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

Disclosures

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

In This Article

Results

Descriptive Characteristics

Table 1 describes characteristics of 3768 women by breast cancer status (628 breast cancer survivors, 3140 cancer-free women). The mean age at diagnosis was 64.5 years and the median year of diagnosis was 2002 (25th-75th percentile: 1996–2009). Breast cancers were primarily ER-positive and diagnosed at an early stage. Among those diagnosed with ER-positive disease, tumors were primarily stage I and 2 cm or less at diagnosis (Supplementary Table 1 available online). The mean time from enrollment into the cohort to index date was 13.3 years (SD = 7.3). Baseline characteristics were overall similar in survivors compared with cancer-free women (postmenopausal: 58.8% vs 56.6%; mean BMI: 26.5 vs 26.1 kg/m2; never smokers: 61.8% vs 61.1%). In addition, variables related to cardiovascular health, such as mean total cholesterol and blood pressure measurements, and the proportion of women taking heart disease and diabetes medications were also similar among breast cancer survivors and cancer-free women.

All-cause Mortality

Over a median follow-up of 10.4 years (maximum, 26 years), there were 916 deaths from any cause (699 in cancer-free women, 217 in survivors) (Table 1; Supplementary Table 2 available online). All-cause mortality was consistently higher among breast cancer survivors relative to cancer-free women after adjusting for age, menopausal status, education level, smoking status, alcohol intake, BMI, and hormone use (Figure 1A). Overall, survivors had an almost 2-fold higher risk of dying compared with cancer-free women (HR = 1.79, 95% CI = 1.53 to 2.09). Similar results were observed for survivors when stratified by tumor stage, ER status, and older age at diagnosis compared with cancer-free women (Figure 1, B-D). Results restricted to women diagnosed within 5 years of completing the enrollment questionnaire were slightly attenuated (HR = 1.72, 95% CI = 1.29 to 2.29). For treatment subgroups, results were similar but also attenuated compared to overall estimates (Supplementary Table 3 available online).

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.

Risk of death from any cause was not statistically different over follow-up (0-5 years: HR = 1.91, 95% CI = 1.45 to 2.52; >5-15 years: HR = 1.70, 95% CI = 1.37 to 2.11; and >15 years: HR = 1.84, 95% CI = 1.28 to 2.66, P interaction = .91) (Table 2). Patterns of association were similar by stage (P interaction: stage I = .17; stage II or III = .47) and for women with ER-positive tumors (P interaction = .36). Among older women, risk of all-cause mortality differed by time with a 44% increased risk of all-cause mortality within the first 5 years after diagnosis (HR = 1.44, 95% CI = 1.01 to 2.04) and an almost 3-fold higher risk of all-cause mortality at more than 15 years after diagnosis (HR = 2.69, 95% CI = 1.59 to 4.55) (P interaction = .05).

CVD-related Mortality

CVD-related mortality (n = 249 deaths) was the second most common cause of death among survivors (20% of deaths; n = 44 CVD-related deaths) and the most frequent cause among cancer-free women (29% of deaths; n = 205 CVD-related deaths). Ischemic heart disease was the leading cause of CVD death (Supplementary Table 2 available online). Based on adjusted cumulative incidence curves, an increase in CVD-related deaths among survivors was observed after approximately 8 years of follow-up (Figure 2A). Similarly, an elevated risk of CVD-related mortality only became apparent after several years of follow-up among stage I, ER-positive, and older breast cancer survivors (Figure 2, B-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.

The adjusted hazard ratio comparing CVD-related deaths in breast cancer survivors with cancer-free women was 0.94 (95% CI = 0.56 to 1.58) at 0–8 years and 1.65 (95% CI = 1.00 to 2.73) after 8 years of follow-up (P interaction = .13) (Table 3). Results for ER-positive breast cancer survivors were similar (0-8 years: HR = 1.06, 95% CI = 0.60 to 1.86; >8 years: HR = 1.85, 95% CI = 1.06 to 3.20; P interaction = .17). Stage I survivors did not have a statistically significant higher risk of CVD-related mortality compared with cancer-free women even after 8 years of follow-up. Among older women, results differed by time since diagnosis with an over 2-fold higher risk of CVD-related mortality after 8 years in breast cancer survivors relative to cancer-free women (HR = 2.24, 95% CI = 1.29 to 3.88) and no statistically significant association before 8 years (HR = 1.10, 95% CI = 0.64 to 1.88) (P interaction = .07). In these analyses, non–CVD-related mortality was most commonly due to cancer (51% and 24% of non–CVD-related deaths in survivors and cancer-free women, respectively). Although survivors had a statistically significant higher risk of non–CVD-related mortality, within the first 8 years of follow-up, risk declined 8 years after diagnosis. Cause-specific hazard ratios were similar and are presented in Supplementary Table 4 (available online).

Because cardiotoxicity of cancer treatments have changed over time, analyses were stratified by year of diagnosis (Supplementary Table 5 available online). A statistically non-significant elevated risk of CVD-related mortality was observed in women diagnosed in 2005 or later but not in women diagnosed before 2005 (HR = 1.66, 95% CI = 0.78 to 3.55; HR = 1.00, 95% CI = 0.69 to 1.43, respectively).

Analyses examining risk of ischemic heart disease mortality found that survivors overall had a statistically non-significant increased risk of dying from ischemic heart disease compared with cancer-free women (HR = 1.22, 95% CI = 0.84 to 1.79) (Supplementary Table 6 available online). However, we observed a statistically significant increased risk of ischemic heart disease death in ER-positive (HR = 1.51, 95% CI = 1.02 to 2.25) and older survivors (HR = 1.55, 95% CI = 1.02 to 2.34).

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