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

Abstract

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.

Figure 1.

Adjusted Kaplan-Meier failure curves and hazard ratios (HRs) with 95% confidence intervals (CIs) for all-cause mortality in breast cancer survivors compared with cancer-free women. Figures are presented overall (A) and by stage at diagnosis (B), estrogen receptor (ER) status (C), and restricted to women aged 70 years or older at diagnosis (D). Results are adjusted for age (years), menopausal status (premenopausal, postmenopausal), education (<12, 12, >12 years), smoking status (never, former, current), alcohol intake (<3 drinks/mo, ≥1 drinks/wk), body mass index (<25, 25 to <30, ≥30 kg/m²), and oral hormone use (ever, never) using inverse probability weighting. P values from log-rank tests were less than .001 for figures A–D.

Figure 2.

Adjusted cumulative incidence function and subdistribution hazard ratios (HRs) with 95% confidence intervals (CIs) for cardiovascular disease (CVD)-related mortality, both of which account for competing risks, in breast cancer survivors compared with cancer-free women. Figures are presented overall (A) and by stage at diagnosis (B), estrogen receptor (ER) status (C), and restricted to women aged 70 years or older at diagnosis (D). Results are adjusted for age (years), menopausal status (premenopausal, postmenopausal), education (<12, 12, >12 years), smoking status (never, former, current), alcohol intake (<3 drinks/mo, ≥1 drinks/wk), body mass index (<25, 25 to <30, ≥30 kg/m²), and oral hormone use (ever, never) using inverse probability weighting. Subdistribution hazard ratios are estimated from Fine and Gray models.