What is the recommended treatment and dosage for postmenopausal women with hormonally-responsive breast cancer using Femara (letrozole)?

Femara (Letrozole) for Postmenopausal Hormone Receptor-Positive Breast Cancer

Letrozole 2.5 mg once daily is the recommended dose for postmenopausal women with hormone receptor-positive breast cancer, administered orally without regard to meals, and should be incorporated into treatment either as initial adjuvant therapy for 5 years, after 2-3 years of tamoxifen to complete 5 years total, or as extended therapy for 5 years following completion of 5 years of tamoxifen. 1

FDA-Approved Indications and Dosing

The FDA has approved letrozole for three distinct clinical scenarios in postmenopausal women with hormone receptor-positive breast cancer 1:

• Adjuvant treatment: 2.5 mg once daily for early breast cancer, with median treatment duration of 5 years in clinical trials 1
• Extended adjuvant treatment: 2.5 mg once daily after completing 5 years of tamoxifen therapy, with optimal duration being 5 years (median treatment duration 60 months in trials) 1
• Advanced/metastatic disease: 2.5 mg once daily as first-line or second-line treatment, continued until tumor progression 1

Treatment Strategy Selection

For postmenopausal women with endocrine-responsive breast cancer, three equally acceptable category 1 treatment strategies exist, and the choice should prioritize aromatase inhibitor incorporation at some point 2:

1. Initial adjuvant therapy: Letrozole for 5 years from the start 2
2. Sequential therapy: Tamoxifen for 2-3 years followed by letrozole to complete 5 years total 2
3. Extended therapy: Approximately 5 years of tamoxifen followed by 5 years of letrozole 2

The BIG 1-98 trial demonstrated that letrozole as initial adjuvant therapy was superior to tamoxifen alone, with improved disease-free survival (HR 0.81,95% CI 0.70-0.93, P=0.003) at median follow-up of 25.8 months 2. The MA.17 trial showed that extended adjuvant letrozole after 5 years of tamoxifen significantly improved 4-year disease-free survival (94.4% vs 89.8%, HR 0.58, P<0.001), with overall survival benefit specifically in node-positive patients (HR 0.61, P=0.04) 2.

Advanced/Metastatic Disease

For metastatic disease, aromatase inhibitors including letrozole should be offered as first-line endocrine therapy except in patients with immediately life-threatening disease or rapid visceral recurrence during adjuvant endocrine therapy 2:

• Letrozole demonstrated superiority over tamoxifen in first-line treatment with median time to progression of 9.9 months versus 6.2 months (P=0.0001) and objective response rate of 32% versus 21% (P=0.0003) 3
• Treatment should continue until unequivocal disease progression documented by imaging, clinical examination, or disease-related symptoms 2, 1
• Sequential hormone therapy should be offered at progression for patients with endocrine-responsive disease 2

Dose Modifications

Special populations require dose adjustments 1:

• Cirrhosis or severe hepatic impairment: Reduce dose to 2.5 mg every other day 1
• Mild to moderate hepatic impairment: No adjustment needed 1
• Renal impairment: No adjustment needed if creatinine clearance ≥10 mL/min 1

Critical Safety Monitoring

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

• At 2 years in extended adjuvant setting, median hip BMD decreased 3.8% with letrozole 1
• Consider BMD monitoring throughout treatment 1
• Cholesterol monitoring should also be considered due to potential increases in total cholesterol 1

Common Adverse Events

The most frequent adverse reactions (>20%) include 1:

• Hot flashes, arthralgia, flushing, asthenia, edema, headache, dizziness, hypercholesterolemia, increased sweating, bone pain, and musculoskeletal symptoms 1

Compared to tamoxifen, letrozole has significantly lower rates of venous thromboembolic events, vaginal bleeding, hot flushes, and night sweats, but higher rates of cardiac failure, bone fractures, and arthralgia 4.

Important Contraindications and Warnings

Letrozole is contraindicated in pregnancy and can cause fetal harm 1:

• Obtain pregnancy test in females of reproductive potential before initiating therapy 1
• Advise effective contraception during treatment 1
• Advise not to breastfeed during treatment 1

Fatigue, dizziness, and somnolence may occur; exercise caution when operating machinery 1.

Treatment Duration and Discontinuation

• Adjuvant setting: Treatment should be discontinued at relapse; optimal duration is 5 years based on trial data 1
• Extended adjuvant setting: Median treatment duration was 60 months, with 71% of patients treated for at least 3 years and 58% completing at least 4.5 years; discontinue at tumor relapse 1
• Advanced disease: Continue until tumor progression is evident 1

Tamoxifen as Alternative

Tamoxifen alone should only be recommended for women who decline, have contraindications to, or cannot tolerate aromatase inhibitors 2. The consistent superiority of aromatase inhibitor-containing regimens over tamoxifen alone in disease-free survival across multiple large trials (ATAC, IES, ITA, BIG 1-98, ABCSG 8/ARNO 95) establishes aromatase inhibitors as the preferred approach 2.