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

Abstract and Introduction


Background: There is growing evidence that breast cancer survivors have higher cardiovascular disease (CVD) mortality relative to the general population. Information on temporal patterns for all-cause and CVD mortality among breast cancer survivors relative to cancer-free women is limited.

Methods: All-cause and CVD-related mortality were compared in 628 women with breast cancer and 3140 age-matched cancer-free women within CLUE II, a prospective cohort. We calculated adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression for all-cause mortality, and Fine and Gray models for CVD-related mortality to account for competing risks.

Results: Over 25 years of follow-up, 916 deaths occurred (249 CVD related). Breast cancer survivors had an overall higher risk of dying compared with cancer-free women (HR = 1.79, 95% CI = 1.53 to 2.09) irrespective of time since diagnosis, tumor stage, estrogen receptor status, and older age at diagnosis (≥70 years). Risk of death was greatest among older survivors at more than 15 years after diagnosis (HR = 2.69, 95% CI = 1.59 to 4.55). CVD (69.1% ischemic heart disease) was the leading cause of death among cancer-free women and the second among survivors. Survivors had an increase in CVD-related deaths compared with cancer-free women beginning at 8 years after diagnosis (HR = 1.65, 95% CI = 1.00 to 2.73), with the highest risk among older survivors (HR = 2.24, 95% CI = 1.29 to 3.88) and after estrogen receptor-positive disease (HR = 1.85, 95% CI = 1.06 to 3.20).

Conclusions: Breast cancer survivors continue to have an elevated mortality compared with the general population for many years after diagnosis. Preventing cardiac deaths, particularly among older breast cancer patients, could lead to reductions in mortality.


Advances in effective screening and treatment strategies have led to an increasing population of over 3.8 million breast cancer survivors in the United States.[1] With 15-year survival rates now at 80%,[2] understanding the long-term health of breast cancer survivors has become an issue of increasing importance. Cardiovascular disease (CVD) is the second leading cause of morbidity and mortality among breast cancer survivors overall.[3] However, women diagnosed with early-stage breast cancer at an older age may be more likely to die from CVD than cancer.[4,5] A number of recent studies have shown that breast cancer survivors have a greater incidence of CVD, including heart failure and cardiac arrhythmias, compared with the general population.[6–8] A higher risk of CVD may result from cancer treatment and manifest either at the time of treatment or as a late effect.[9–12] CVD risk may also be elevated due to shared risk factors between CVD and breast cancer, such as increasing age, early menopause, and lifestyle factors.[9,13] To determine if breast cancer and its related treatment have an independent effect on CVD burden, it is important to examine CVD in survivors with a cancer-free comparison and to account for these shared factors.

Previous studies of CVD mortality in breast cancer survivors compared with the general population have been limited in scope.[14–19] To date, only 2 studies have accounted for risk factors[18,19] and only 1 examined trends over time.[18] Furthermore, although prognosis and treatment differ by clinical characteristics, whether associations vary by age at diagnosis, tumor stage, and estrogen receptor (ER) status remains unclear. To address these gaps in the literature, we prospectively examined all-cause and CVD-related mortality in women diagnosed with breast cancer by clinical characteristics and time since diagnosis relative to age-matched cancer-free women in a prospective community-based cohort with over 25 years of follow-up.