Hormone-receptor-positive (HR+) breast cancer is the most common form of the disease, and its growth is often fueled by the hormone estrogen. For postmenopausal women, the primary strategy involves lowering the body’s estrogen levels to starve the cancer cells. A class of medications known as Aromatase Inhibitors (AIs) blocks the enzyme responsible for converting androgens into estrogen (aromatization). Exemestane (Aromasin) and Letrozole (Femara) are two widely used AIs that reduce the risk of cancer recurrence. While both drugs serve the same purpose, they differ fundamentally in their chemical structure and how they interact with the aromatase enzyme, leading to distinctions in clinical use and side effect profiles.
Defining the Mechanism of Action
The primary difference between these two medications lies in their molecular interaction with the aromatase enzyme. Letrozole is classified as a non-steroidal AI, meaning its chemical structure is distinct from natural hormones. It acts as a reversible inhibitor, temporarily binding to the active site of the aromatase enzyme. This binding blocks the enzyme’s function and suppresses estrogen production, but the drug can eventually detach, allowing the enzyme to potentially resume its activity.
Exemestane is a steroidal AI because its structure is similar to the natural hormone androstenedione, the substrate for the aromatase enzyme. It is known as an irreversible inactivator, or “suicide inhibitor,” because it permanently binds to the aromatase enzyme. This permanent bond destroys the enzyme’s function, requiring the body to synthesize new aromatase enzymes before estrogen production can resume. Due to this permanent inactivation, Exemestane achieves a sustained suppression of circulating estrogen levels, distinguishing it from the reversible action of Letrozole.
Comparative Clinical Effectiveness and Sequencing
Both Letrozole and Exemestane are highly effective in the adjuvant setting, meaning they are used after primary treatment to reduce the risk of cancer recurrence in postmenopausal women with HR+ breast cancer. In first-line treatment for early-stage disease, both non-steroidal AIs like Letrozole and steroidal AIs like Exemestane have demonstrated superior efficacy compared to older hormonal therapies like Tamoxifen. Head-to-head comparisons between the three third-generation AIs often show similar disease-free survival rates when used upfront, suggesting that all are viable first choices.
Sequencing is where the distinct mechanisms of action become clinically relevant, particularly in the case of advanced or metastatic disease. Exemestane is frequently used sequentially after a patient’s cancer progresses while on a non-steroidal AI, such as Letrozole or Anastrozole. This strategy leverages the unique irreversible mechanism of Exemestane, which can overcome resistance that develops toward the reversible non-steroidal inhibitors. Studies confirm that Exemestane remains active and provides clinical benefit even after the failure of Letrozole or Anastrozole, highlighting the value of switching between the two drug classes.
Exemestane is a well-established option in the “switch” strategy, where a patient begins treatment with Tamoxifen for two to three years and then switches to the AI for the remainder of the five-year treatment plan. The Intergroup Exemestane Study (IES) demonstrated that switching to Exemestane after a period on Tamoxifen significantly improved disease-free survival compared to remaining on Tamoxifen for five years. The ability to switch between drug classes provides flexibility in managing endocrine resistance and offers continued therapeutic options for patients.
Analyzing the Side Effect Profiles
Both medications share a similar spectrum of adverse effects that arise directly from the resulting hormone deprivation. Musculoskeletal symptoms, collectively known as Aromatase Inhibitor-Associated Musculoskeletal Symptoms (AIMSS), are the most frequent complaint for both drugs, including arthralgia (joint pain) and myalgia (muscle aches). The reported incidence of these symptoms is high, often affecting 20% to 50% of patients, and is a major reason for treatment discontinuation.
Comparing these musculoskeletal effects is challenging because clinical trials often use different reporting methods, but evidence suggests that the incidence or severity of joint pain may vary. Both drugs also increase the risk of accelerated bone density loss, leading to a higher risk of osteoporosis and fractures. The steroidal structure of Exemestane may have a less detrimental effect on bone health compared to Letrozole, although this finding is not universally accepted.
Beyond musculoskeletal issues, both drugs can cause common menopausal-like symptoms, such as hot flashes, fatigue, and night sweats. Differences in lipid metabolism impact have been noted, with Letrozole sometimes associated with a less favorable effect on plasma lipid levels compared to Exemestane. Ultimately, the choice between the two often comes down to an individual patient’s tolerance, as a drug’s effectiveness is only realized if the patient can adhere to the full course of therapy.