Letrozole and anastrozole are commonly prescribed medications for postmenopausal women diagnosed with hormone-receptor-positive breast cancer. Both drugs are Aromatase Inhibitors (AIs) that function by significantly reducing the amount of estrogen in the body. Since estrogen can fuel the growth of hormone-sensitive tumors, lowering its concentration is a standard strategy in cancer care. Understanding the differences in how letrozole and anastrozole work, their performance in clinical trials, and their side effect profiles helps patients and physicians make an informed choice.
The Mechanism of Aromatase Inhibition
The primary goal of both letrozole and anastrozole is to block the production of estrogen outside of the ovaries in postmenopausal women. While the ovaries cease estrogen production after menopause, the body still generates the hormone in fat, muscle, and breast tissue through a process called aromatization. This process is carried out by the aromatase enzyme, which converts androgen hormones like androstenedione and testosterone into estrogens such as estrone and estradiol.
Both letrozole and anastrozole are classified as non-steroidal, third-generation aromatase inhibitors. They work by reversibly binding to the active site of the aromatase enzyme, effectively competing with androgens and preventing the conversion process. This action leads to a substantial reduction in circulating estrogen levels, which starves the estrogen-dependent cancer cells. Letrozole has been shown in some studies to be a more potent inhibitor, suppressing aromatase activity and plasma estrogen levels to a greater degree than anastrozole.
Clinical Efficacy and Treatment Selection
Despite the difference in potency observed in laboratory settings, large-scale clinical trials have generally demonstrated that both letrozole and anastrozole offer comparable efficacy in treating hormone-receptor-positive breast cancer. The Femara Versus Anastrozole Clinical Evaluation (FACE) trial directly compared the two in over 4,000 postmenopausal women with early-stage disease. The results showed no statistically significant difference in five-year disease-free survival (DFS) or overall survival (OS) between the two groups.
The five-year estimated DFS rate in the FACE trial was 84.9% for letrozole compared to 82.9% for anastrozole, a difference that was not statistically significant. Similarly, the five-year estimated OS rates were 89.9% and 89.2%, respectively, supporting the conclusion that the two drugs are largely equivalent in the adjuvant setting. A separate study involving patients with advanced breast cancer suggested that letrozole resulted in a higher response rate compared to anastrozole, but the overall survival remained similar.
A physician’s choice between the two is influenced by factors beyond simple comparative efficacy. Considerations include the specific treatment setting, such as initial adjuvant treatment or extended adjuvant therapy after tamoxifen. Patient history, existing health conditions, and institutional preference also play a role. While letrozole might be a powerful estrogen suppressor biochemically, this does not consistently translate into superior clinical outcomes in major head-to-head adjuvant trials.
Comparative Side Effects and Administration Differences
Letrozole and anastrozole share many common side effects because they both drastically reduce estrogen levels. These shared adverse reactions often include hot flashes, fatigue, headache, and a decrease in bone mineral density leading to an increased risk of osteoporosis. The most frequently reported side effect for both drugs is joint pain, or arthralgia, which affects nearly half of patients.
While the overall safety profiles are similar, subtle differences exist that influence patient tolerability. Some studies suggest that letrozole may be more likely to cause severe joint pain, potentially leading to a higher rate of treatment discontinuation. Conversely, anastrozole has been more closely linked to bone fractures in some reporting systems, though both drugs require bone density monitoring. Cardiovascular events, such as high blood pressure, might also be slightly more common with letrozole due to its greater estrogen-suppressing effect.
The standard daily dosage for anastrozole is a 1 mg tablet, while letrozole is a 2.5 mg tablet, both typically taken once a day. These different dosages reflect the distinct pharmacological properties of each drug, but both are generally taken as a simple, once-daily pill. Since side effects are highly personal, physicians often view the two as interchangeable options, allowing patients to switch from one drug to the other if they experience intolerable side effects.