SAN ANTONIO (FRONTLINE MEDICAL NEWS) – Aromatase inhibitors, a mainstay of therapy in postmenopausal women with operable hormone receptor–positive breast cancers, are associated with reductions in endothelial function that could contribute to the development of cardiovascular disease, independent of the duration of therapy, investigators have found.

In a cross-sectional study examining endothelial function among postmenopausal women with locally advanced breast cancer on an aromatase inhibitor (AI), there were trends toward reduction in large and small artery elasticity and a significant decrement in vascular tone, compared with the vessels of healthy controls, reported Anne Blaes, MD, from the Masonic Cancer Center at the University of Minnesota in Minneapolis.

“Other studies have suggested that the cardiac risk from aromatase inhibitors is increased further in those with a previous diagnosis of cardiovascular disease. In this study we did not include this patient population, but I really think further work needs to be done in this area,” she said at the San Antonio Breast Cancer Symposium.

Her group’s findings suggest that prospective breast cancer trials need biomarkers to predict cardiovascular risk for patients who are on chronic AI therapy, she said.

CV incidence modest, deaths lows

The incidence rates of cardiovascular disease in clinical trials of adjuvant AI therapy have ranged from 3% to 17%, although the incidence of death from cardiovascular disease was relatively low in these trials, on the order of 1%-2%. Data on cardiovascular risk factors, however, were inconsistently collected across the various studies, Dr. Blaes noted.

“More recently, a lot of discussion has gone on about both the use of prolonged endocrine therapy using aromatase inhibitors – whether to consider 5 or 10 years – and in addition, as our population is aging, competing risks for mortality, whether that’s breast cancer or cardiovascular risk,” she said.

The investigators examined endothelial function in 36 postmenopausal women with locally advanced, operable breast cancer treated with curative intent with adjuvant AI therapy, and compared results with those of 25 healthy postmenopausal volunteers, five of whom were excluded from the final analysis due to prior use of exogenous estrogen.

About half of the patients had received chemotherapy, and two-thirds had received radiation therapy. The AIs used for most patients were anastrozole (Arimidex) and letrozole (Femara). Seven of the 36 cases had previously received tamoxifen.

The authors measured endothelial function using the EndoPAT (Itamar Medical) system that measures peripheral arterial tone (PAT) to identify reactive hyperemia. Endothelial dysfunction measured this way has been associated with an increased risk of cardiac adverse events independent of the Framingham Risk Score, Dr. Blaes said.

The participants underwent biomarker analysis and pulse wave analysis using a cardiovascular profiling system, and pulse contour analysis using the Endo-PAT2000 system. The investigators then compared biomarkers and functional test markers between cases and controls using T-tests and Wilcoxon Rank-Sum tests.

Biomarkers included inflammatory markers (high-sensitivity C-reactive protein, white blood cell count, interleukin 6), markers of hemostasis (fibrinogen, d-dimer, plasminogen-activator inhibitor-1, tissue-type plasminogen activator), and endothelial function markers (von Willebrand factor, circulating endothelial cells, soluble vascular cell adhesion molecule-1, and others).

They measured large-artery elasticity (LAE), small-artery elasticity (SAE), and the EndoPAT ratio, or reactive hyperemia index (RHI), the post-to-pre occlusion PAT signal ratio in the occluded side, normalized to the control side and further corrected for baseline vascular tone. An RHI score above 1.67 is considered normal, and a score of 1.67 or below is considered abnormal.

They found that both LAE and SAE trended toward significantly worse vascular tone in cases, compared with controls, but the differences were not statistically significant. The EndoPAT ratio, however, was significantly worse among cases, at 0.8, compared with 2.6 for controls, a difference that remained significant after controlling for systolic blood pressure (P less than .0001).

Hemostatic and endothelial biomarkers were significantly elevated in cases, compared with controls, but there were no significant differences in inflammatory markers.

When the investigators looked at the association between vascular function and cancer treatment characteristics, they found no differences in the use of chemotherapy, radiation, or left vs. right breast treated.

The use of anastrozole was associated with a significant reduction in LAE, compared with either letrozole or exemestane (P = .03). There was no association between duration of AI therapy and EndoPAT ratio.

Estradiol levels implicated

Not surprisingly, women on endocrine therapy in the study had significantly lower levels of estradiol than controls. Estradiol appears to be important for regulating healthy endothelial function, commented Patricia A. Ganz, MD, of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, who was the invited discussant.

“I think these are very provocative, hypothesis-generating findings, and I think they really fit what we expect the physiology should be in terms of endothelial function, even within this postmenopausal group of women where we’re looking at two discrete groups in terms of the estradiol level,” she said.

The study was funded by Building Interdisciplinary Research Careers in Women’s Health and a Masonic Scholar Award. Dr. Blaes and Dr. Ganz reported no relevant conflicts of interest.


You May Also Like