Chemo-Induced Vascular Dysfunction More Likely When Breast Cancer Occurs After Menopause

Women who undergo medical treatment for breast cancer are at greater risk for suffering from later vascular damage if they’ve already reached menopause, according to new data.

Among the female patients who received neoadjuvant chemotherapy using the TAC protocol, researchers found evidence of endothelial dysfunction in surgically removed mammary artery tissue of women who were postmenopausal but not those who were premenopausal. This illustrates the protective effect of estrogens against oxidative stress and in the inhibition of endothelial nitric oxide synthase (eNOS), they say.

Breast cancer therapies, including radiation and chemotherapy, are known to increase later cardiovascular risk. There is not yet enough evidence to support using hormone status to influence treatment decisions, though that might one day happen, senior author Tomasz J. Guzik, MD, PhD (Jagiellonian University Medical College, Cracow, Poland), told TCTMD.

“We need to make sure that we assure patients that the primary importance is taking medications that increase survival, but then do not forget that, unfortunately, every treatment may have side effects and therefore long-term care is needed in our patients,” he said. “So as cardiologists setting up cardio-oncology clinics, we should start thinking about the vascular prevention and vascular aspects as a core part of cardio-oncology, not as an optional add-on as it is a bit now.”

Practically speaking, it’s still “very important” to assess baseline cardiovascular risk and control blood pressure in cancer patients both during and after treatment, Guzik continued.

TAC and Menopause

For the study, published online last week in JACC, researchers led by Piotr Szczepaniak, PhD (Jagiellonian University Medical College), included 62 women diagnosed with locally advanced breast cancer eligible for surgical treatment, of whom 40 were postmenopausal. Fourteen premenopausal and 20 postmenopausal women received standard TAC, consisting of intravenous docetaxel 75 mg/m² body surface area (BSA), doxorubicin (50 mg/m² BSA), and cyclophosphamide (500 mg/m² BSA) every 3 weeks for an average of eight cycles, with the last dose given approximately 4 weeks before surgery.

When the women were divided into four groups dependent on menopause status and TAC, only those who were postmenopausal and received TAC showed signs of endothelial dysfunction. No impairment was noted in any patient who did not receive TAC, regardless of menopausal status.

Upon assessing vascular oxidative stress in the arterial samples, researchers found that TAC increased superoxide production in postmenopausal but not premenopausal arteries.

Additional analyses in an animal model confirmed that estrogen suppresses the ability of docetaxel to generate reactive oxygen species (ROS), which can cause endothelial dysfunction.

“The notable lack of vascular dysfunction with docetaxel exposure in the premenopausal and nonovariectomized female mice underscores estrogen’s known vascular protective function and how it may be a contributor to lower age-adjusted CVD risk in premenopausal compared with postmenopausal breast cancer survivors,” write Julia Bertazzo, MD, and Caitlin F. Bell, MD (both University of Colorado Anschutz Medical Center, Aurora), in an accompanying editorial.

Further work looking into the mechanisms behind estrogen’s protective effects could “reveal exciting therapeutic targets in the vascular toxicity space,” they add.

Bertazzo and Bell note that there are no current guidelines for preventing CVD in breast cancer survivors, but say this may be possible in the future. “Clinical vigilance in survivorship is critical, but what if CVD risk could be minimized up-front?” they ask. “Examining vascular dysfunction as an early harbinger for elevated CVD risk provides a novel and underexplored angle to think about toxicity prevention and risk stratification.”

Guzik would also like to see more research looking into preventing and even reversing endothelial dysfunction, generally and specifically in breast cancer survivors.

“We can start with considering medication such as statins that have been shown to improve endothelial function independently of the lipid-related effects,” he said. Potentially targeting aspects of the vasculature’s signaling pathway might also be possible. “We hope that our study will initiate such studies because there is number of medications that can target different elements of this pattern.”