 3, 5

Cholesterol Monitoring

Consider cholesterol monitoring, as increases in total cholesterol may occur. 1

Quality of Life Considerations

• Extended therapy causes worsening in physical role functioning compared to placebo 3, 5
• Common adverse events (>20%) include hot flashes, arthralgia, flushing, asthenia, edema, headache, dizziness, hypercholesterolemia, increased sweating, and bone pain 1
• Fatigue, dizziness, and somnolence may occur; exercise caution when operating machinery 1

Important Caveats and Pitfalls

Menopausal Status Verification

Letrozole only works in postmenopausal women—confirm menopausal status before initiating therapy. 9

• In premenopausal women, aromatase inhibitors must be combined with ovarian function suppression (LHRH agonists, surgical oophorectomy, or radiotherapeutic ablation) 2, 9

Contraindications

• Pregnancy: Letrozole can cause fetal harm; obtain pregnancy test in females of reproductive potential and advise effective contraception 1
• Known hypersensitivity to letrozole or excipients 1
• Advise not to breastfeed 1

Treatment Cascade After Aromatase Inhibitor Failure

No definitive recommendation exists for optimal treatment cascade after aromatase inhibitor failure. 2

• Options include: switching to steroidal AI (exemestane) after nonsteroidal AI failure, tamoxifen, fulvestrant, progestins, or high-dose estrogens/androgens 2, 9
• Sequential endocrine therapy is appropriate for patients demonstrating clinical benefit with prior endocrine treatments 9