Coronary artery calcification scores based on routine computed tomography (CT) scans used for planning radiotherapy therapy may be able to predict which women with breast cancer have a high probability of developing cardiovascular disease. The promise of this research is that once high-risk patients are identified by this cost-effective technology, interventions may help to reduce the risk for cardiovascular disease.

“We believe this is the first time anyone has conducted a large-scale study like this. We’ve shown that we can use routine CT scans to indicate which patients with breast cancer are most likely to develop cardiovascular disease. Now, we need to do more research to find out what can be done to help minimize this risk, for instance, whether patients’ cardiovascular health should be monitored or treated,” said senior author Helena Verkooijen, MD, of the Division of Imaging and Oncology, University Medical Center Utrecht, the Netherlands, speaking at the European Organisation for Research and Treatment of Cancer (EORTC) 12th European Breast Cancer Conference, which was held virtually this year.¹ “Identifying cardiovascular disease risk will enable patients to adopt targeted cardiopreventive interventions, including lifestyle changes and pharmacoprevention strategies,” she added.

“Coronary calcifications are a strong independent risk factor for cardiovascular disease. They can present without other risk factors and are visible on CT planning scans.”

— Helena Verkooijen, MD

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Commonly used breast cancer treatments, such as anthracyclines, trastuzumab, and radiation, may produce cardiotoxicity, which can lead to cardiovascular disease. Dr. Verkooijen noted that, although these treatments improve survival, they have side effects. “In my opinion, treating breast cancer means finding the right balance between maximizing the chances of tackling the tumor while minimizing the risks of side effects, including cardiovascular disease,” she stated.

Coronary Artery Calcification Scores

The beauty of the study is that it shows that analyzing already-available CT scans using a computer-generated deep learning algorithm to calculate coronary artery calcification scores can identify women with a greater than one in four risk of developing cardiovascular disease. Thus, it is cost-effective, Dr. Verkooijen noted.

Coronary artery calcification scores are already being used in general medical practice to determine a patient’s risk of developing cardiovascular disease. The American Heart Association/American College of Cardiology guidelines suggest considering coronary artery calcification testing in adults between the ages of 40 and 75 at intermediate risk as a predictive test. Coronary artery calcification scores between 100 and 400 are considered intermediate risk—in other words, there is a 10-year chance of 13% to 16% of having a cardiovascular event. Coronary artery calcification scores above 400 are considered high risk.

“Coronary calcifications are a strong independent risk factor for cardiovascular disease. They can present without other risk factors, such as fa amily history of cardiovascular disease, being overweight, or having diabetes, and are visible on CT planning scans,” Dr. Verkooijen explained.

Study Description

The multicenter, retrospective cohort Bragatston study was based on about 15,000 patients with breast cancer slated for radiotherapy at three large hospitals in the Netherlands between 2005 and 2016. All women underwent planning CT scans of the chest. A deep learning algorithm was used to classify the scans according to five categories (from very low to very high risk) based on coronary artery calcification scores: 0, 1–10, 11–100, 101–399, and > 400.

Data on cardiovascular disease occurrence were obtained from Dutch Hospital Data and the National Cause of Death Register. The association between coronary artery calcification scores and cardiovascular disease risk was calculated using Cox proportional hazard regression models. Stratification factors included left- vs right-sided irradiation and treatment with or without anthracyclines.

At baseline, the mean patient age was 58 years. Patients were followed for the cause and the date of death as well as the discharge diagnosis. A diagnosis of cardiovascular disease included myocardial infarction, stroke, and heart failure. They were also followed for diagnosis of a subgroup of cardiovascular disease, coronary heart disease, which included myocardial infarction and angina pectoris.

Key Findings

Among 15,919 women irradiated for breast cancer, the majority (70%) had no coronary artery calcification detected on CT planning scan. About 10% to 12% were found to be at intermediate risk based on the coronary artery calcification score; 5% were at high risk and 3% were at very high risk.

“We’ve shown that we can use routine CT scans to indicate which patients with breast cancer are most likely to develop cardiovascular disease.”

— Helena Verkooijen, MD

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There was a linear relationship between median age and coronary artery calcification risk score. “Women without coronary artery calcification were younger,” Dr. Verkooijen said. “However, younger women were more often exposed to anthracycline.”

The absolute risk of developing cardiovascular disease at 52 months of follow-up increased from 5% in those without calcifications (coronary artery calcification score = 0) to 28% for those with calcifications. The risk of coronary heart disease increased from 1% to more than 10% in patients with calcifications.

A similar pattern was observed for all-cause mortality. The risk was 7% among those with no calcifications and four times higher (28%) for women with a high coronary artery calcification score (ie, > 400).

‘Stronger Association With Anthracyclines’

In a multivariate analysis adjusted for age, laterality, and treatment with anthracycline and trastuzumab, a similar risk pattern was observed. For those in the very high–risk group (coronary artery calcification score > 400), the risk of coronary heart disease was 8.2%, and the risk of death was 2.3%. For those in the intermediate-risk group (coronary artery calcification score between 100 and 400), the corresponding percentages for risks of coronary heart disease and death were 4.3% and 2.8%, respectively. Risks were similar for right-sided vs left-sided radiotherapy.

“There was a stronger association with anthracyclines. In fact, the risk of developing cardiovascular disease was sixfold higher for very high–risk women treated with anthracyclines than for women treated without anthracyclines who had no calcifications,” noted Dr. Verkooijen.

“We wanted to see whether women would like to be informed of their risk level without proven strategies to reduce coronary artery calcification. We found that about 90% wanted to be informed of the risk according to coronary artery calcification scores on CT scan,” she told listeners.

One limitation of the study is that it did not take into account other established cardiovascular disease risk factors, such as smoking, high blood pressure, and diabetes. Dr. Verkooijen and co-investigators plan to look at these factors in another study. They are also currently involved in an effort to have this technique introduced to other radiology units in the Netherlands.

Additional Commentary

Nadia Harbeck, MD

Chair of this year’s European Breast Cancer Conference, Nadia Harbeck, MD, of the LMU University Hospital, Munich, Germany, commented on this study: “Our key aim is to treat patients with breast cancer effectively. However, it is just as important not to overtreat patients, because cancer therapies can have serious and long-term side effects.”

“This is a clever study because it shows how the CT scans we are already taking can also be used to discover which women may have the highest risk of cardiovascular disease. We look forward to further results from these researchers and hope they might show us how best to help women who are at a higher risk of cardiovascular disease,” Dr. Harbeck stated. 

DISCLOSURE: This research was funded by the Dutch Cancer Society. Dr. Verkooijen reported financial relationships with Elekta Sweden. Dr. Harbeck holds stock or other ownership interests in the West German Study Group; has received honoraria from Amgen, AstraZeneca, Novartis, Pfizer, Pierre Fabre, Roche, and Zodiac Pharma; has served as a consultant or advisor to AstraZeneca, Celgene, Daiichi Sankyo, Lilly, Merck Sharp & Dohme, Novartis, Odonate Therapeutics, Pfizer, Pierre Fabre, Roche/Genentech, Sandoz, and Seattle Genetics.

REFERENCE

1. Gal R, van Velzen SG, Emaus MJ, et al: The risk of cardiovascular disease in irradiated breast cancer patients: The role of cardiac calcifications and adjuvant treatment. 2020 European Breast Cancer Conference. Abstract 7. Presented October 1, 2020.