Real-World Data Suggests Anastrozole and Letrozole May Outperform Exemestane for Postmenopausal Women

Aromatase Inhibitors: A Closer Look at Real-World Effectiveness

Aromatase inhibitors (AIs)—anastrozole, letrozole, and exemestane—are foundational in treating postmenopausal women with hormone receptor–positive early-stage breast cancer. While all three are widely recommended, their direct comparison in real-world settings has been limited—until now.

Nationwide Analysis: Who Was Studied?

Researchers tapped into the massive French Early Breast Cancer Cohort, analyzing records from nearly 150,000 women aged 50–75 diagnosed between 2011 and 2020. These women started AI therapy (without ovarian suppression) after breast surgery and were followed for up to eight years, offering unprecedented insight into the comparative performance of these medications.

Key Findings: Survival and Persistence

After a median follow-up of over five years:

Letrozole and anastrozole users enjoyed slightly better 8-year disease-free survival (DFS) and overall survival (OS) compared to those on exemestane.

Eight-year DFS was around 81% for anastrozole and letrozole, versus 79% for exemestane.

OS at 8 years was 90.5% (anastrozole), 89.9% (letrozole), and 88.8% (exemestane).

Exemestane users were more likely to stop their medication early.

Even when researchers adjusted for the “perfect” scenario—assuming everyone stayed on their assigned AI for five years—the slightly lower survival rates for exemestane persisted.

What Might Explain These Differences?

While all AIs suppress estrogen, their pharmacology differs. Letrozole tends to achieve the most profound estrogen suppression, possibly explaining its slight edge. Exemestane, with its unique steroidal structure, may not suppress estrogen as thoroughly and may even activate certain hormone receptors that could promote tumor growth in some cases.

Side Effects and Switching

All three drugs had similar bone fracture risks.

Exemestane had a marginally better lipid (cholesterol) profile but was associated with slightly higher diabetes risk.

Over a third of women stopped their therapy within five years, with the highest discontinuation rates seen in the exemestane group. Switching between drugs was common.

Clinical Takeaway

While differences are modest, anastrozole and letrozole appear to provide a small but meaningful advantage over exemestane for postmenopausal women with early-stage, hormone receptor–positive breast cancer. These findings—powered by real-world data from routine clinical practice—suggest that anastrozole or letrozole may be preferable as initial therapy. However, individual patient factors and side effect profiles still matter.

Key Points at a Glance

Largest real-world study to date comparing three leading aromatase inhibitors.

Anastrozole and letrozole associated with slightly better 8-year disease-free and overall survival than exemestane.

Exemestane users more likely to discontinue therapy early.

Differences held even with perfect therapy adherence.

Results support choosing anastrozole or letrozole as initial therapy for most postmenopausal women.

Citation:

Dumas E, Hamy A-S, Wanis KN, et al. Outcomes of Anastrozole, Letrozole, and Exemestane in Patients With Postmenopausal Breast Cancer. JAMA Network Open. 2025;8(12):e2550842. doi:10.1001/jamanetworkopen.2025.50842