All-Cause and Cardiovascular Disease Mortality Among Breast Cancer Survivors in CLUE II, a Long-Standing Community-Based Cohort

Cody Ramin, PhD; Marcy L. Schaeffer, PhD; Zihe Zheng, MHS; Avonne E. Connor, PhD; Judith Hoffman-Bolton, AA; Bryan Lau, PhD; Kala Visvanathan, MD, MHS


J Natl Cancer Inst. 2021;113(2):137-145. 

In This Article


After 25 years of follow-up, we observed that breast cancer survivors had a 79% higher risk of death from any cause relative to cancer-free women. All-cause mortality was consistently higher in survivors regardless of tumor stage, ER status, and older age at diagnosis, whereas CVD deaths were increased only after 8 years since diagnosis, particularly among women diagnosed at an older age or with an ER-positive tumor.

Although CVD mortality has been commonly reported in case-only studies among breast cancer survivors[3–5,30–34] and compared with the general population in a few studies,[14–19] these studies, however, lacked information on risk factors and trends over time. To date, only 2 studies have examined all-cause and CVD-related mortality in breast cancer survivors relative to cancer-free women after accounting for shared risk factors[18,19] and only 1 examined temporal trends.[18] Neither study examined mortality by clinical characteristics. The first of these studies, conducted in the Long Island Breast Cancer Study Project from 1996 to 2009, found that breast cancer survivors had an 80% increased risk of all-cause mortality compared with cancer-free women (HR = 1.8, 95% CI = 1.5 to 2.1) even after accounting for age, menopause, and other potential confounding factors.[18] This study also observed that CVD-related mortality was almost 2-fold higher in breast cancer survivors relative to cancer-free women only after 7 years since diagnosis.[18] Although results were consistent with our findings, the study had several limitations, including a short period of ascertainment for cancer cases (1996–1997), which did not extend into the more recent treatment era, lack of follow-up for incident cancers, minimal information on tumor characteristics, and a shorter duration of follow-up through 2009 (maximum follow-up, 13.5 years). The second study, conducted in the Women's Health Initiative (WHI) from 1993 to 2010, reported a higher total mortality rate in women with localized breast cancer compared with cancer-free women. The study also found that CVD was the leading cause of death among women aged 70–79 years at breast cancer diagnosis.[19] Results were restricted to 10 years postdiagnosis and may be less generalizable because WHI participants were postmenopausal women aged 60–79 years who had a predicted survival of more than 3 years at enrollment. Notably, the WHI study did not stratify by time since diagnosis, which may have attenuated any increase in CVD mortality among breast cancer survivors compared with cancer-free women.

Our results suggest that ischemic heart disease is a major cause of CVD death among breast cancer survivors. Primary mechanisms that have been proposed for CVD risk among survivors include both a higher prevalence of CVD risk factors (eg, older age, obesity, hypertension, diabetes, and physical inactivity)[35] and cardiotoxic effects from breast cancer treatment.[36] Radiotherapy, particularly to the left side of the chest wall, has been associated with both cardiomyopathy and ischemic heart disease.[37] Radiation-related ischemic heart disease has been shown to develop within a few years after exposure or as a late-effect up to 20 years after treatment.[38] The development of cardiomyopathy and subsequent heart failure has also been associated with the use of specific chemotherapeutic agents (eg, anthracyclines) and trastuzumab, a targeted therapy used to treat human epidermal growth factor receptor 2-positive breast cancers. Finally, aromatase inhibitors used to treat postmenopausal ER-positive breast cancer have been associated with an increased risk of CVD events[39] as well as hypertension, vascular dysfunction, and unfavorable lipid changes.[40–42]

Adding to the literature, our findings support that CVD may manifest as a late toxicity and that older women and women diagnosed with ER-positive tumors are most at risk, particularly for ischemic heart disease death. It is plausible that hormone therapy may be driving the elevated mortality in women with ER-positive tumors. Survivors treated with aromatase inhibitors may have increased CVD relative to those treated with tamoxifen therapy,[43] and this may be of particular importance among older women.[44] However, the effect of hormone therapy when compared with no treatment is still uncertain. The underlying mechanisms of higher CVD-related mortality in older breast cancer survivors may be due to treatment-related cardiotoxicity[9] and higher prevalence of shared risk factors or comorbidities compared with the general population.[45]

Strengths of our study include the fact that both women with breast cancer and cancer-free women were from the same community-based cohort, which had data on risk factors and tumor characteristics and over 25 years of follow-up. There are also several limitations of our study. First, power was limited to detect more modest associations and interactions. Further, we were unable to conduct subgroup analyses by breast cancer treatment for CVD-related mortality. However, we did examine associations by tumor characteristics, which can be considered proxies for hormone therapy treatment because ER status is highly correlated with hormone therapy[46] and early-stage ER-positive tumors may be treated with hormone therapy alone. Finally, our study consisted of primarily White participants (>98%) and, although population based, was restricted to women living in Washington County, Maryland. Therefore, results may not be generalizable to women of other racial groups or women outside of Washington County. Future studies are needed to examine these associations over time among more diverse populations.

In conclusion, our results show that breast cancer survivors continue to have an elevated long-term risk of mortality compared with the general population, supporting the need for novel approaches to reduce mortality in these women. Survivors, particularly those diagnosed at an older age or with an ER-positive tumor, may have a higher risk of dying from CVD than comparable cancer-free women and therefore would benefit from targeted approaches to CVD prevention. Large prospective studies are needed to evaluate specific breast cancer treatments on CVD incidence and mortality compared with the general population.