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Aromatase Inhibitors Have Different Cardiovascular Safety Profiles: Presented at ECCO

By Jill Stein

PARIS, FRANCE -- November 2, 2005 -- The various aromatase inhibitors (AIs) are not interchangeable, according to safety data from 4 clinical trials presented here at the 13^th Annual Meeting of the European Cancer Conference (ECCO).

The study investigated the use of various AIs in the adjuvant setting for women with breast cancer, and suggests that each AI has a different cardiovascular (CV) safety profile.

"To date, anastrozole is the only AI in the adjuvant setting with a detailed benefit/risk profile from over 5 years of follow-up from which no CV safety concerns have emerged," said principal investigator Jean-Marc Nabholtz, MD, chairman of the Breast Cancer Research Institute in Paris, France, during his presentation on October 31^st.

His team compared safety data from the Letrozole as Adjuvant Endocrine Therapy for Postmenopausal Women with Receptor-Positive Breast Cancer (BIG 1-98) trial, the Intergroup Exemestane Study (IES), and the monotherapy arms of the Arimidex or Tamoxifen Alone or in Combination (ATAC) trial.

The BIG 1-98 trial compared letrozole and tamoxifen in 8028 women, and the IES-trial compared exemestane and tamoxifen in 4742 women. The ATAC study compared anastrozole and tamoxifen in 6186 women.

"Third-generation AIs -- including the nonsteroidal AIs anastrozole and letrozole and the steroidal AI exemestane -- have shown improved efficacy and tolerability compared with tamoxifen in the treatment of postmenopausal women with hormone receptor-positive breast cancer," Dr. Nabholtz said.

In the adjuvant setting, the increasing use of AIs in place of tamoxifen for all or part of the 5-year treatment period has potential safety implications for patients, who will be exposed to AIs for longer durations than previous patients.

Emerging data have raised concerns that long-term use of certain AIs could increase the risk of cardiovascular disease, Dr. Nabholtz said. However, it remains unclear whether or not molecular differences between the AIs account for any differential effects on the CV system.

Data from BIG 1-98 at a median follow-up of 26 months demonstrated a significantly greater incidence of moderate to severe (grade 3-5) cardiac events with letrozole versus tamoxifen (2.1% vs 1.1%, respectively; P = .0003). There were 7 cerebrovascular deaths with letrozole compared with 1 death with tamoxifen, and twice the number of cardiac deaths with letrozole versus tamoxifen treatment (13 vs 6, respectively).

Data from IES at a median of 37.4 months showed significantly more cases of myocardial infarction with exemestane than tamoxifen (20 vs 8, respectively; P = .02). However, data from ATAC at a median of 68 months showed a significantly decreased stroke incidence with anastrozole versus tamoxifen (62 vs 88, respectively; P = .03).

The number of ischemic CV events differed in anastrozole and tamoxifen patients, however the difference was not significant (127 vs 104, respectively; P = .1). Most of these events were mild to moderate in severity, and there was no difference in the incidence of MI (1.2% vs 1.1%, respectively).

Results also showed that the number of CV deaths remained low and similar for the 2 groups (anastrozole 49, tamoxifen 46), and most CV deaths occurred after the end of study treatment or after it had been stopped.

"One possibility for the apparent variability in the CV safety profile of the AIs is the possibility that structural differences play a role in selectivity (ie, their ability to interact with other molecules or metabolic pathways not involving the aromatase enzyme), suggesting that AIs should not be considered equivalents in clinical practice," Dr. Nabholtz said.

He emphasized that additional follow-up and more data are needed before establishing a mature and detailed CV safety profile for letrozole and exemestane in the adjuvant setting.

The study was supported by AstraZeneca.


[Presentation title: Comparison of Cardiovascular (CV) Safety Profiles of Aromatase Inhibitors (AIs). Abstract 343]

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