Letrozole: Mechanism and Side Effects
What is Letrozole?
Letrozole is a highly potent, third-generation nonsteroidal aromatase inhibitor that blocks estrogen production by inhibiting the aromatase enzyme, which converts androgens to estrogens throughout the body. 1, 2
- Letrozole binds to the heme component of the cytochrome P450 subunit of aromatase, achieving over 98% inhibition of peripheral aromatase activity 2, 3
- This results in suppression of blood and urinary estrogen levels by over 95% within 2 weeks of treatment in postmenopausal women 2
- The drug is administered orally once daily at a dose of 2.5 mg 1, 4
Clinical Uses
- First-line treatment for postmenopausal women with hormone receptor-positive metastatic breast cancer, where it demonstrates superior efficacy compared to tamoxifen 5
- Adjuvant therapy for early-stage hormone-responsive breast cancer in postmenopausal women 5
- Extended adjuvant therapy after 4.5-6 years of tamoxifen treatment 5, 1
- Second-line therapy following tamoxifen failure 5
Critical caveat: Letrozole should NEVER be used in premenopausal women outside clinical trials unless combined with ovarian suppression, as it does not adequately suppress ovarian estrogen synthesis and can cause benign ovarian pathology. 5
Side Effects Profile
Common Side Effects
The most frequently reported adverse events with letrozole include:
- Hot flushes (4.9-5% in clinical trials) 2, 4
- Arthralgia (joint pain) - reported more frequently than with placebo in extended adjuvant therapy 5, 1
- Myalgia (muscle pain) 5, 4
- Arthritis 5
- Headache (1.1-7%) 2
- Nausea (6-10.3%) 2, 4
- Fatigue (3.2-5%) 2
- Hair thinning 4
- Peripheral edema (6%) 2
Serious Side Effects
Musculoskeletal and Bone Effects:
- Greater loss of bone mineral density compared to tamoxifen, requiring monitoring 5
- Increased rate of bone fractures compared to tamoxifen 5, 1
- Musculoskeletal symptoms are more common with aromatase inhibitors than with tamoxifen 5
Cardiovascular Effects:
- The incidence of grade 3-5 cardiac adverse events was significantly higher with letrozole compared to tamoxifen in the BIG 1-98 trial 5
- Overall cardiac adverse event rates were similar between letrozole (4.8%) and tamoxifen (4.7%), but severity differed 5
Favorable Safety Profile Compared to Tamoxifen
Letrozole has significantly LOWER rates of:
- Venous thromboembolic events compared to tamoxifen 5, 1
- Vaginal bleeding 1
- Endometrial effects (lesser effect on endometrial tissue than tamoxifen) 5
- Thromboembolic events overall (both overall incidence and grade 3-5 events were higher with tamoxifen) 5
Tolerability
- Adverse events are usually mild to moderate in severity 2
- Treatment discontinuation due to adverse events occurs in only 3% of patients receiving letrozole 2.5 mg/day 2
- Letrozole is generally well tolerated with a similar overall tolerability profile to tamoxifen 4
- Quality of life is reasonably preserved during extended endocrine therapy, though women may experience ongoing menopausal symptoms 5
Long-term Monitoring Considerations
Important clinical pitfall: Long-term effects on bone mineral density require monitoring, as these parameters have not been fully determined in extended follow-up studies. 4