Women with breast cancer (BC) face a higher risk of death from cardiovascular disease (CVD) than women in the general population without BC. There is interest in determining how antiestrogenic therapy affects this risk. While menopausal hormonal therapy is not recommended for the prevention of CVD, evidence points to a beneficial role of endogenous estrogens in younger or early postmenopausal women.

In postmenopausal women, aromatase inhibitors (AIs) produce a virtually complete deficiency of circulating estradiol by inhibiting >95% of aromatase, which is the rate-limiting enzyme in the conversion of androgens to estradiol. Plasma levels of estradiol are reduced to <3 pmol/L, which is the lower limit of detection sensitivity for mass spectrometry-based assays. Tamoxifen, on the other hand, while acting as a pure estrogen receptor antagonist in breast tissue, functions as a partial estrogen receptor agonist in other tissues, including the coagulation system.

In this review, the authors examined the cardiometabolic effects of adjuvant endocrine therapy on metabolic parameters in women with hormone receptor–positive (HR+) early BC. In particular, they compared the effects of adjuvant endocrine therapy with either tamoxifen or AIs on body composition, hepatic fat accumulation, glucose metabolism, lipid metabolism, arterial wall thickness/function, and cardiovascular (CV) events.
Tamoxifen is associated with an increase in body and visceral fat and decreased lean body mass, whereas AIs demonstrate the opposite effect—decreased fat mass and increased lean body mass relative to tamoxifen.

The risk of steatosis with tamoxifen is well documented. This may be associated with higher serum triglyceride (TG) and lower high-density lipoprotein (HDL) levels. AIs, however, decrease the risk of hepatic fat accumulation, although this is not well studied. Hepatic steatosis may be an independent risk factor for CVD because of its correlation with metabolic syndrome.

While tamoxifen may increase the risk of developing diabetes, it is less clear what effect AIs have on this endocrine disease, although some evidence points to an increased risk with both tamoxifen and AIs when they are used for more than 2 years.

Tamoxifen decreases total cholesterol by 12% to 14%, low density lipoprotein (LDL) by about 20%, and lipoprotein-a, but it can also increase TG, which can be severe in some cases. AIs increase total cholesterol and have inconsistent effects on other lipemic parameters. They may decrease HDL. Studies examining the lipid effects associated with AIs have been confounded by washout effects since tamoxifen is often administered prior to AI therapy.

Tamoxifen decreases carotid intimal-media thickness and increases flow-mediated dilation, whereas AIs have been associated with adverse effects on endothelial and vascular function.

Tamoxifen has been associated with a decrease in CV events, even though its use is correlated with an increased risk of thromboembolic disease. AIs may increase CV risk compared with tamoxifen. There may be a difference in findings between those obtained from observational studies compared with those from randomized, controlled trials. The authors caution that data on the cardiometabolic effects of BC endocrine therapy are often observational and, therefore, are not conclusive.

However, they did encourage cancer survivorship programs to promote the American Cancer Society/American Society of Clinical Oncology guidelines, which recommended healthy lifestyle choices such as smoking cessation, eating a nutritious, low-fat diet, and exercising.

As cardiometabolic risk is often assessed either as part of safety monitoring or as a secondary endpoint in endocrine therapy studies, more emphasis needs to be placed on this risk by making the assessment of the effects of these drugs on the CV system a primary goal.

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