Journal of Steroid Biochemistry & Molecular Biology 95 (2005) 143–149 Vascular effects of aromatase inhibitors: Data from clinical trials  Anthony Howell a,* , Jack Cuzick b a CRUK Department of Medical Oncology, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK b CRUK Department of Epidemiology, Mathematics and Statistics, Wolfson Institute of Preventive Medicine, Charterhouse Square, London EC1M 6BQ, UK Abstract Aromatase inhibitors (AIs) are becoming the endocrine treatment of first choice for postmenopausal women with hormone receptor-positive breast cancer and are under investigation for use in breast cancer prevention. AIs reduce circulating estrogen to barely detectable concentrations. It is possible that such a low concentration will be deleterious to the vascular system since estrogen receptors are known to be in the cell walls of blood vessels and estrogen is thought to be important in maintaining blood vessel integrity. Because most women who present with primary breast cancer are cured by surgery and systemic therapy and the major cause of female death is vascular disease, it is particularly important to investigate the vascular side effects of AIs in current breast cancer adjuvant and prevention trials. In order to set the vascular toxicities of AIs reported in the current adjuvant trials into context, here we compare them with the toxicities seen during treatment with hormone replacement therapy (HRT) and selective estrogen receptor modulators (SERMs). Clinical trial evidence indicates that HRT increases risk of coronary heart disease (CHD) whereas SERMs and AIs (to date) appear to be neutral. Cerebrovascular disease and venous thromboembotic events are increased by HRT and SERMs but appear to be unaffected by treatment with AIs. Cognitive function is also considered here since it may also have a vascular component and is potentially a serious potential side effect/benefit of AIs. Recent studies indicate that HRT has a small detrimental effect on cognitive function and is associated with a doubling of the incidence of dementia. A comprehensive study of the SERM, raloxifene, on cognitive function showed no significant effect. There are no definitive reported studies investigating tamoxifen and none for AIs on cognitive function, although there is one in progress in the context of the IBIS II prevention trial which compares anastrozole to placebo in women at high risk. At present concerns about deleterious vascular side effects are confined to HRT and SERMs. However, we have few long-term data using AIs for the treatment and prevention of breast cancer. © 2005 Elsevier Ltd. All rights reserved. 1. Introduction Until recently 5 years’ treatment with the SERM tamox- ifen was standard adjuvant therapy given after surgery for primary breast cancer in order to prevent relapse in patients with hormone receptor (HR) positive tumours. Tamoxifen in- hibits the proliferative effects of estrogen on breast epithelial cells and by doing so reduces relapse by approximately 50% and improves survival by 25% in women with HR-positive disease [1]. AIs inhibit peripheral aromatase and thus reduce the concentration of estradiol within tumour cells and thus  Presented at the VIIth International Aromatase Conference: AROMATASE 2004, Edinburgh, Scotland, UK, 6–8 September 2004. * Corresponding author. Tel.: +44 161 446 8037; fax: +44 161 446 8000. E-mail addresses: anthony.howell@christie-tr.nwest.nhs.uk (A. Howell), jack.cuzick@cancer.org.uk (J. Cuzick). prevent ER activation. Recent adjuvant trials indicate that estrogen deprivation by AIs is therapeutically superior to blocking the estrogen receptor (ER) with tamoxifen [2–4]. Although AIs have been shown to be superior to tamoxifen for the treatment of advanced breast cancer [5,6] and provide some toxicity data in that clinical situation, these studies are often confounded by symptoms associated with metastatic disease. Randomised controlled adjuvant and prevention trials give clearer toxicity data since patients either have symptomless micrometastatic disease or no disease and thus we will focus on these studies [2–4]. Approximately 1 in 9 women develop breast cancer but only 1 in 25 die from it, indicating a high cure rate as a result of early detection (screening) and standard treatment [7]. Thus, most women who develop breast cancer do not die from the disease but from what is termed a competing cause of death. Until recently extensive data on competing 0960-0760/$ – see front matter © 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.jsbmb.2005.04.005