The Rapid Evolution of Cardiotoxicity in Breast Cancer and Why More Data is Needed

Despite a relatively small, though increasing, level of focus in oncology, radiation-induced heart damage in breast cancer is a relevant clinical problem that needs more attention.

Radiation-induced heart damage in patients with breast cancer is an important clinical issue for which biomarkers and preventive therapies are currently lacking. At the 2025 Miami Breast Cancer Conference, Carmen Bergom, MD, PhD, an associate professor in the Department of Radiation Oncology at Washington University in St. Louis, Missouri, presented clinical findings on this issue, as well as potential techniques that may reduce harmful effects.¹

Of the 250,000 patients in the US diagnosed with breast cancer each year, over half of these patients will receive some form of radiation therapy. While radiation improves cancer-specific survival, it can damage the heart tissue and lead to long-term toxicities.^2,3 Most patients are already going to receive cardiotoxic systemic therapy and are at high risk for heart disease due to other comorbidities.

Most commonly, radiation-induced cardiac changes appear as late-stage adverse effects and manifest in various forms including coronary artery disease, myocardial fibrosis, pericardial disease, microvascular dysfunction, abnormal conduction, and valvular heart disease.⁴

A search on PubMed demonstrated a 24-fold increase in “radiation cardiac toxicity” results from 2005 to 2013 (174 publications) and 2014 to 2022 (4288 publications), emphasizing an increased focus on radiation-induced cardiac toxicity in recent times.

Bergom went on to discuss which risk factors to be aware of for radiation-induced cardiotoxicity, what techniques may minimize cardiac doses, emerging data for cardiac imaging, and what guidelines or surveillance to follow.

Risk Factors

The mean heart dose of patients with breast cancer is linearly associated with major coronary events as there is approximately a 4% to 16% per Gy increase.^5,6,7 There was no threshold for the risk where there was no risk below a certain point.

Underlying factors such as smoking, hypertension, diabetes, and coronary artery calcifications are also linked to the cumulative risk of cardiac event; in fact, the risk of a major coronary event was doubled in the presence of cardiovascular risk factors and baseline ischemic heart disease was found to have a more than 6-times higher risk of a coronary event.⁵

A study that evaluated over 4000 patients with breast cancer found that, with a median follow-up of 18 years, history of smoking and radiation tripled the risk of myocardial infarction (HR, 3.04; 95% CI, 2.0-4.9; P = .039).⁸

Technique to Minimize Cardiac Dosage

Over time, the methods and techniques used to evaluate and administer the amount of radiation the heart receives, known as heart doses, have evolved greatly. Dating back to the pre-1990s and early 2000s, hand and digitized planning was standard. It was based on patient contours, patients in free breathing, and utilized dosimetry using 2D tangential fields; with these tools, heart volume was unable to be defined. The increased mean heart dose was unable to be quantified.^5,9

Between the 2000s and 2010s, CT planning became the standard. Supine position became common, patients remained in free breathing, and dosimetry evolved to using 3D conformal radiotherapy. The mean heart dose during this period was greater than 1 to 3 Gy.^6,7

Most recently, advanced CT planning has been used from the 2010s to the 2020s. Now, supine vs prone positioning is used, patients use deep inspiration breath hold, dosimetry is done with intensity-modulated radiation therapy (IMRT)/volumetric modulated arc therapy (VMAT), and it’s possible to do partial breast irradiation or omit radiotherapy altogether if clinically appropriate. The mean heart dose during this period is often less than 1 Gy.

Methods that have been implemented to reduce heart doses include prone positioning compared with the standard supine position, deep inspiration breathing, and the inclusion of protons. Additionally, delineating between the heart and lungs, and tracking doses has led to decreases in heart doses.

Deep inspiration breathing, for one example, moves the heart inferiorly and posteriorly, and keeps it away from tangential radiation beams; with this technique, the decrease in dose to heart and left anterior descending coronary artery was 20% to 70%. The method of breathing also works with IMRT.

Cardiac Doses and Dose Constraints

There are no well-established cardiac dose constraints for cardiac substructures aside from mean heart dose, no biomarkers or genetic markers known or currently used to identify patients with increased risk, and no well-established surveillance imaging or biomarkers for survivors after exposure to cardiac radiation.

The phase 3 NSABP-B51 trial (NCT01872975) and the phase 3 Alliance A221505 trial (NCT03414970) used a 3 to 5 Gy threshold mean heart dose to deem a plan acceptable.

There are also recent studies that have shown that specific doses to certain cardiac regions are associated with outcomes.¹⁰ Additionally, one study found that dose to the left ventricle was able to better predict cardiac outcomes than mean heart dose; the formula for long-term cardiac risk was based on left ventricle dose, age, and cardiac risk factors.⁷

Artery Calcification Screening/Surveillance

Coronary artery calcifications (CACs) are the best predictor of future cardiovascular events in the general population and, when spotted on non-contrast CT, are a direct measure of atherosclerotic burden.^10,11

Pre-radiation therapy, CACs are independently associated with cardiac events after breast radiation; assessment of CACs on radiation therapy planning and follow-up scans can be indicative of patients who are at the highest risk of undergoing cardiac events.

There are also various guidelines that can be used on baseline and surveillance follow-up in at-risk patient populations for cardiovascular toxicity induced by radiation.¹²

Cardiac Imaging and Emerging Data

There is a chance conventional imaging is not sensitive enough to detect relevant cardiac dysfunction, as recent series of patients with breast cancer who received radiation have shown. Regional assessment of dysfunction and strain imaging may prove to be more sensitive.^13,14,15

A study from 2021 performed echo strain imaging at baseline, 6 weeks, and 12 months, and found that changes in strain were associated with the dose received to left ventricular segments.¹⁶ The segments with the worst levels of deterioration from baseline strain were the same segments that received the largest doses; it was unclear how this correlated with clinical dysfunction.

Bergom ended her presentation by highlighting that, since 2013, the percentage of trials that have cardiotoxicity end points is still low, and that more data in prospective, clinical settings is needed.

References

1. Bergom C. Radiation-induced cardiotoxicity in patients with breast cancer. Presented at the 2025 Miami Breast Cancer Conference; March 6-9, 2025; Miami, FL.
2. Bilani N, Zabor EC, Elson L, Elimimian EB, Nahleh Z. Breast cancer in the United States: a cross-sectional overview. J Cancer Epidemiol. 2020;6387378. doi:10.1155/2020/6387378
3. Clarke et al. Lancet. 2020.
4. Zorn S, Rayan D, Brown SA, Bergom C. Radiation-induced cardiotoxicity: from bench to bedside and beyond. Adv Oncology. 2022;1:P1-13. doi:10.1016/j.yao.2021.02.001
5. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368(11):987-998. doi:10.1056/NEJMoa1209825
6. Taylor C, Correa C, Duane FK, et al. Estimating the risks of breast cancer radiotherapy: evidence from modern radiation doses to the lungs and heart and from previous randomized trials. J Clin Oncol. 2017;35(15):1641-1649. doi:10.1200/JCO.2016.72.0722
7. van den Bogaard VA, Ta BD, van der Schaaf A, et al. Validation and modification of a prediction model for acute cardiac events in patients with breast cancer treated with radiotherapy based on three-dimensional dose distributions to cardiac substructures. J Clin Oncol. 2017;35(11):1171-1178. doi:10.1200/JCO.2016.69.8480. Published correction appears in J Clin Oncol. 2017;35(32):3736. doi: 10.1200/JCO.2017.76.2732
8. Hooning MJ, Botma A, Aleman BM, et al. Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. J Natl Cancer Inst. 2007;99(5):365-375. doi:10.1093/jnci/djk064
9. van Nimwegen FA, Schaapveld M, Cutter DJ, et al. Radiation dose-response relationship for risk of coronary heart disease in survivors of Hodgkin lymphoma. J Clin Oncol. 2016;34(3):235-243. doi:10.1200/JCO.2015.63.4444
10. Bergom C, Bradley JA, Ng AK, et al. Past, present, and future of radiation-induced cardiotoxicity: refinements in targeting, surveillance, and risk stratification. JACC CardioOncol. 2021;3(3):343-359. doi:10.1016/j.jaccao.2021.06.007
11. Phillips WJ, Johnson C, Law A, et al. Comparison of Framingham risk score and chest-CT identified coronary artery calcification in breast cancer patients to predict cardiovascular events. Int J Cardiol. 2019;289:138-143. doi:10.1016/j.ijcard.2019.01.056
12. Mitchell JD, Cehic DA, Morgia M, et al. Cardiovascular manifestations from therapeutic radiation: a multidisciplinary expert consensus statement from the international cardio-oncology society. JACC CardioOncol. 2021;3(3):360-380. doi:10.1016/j.jaccao.2021.06.003
13. Harrow S, Palma DA, Olson R, et al. Stereotactic radiation for the comprehensive treatment of oligometastases (SABR-COMET): extended long-term outcomes. Int J Radiat Oncol Biol Phys. 2022;114(4):611-616. doi:10.1016/j.ijrobp.2022.05.004
14. Bergom C, Rubenstein J, Wilson JF, et al. A pilot study of cardiac MRI in breast cancer survivors after cardiotoxic chemotherapy and three-dimensional conformal radiotherapy. Front Oncol. 2020;10:506739. doi:10.3389/fonc.2020.506739
15. Boda-Heggemann J, Knopf AC, Simeonova-Chergou A, et al. Deep inspiration breath hold-based radiation therapy: a clinical review. Int J Radiat Oncol Biol Phys. 2016;94(3):478-492. doi:10.1016/j.ijrobp.2015.11.049
16. Trivedi SJ, Tang S, Byth K, et al. Segmental cardiac radiation dose determines magnitude of regional cardiac dysfunction. J Am Heart Assoc. 2021;10(7):e019476. doi:10.1161/JAHA.120.019476