By Michael H. Crawford, MD, Editor

SYNOPSIS: A study of breast cancer survivors revealed left breast radiation therapy doubles the subsequent risk of coronary heart disease vs. right-sided radiation.

SOURCE: Carlson LE, Watt GP, Tonorezos ES, et al. Coronary artery disease in young women after radiation therapy for breast cancer. JACC CardioOncol 2021;3:381-392.

Although radiation therapy is known to increase the risk of developing cardiovascular disease in older patients (older than age 50 years) with breast cancer, little is known about its effects in younger women. Researchers from the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) follow-up study described the self-reported incidence of cardiovascular disease in younger women diagnosed with breast cancer in relation to the treatment they received and lifestyle factors.

WECARE was a population-based study of women diagnosed with stage I or II breast cancer before age 55 years between 1985 and 2008 from five medical centers (three in in the United States and one each in Denmark and Canada). Data were collected from medical record abstraction and structured phone interviews conducted between 2013 and 2015 among living women from the study. From the total population of 2,342 women contacted, participants were excluded if they did not complete the questionnaire, declined to participate, did not undergo radiation therapy, or had a history of cardiovascular (CV) disease before breast cancer diagnosis, resulting in the final study population of 972 women. The follow-up time was defined as the time from breast cancer diagnosis until the diagnosis of a second primary cancer, breast cancer recurrence or metastasis, or the end of the prescribed follow-up. The average radiation dose was 55 Gy (range was 45 Gy to 65 Gy) and did not differ by laterality. The primary endpoint was the development of CV disease in right vs. left breast radiation therapy patients. Adjustments were made for baseline lifestyle and CV risk factors. Lifestyle and risk factors for CV disease were distributed evenly between the 48% who underwent left-sided radiation and the 52% who underwent right-sided treatment. The median age of breast cancer diagnosis was 46 years and the median follow-up was 14 years (range = one year to 29 years). Most patients were white, and two-thirds had stage I cancer. Adjuvant chemotherapy was administered in 60% (half of that was an anthracycline). Less than half underwent hormone therapy.

After a five-year latency period, the incidence of coronary artery disease (CAD) increased more in those who underwent left-sided vs. right-sided radiation therapy (adjusted HR, 2.5; 95% CI, 1.3-4.7; P = 0.01). The overall cumulative incidence of CAD after 27.5 years was 10.5% for left-sided radiation and 5.8% for right-sided (P = 0.01). There was no interaction with baseline risk factors or lifestyle that reached statistical significance. Also, CAD risk was not modified by chemotherapy or hormone therapy. The authors concluded the risk of CAD in women with breast cancer who underwent left-sided radiation therapy was twice that of women who underwent right-sided therapy. This risk was independent of other risk factors and should be considered in the management of breast cancer survivors.

COMMENTARY

About half of women with breast cancer receive radiation therapy as part of a breast-conserving strategy. For women younger than age 50 years with stage I or II breast cancer, there is ample time to develop CV disease. Any treatments that affect the development of CV disease would be of importance, especially in younger women who generally are at low risk for CV disease. Thus, this study of the effects of radiation therapy on the risk of CAD in younger women with breast cancer is of interest. Rather than studying women who did or did not receive radiation therapy, which could have led to selection bias, Carlson et al chose to study the laterality of therapy in those who did undergo radiation. Left-sided breast radiation delivers an average of 3.7 Gy more radiation to the heart compared to right-sided therapy, creating a natural randomized experiment. The authors demonstrated that left-sided radiation therapy was an independent risk factor for CAD in women with breast cancer diagnosed before age 55 years.

In the WECARE study, the incidence of CAD in those ages 25-39 years who received right-sided radiation therapy was zero. In those ages 40-54 years, the incidence was 5.9% over 28 years of follow-up. Also, at less than five years of follow-up in WECARE, the incidence of CAD was 9%. This is a long-term concern for breast cancer survivors. In addition, lifestyle, other CAD risk factors, and adjuvant therapies did not alter the results, which emphasizes the fact radiation therapy is an independent factor.

WECARE included a relatively large study population, and the follow-up period was long. However, there was no cardiac dosimetry, so the authors used laterality as a substitute, which is reasonable. Also, there are no data on the use of heart-sparing techniques, such as prone positioning. CAD was self-reported and not verified, but the Danish group conducted a validation study, finding 80% agreement between self-reporting and the clinical record. In addition, laterality would not affect any reporting errors. Finally, there may be a selection bias in those who agreed to the study vs. those who did not. Left-sided radiation therapy should be added to the risk factors when it comes to protecting the CV health of breast cancer patients.