Clinical Investigation
Cardiovascular Disease Risk in a Large, Population-Based Cohort of Breast Cancer Survivors

Presented in part at the 2nd European Society for Radiotherapy & Oncology (ESTRO) forum, April 19-23, 2013, Geneva, Switzerland; Werkgroep Epidemiologisch Onderzoek Nederland (WEON), June 6-7, 2013, Utrecht, The Netherlands; and the European Cancer Congress, September 27-October 1, 2013, Amsterdam, The Netherlands.
https://doi.org/10.1016/j.ijrobp.2015.11.040Get rights and content

Purpose

To conduct a large, population-based study on cardiovascular disease (CVD) in breast cancer (BC) survivors treated in 1989 or later.

Methods and Materials

A large, population-based cohort comprising 70,230 surgically treated stage I to III BC patients diagnosed before age 75 years between 1989 and 2005 was linked with population-based registries for CVD. Cardiovascular disease risks were compared with the general population, and within the cohort using competing risk analyses.

Results

Compared with the general Dutch population, BC patients had a slightly lower CVD mortality risk (standardized mortality ratio 0.92, 95% confidence interval [CI] 0.88-0.97). Only death due to valvular heart disease was more frequent (standardized mortality ratio 1.28, 95% CI 1.08-1.52). Left-sided radiation therapy after mastectomy increased the risk of any cardiovascular event compared with both surgery alone (subdistribution hazard ratio (sHR) 1.23, 95% CI 1.11-1.36) and right-sided radiation therapy (sHR 1.19, 95% CI 1.04-1.36). Radiation-associated risks were found for not only ischemic heart disease, but also for valvular heart disease and congestive heart failure (CHF). Risks were more pronounced in patients aged <50 years at BC diagnosis (sHR 1.48, 95% CI 1.07-2.04 for left- vs right-sided radiation therapy after mastectomy). Left- versus right-sided radiation therapy after wide local excision did not increase the risk of all CVD combined, yet an increased ischemic heart disease risk was found (sHR 1.14, 95% CI 1.01-1.28). Analyses including detailed radiation therapy information showed an increased CVD risk for left-sided chest wall irradiation alone, left-sided breast irradiation alone, and internal mammary chain field irradiation, all compared with right-sided breast irradiation alone. Compared with patients not treated with chemotherapy, chemotherapy used ≥1997 (ie, anthracyline-based chemotherapy) increased the risk of CHF (sHR 1.35, 95% CI 1.00-1.83).

Conclusion

Radiation therapy regimens used in BC treatment between 1989 and 2005 increased the risk of CVD, and anthracycline-based chemotherapy regimens increased the risk of CHF.

Introduction

Breast cancer (BC) survival rates have substantially improved by earlier diagnosis and more effective treatment, such as more effective systemic therapy and more precise radiation therapy (RT). Radiation therapy reduces the risk of local recurrence and overall mortality in BC patients (1). However, it may expose the heart to radiation, which can increase the risks of cardiovascular disease (CVD) 2, 3, 4, 5, 6. Over the past 2 decades, changes in RT techniques likely reduced the radiation exposure of the heart. Yet only a few studies have assessed CVD morbidity 4, 6 and mortality 3, 8, 9, 10 among BC patients treated after the 1980s. These studies still showed increased risks of cardiovascular morbidity (ischemic heart disease [IHD] 4, 6, valvular heart disease [VHD] [6]) and mixed results on cardiovascular mortality 3, 8, 9, 10. However, the heart is mostly exposed from internal mammary chain (IMC) irradiation 5, 10, 11. It remains unclear whether risks are also increased after tangential breast irradiation alone.

Current chemotherapy regimens may also increase CVD incidence. In children, anthracycline-containing chemotherapy is associated with congestive heart failure (CHF) in a dose-dependent way 12, 13. However, few large studies on long-term CVD risks in BC survivors treated with anthracyclines were performed 14, 15.

With the growing number of BC survivors, it is important to better understand the risks associated with contemporary BC treatment. Therefore, we conducted a large, population-based study on CVD in BC survivors treated in 1989 or later.

Section snippets

Data collection procedures

A cohort comprising 72,045 female patients diagnosed with stage I to III BC as their first malignancy between 1989 and 2005, aged <75 years, was selected from the Netherlands Cancer Registry (NCR). The NCR has nationwide coverage since 1989 (16) and performs annual linkage with the population-based municipal personal records database for date of death. For both initial and subsequent malignancies, NCR provided dates of birth, diagnosis, and death, topography, morphology, stage, type of surgery,

Results

In total, 70,209 patients were available for analysis (Table 1). Characteristics did not differ between patients diagnosed with left- and right-sided BC. Median follow-up was 9 years (range, 0-21 years). During this time, 7435 patients experienced at least 1 cardiovascular event, including 2411 cardiovascular deaths, 5226 hospital admissions for CVD, and 2331 cardiovascular surgical interventions (Table E1; available online at www.redjournal.org).

Discussion

In this large, population-based cohort of BC patients we found that, compared with the general population, BC patients have a slightly lower CVD mortality risk. However, death due to VHD was more frequent. Moreover, left-sided RT after mastectomy increased the risk of any cardiovascular event, IHD, CHF, and VHD, compared with both surgery alone and right-sided RT. This increase seemed to be caused by IMC field as well as chest wall irradiation. The CVD risk after both left- and right-sided RT

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    This study was supported by Dutch Cancer Society grant NKI 2008-3994.

    M.S. and J.A.G. contributed equally to this work.

    B.M.P.A. and F.E.v.L. contributed equally to this work.

    Conflict of interest: none.

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