Abstract
Background
Although breast cancer survivors are at risk for cardiovascular disease (CVD) from treatment late effects, evidence to inform long-term and age-specific cardiovascular surveillance recommendations is lacking.
Methods
We conducted a retrospective cohort study of 10 211 women diagnosed with first primary unilateral breast cancer in Kaiser Permanente Washington or Colorado (aged 20 years and older, survived ≥1 year). We estimated multivariable adjusted hazard ratios (HRs) for associations between initial chemotherapy regimen type (anthracycline and/or trastuzumab, other chemotherapies, no chemotherapy [referent]) and CVD risk, adjusted for patient characteristics, other treatments, and CVD risk factors. Cumulative incidence was calculated considering competing events.
Results
After 5.79 median years, 14.67% of women developed CVD (cardiomyopathy and/or heart failure [HF], ischemic heart disease, stroke). Women treated with anthracyclines and/or trastuzumab had a higher risk of CVD compared with no chemotherapy (adjusted HR = 1.53, 95% confidence interval [CI] = 1.31 to 1.79), persisting at least 5 years postdiagnosis (adjusted HR5-<10 years = 1.85, 95% CI = 1.44 to 2.39; adjusted HR≥10 years = 1.83, 95% CI = 1.34 to 2.49). Cardiomyopathy and/or HF risks were elevated among women treated with anthracyclines and/or trastuzumab compared with no chemotherapy, especially for those aged younger than 65 years (adjusted HR20-54years = 2.97, 95% CI = 1.72 to 5.12; adjusted HR55-64years = 2.21, 95% CI = 1.52 to 3.21), differing for older women (adjusted HR≥65 years = 1.32, 95% CI = 0.97 to 1.78), and at least 5 years postdiagnosis (adjusted HR5-<10years = 1.89, 95% CI = 1.35 to 2.64; adjusted HR≥10 years = 2.21, 95% CI = 1.52 to 3.20). Anthracyclines and/or trastuzumab receipt was associated with increased ischemic heart disease risks after 5 or more years (adjusted HR5-<10years = 1.51, 95% CI = 1.06 to 2.14; adjusted HR≥10 years = 1.86, 95% CI = 1.18 to 2.93) with no clear age effects, and stroke risk (adjusted HR = 1.33, 95% CI = 1.05 to 1.69), which did not vary by time or age. There was some evidence of long-term cardiomyopathy and/or HF and ischemic heart disease risks with other chemotherapies. Among women aged younger than 65 treated with anthracyclines and/or trastuzumab, up to 16% developed CVD by 10 years (20-54 years = 6.91%; 55-64 years = 16.00%), driven by cardiomyopathy and/or HF (20-54 years = 3.90%; 55-64 years = 9.78%).
Conclusions
We found increased long-term risks of cardiomyopathy and/or HF and ischemic heart disease among breast cancer survivors treated with anthracyclines and/or trastuzumab and increased cardiomyopathy and/or HF risk among women aged younger than 65 years.
More than 4 million breast cancer survivors currently live in the United States, and advances in breast cancer screening and treatments have resulted in a 10-year relative survival of 84% (all stages combined) (1). Although women are living longer, they are at greater risk for developing and dying of cardiovascular disease compared with the general population, partially because of the late effects of cardiotoxic treatments (2-6). Incident cardiovascular disease can occur shortly after cardiotoxic cancer treatment, such as anthracyclines and/or trastuzumab, which has led to the development of clinical guidelines for short-term cardiovascular surveillance and management of treatment-related cardiovascular disease (7,8). Current clinical guidelines recommend cardiac function surveillance among patients who receive anthracycline-based chemotherapy and/or trastuzumab-targeted therapy, before therapy administration, regularly during treatment, and 1-2 years after treatment completion (7-11). Data underpinning these guidelines are limited because of the lack of studies and do not specify cardiovascular surveillance recommendations for younger patients or long-term follow-up, and prior studies primarily include breast cancer survivors aged 65 years and older (12-15) or patients treated with older treatment regimens (16). Few studies have assessed more recent cardiotoxic regimens (eg, anthracyclines, trastuzumab) but did not include younger patients and/or had short-term follow-up (14-20). To address these gaps, our study aim was to evaluate incident cardiovascular disease after breast cancer treatment among 1-year breast cancer survivors within 2 integrated US health-care systems with up to 24 years of follow-up.
Methods
Study population
The Kaiser Permanente (KP) Breast Cancer Survivors Cohort is a retrospective cohort study linking data from cancer registries, electronic medical record, pharmacy files, and death records (21). We leveraged detailed treatments, cause-specific cardiovascular disease, and comorbidity data among 14 614 women aged 20 years and older diagnosed with first primary unilateral breast cancer and with stage I-III between 1993 and 2016, treated with surgery, enrolled in a KP Washington or Colorado health insurance plan, and survived at least 1 year without second cancer or cardiovascular disease. We excluded women with unknown chemotherapy type and had preexisting diseases of all 3 outcomes (cardiomyopathy, ischemic heart disease, stroke) at breast cancer diagnosis. The flow diagram further describing the inclusion and exclusion criteria can be found in Figure 1. There were 10 211 women in the final analytic study population. This study was approved by the institutional review boards of the National Institutes of Health, KP Washington, and KP Colorado with a waiver of consent to collect patient data.
Figure 1.
Inclusion and exclusion criteria of 10 211 women diagnosed with first primary breast cancer at 2 Kaiser Permanente sites, 1993-2016 and followed through 2017. WA = Washington; CO = Colorado.
Outcome
Our outcome of interest was incident cardiovascular disease defined using an algorithm (set of rules) on the basis of the International Classification of Disease (ICD) ninth and tenth revisions diagnosis codes, Current Procedural Terminology codes, and Healthcare Common Procedure Coding System codes (Supplementary Table 1, available online) adapted from prior studies (13,16,22) and expert opinion from a cardio-oncologist (A. Barac). To optimize specificity and sensitivity (23), the algorithm identified an incident event if the specific cardiovascular disease code occurred after study entry (1 year after breast cancer diagnosis) in 2 or more outpatient diagnoses on separate dates in the electronic medical record; 1 inpatient diagnosis in the electronic medical record; or primary cause of death per electronic medical record, cancer registry, or National Death Index. The date of the event was considered as the first date when the definition was met (eg, first inpatient visit, second outpatient visit, death). The outcomes of interest were cardiomyopathy and/or heart failure, ischemic heart disease, stroke, and the combination of these major groups of cardiovascular diseases (13,22).
Women with preexisting cardiovascular disease (defined as any ICD-9/10 or procedure code ascertained from electronic medical records up to 12 months before and after the breast cancer diagnosis date) were excluded from relevant analyses. Specifically, women with preexisting cardiomyopathy, ischemic heart disease, and/or stroke were excluded (n = 1242) from the combined cardiovascular disease analyses, but only women with preexisting cause-specific cardiovascular diseases were excluded from the same cause-specific analyses (heart failure and/or cardiomyopathy, n = 454; ischemic heart disease, n = 717; or stroke, n = 314).
Exposure
Our exposure of interest was initial chemotherapy regimen type categorized into 3 mutually exclusive groups on the basis of risk of cardiotoxicity: 1) anthracycline-based chemotherapies and/or trastuzumab-targeted therapy (anthracyclines and/or trastuzumab) (n = 2712), 2) other chemotherapies (n = 1185), or 3) no chemotherapy (n = 6314). Data on receipt of initial chemotherapy were ascertained from KP electronic pharmacy data sources. Further, we conducted sensitivity analyses examining anthracyclines only (n = 2069), anthracyclines with trastuzumab (n = 303), and trastuzumab only (n = 340). Among women who received anthracyclines with trastuzumab, 291 received concurrent and 12 received sequential anthracycline and trastuzumab treatment. Women categorized in the anthracyclines and/or trastuzumab or other chemotherapies groups may have also received taxanes, fluorouracil, cyclophosphamide, methotrexate, or carboplatin, but the other chemotherapies group did not receive anthracyclines or trastuzumab (Supplementary Table 2, available online).
Covariates
Other characteristics from electronic medical records, cancer registry files, or pharmacy files included age, self-reported race and ethnicity, date of breast cancer diagnosis, stage, hormone receptor status, and other cancer treatments (surgery, radiotherapy, endocrine therapy). Preexisting cardiovascular disease risk factors, including hypertension, dyslipidemia, and diabetes, were ascertained from the electronic medical record using ICD-9/10 codes from 12 months before breast cancer diagnosis. Smoking status was abstracted from social history files, and body mass index (BMI) was calculated based on height or weight abstracted 24 months before and up to 12 months after breast cancer diagnosis.
Statistical analyses
Follow-up began 12 months after breast cancer diagnosis and ended at the first date of cardiovascular disease incidence, death, KP disenrollment, or end of follow-up (December 31, 2017, for KP Washington; December 31, 2015, for KP Colorado). We used Cox proportional hazards regression with attained age as the timescale to estimate the multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between initial chemotherapy regimen type and risk of cardiovascular disease and cause-specific cardiovascular disease. Models were adjusted for study site (KP Washington, KP Colorado), race and ethnicity (non-Hispanic White; non-Hispanic Black; non-Hispanic American Indian, Alaska Native, and Pacific Islander; non-Hispanic Asian; Hispanic; Unknown), and potential confounders selected a priori (other breast cancer treatments: radiation and laterality [right, left, no or unknown laterality (<1%)], any tamoxifen [yes, no], any aromatase inhibitors [yes, no]; preexisting cardiovascular disease risk factors: hypertension [yes, no], dyslipidemia [yes, no], diabetes [yes, no], smoking [ever, never, unknown or missing], and BMI [kg/m2] category [<25, 25 to <30, ≥30, unknown or missing]). We tested proportional hazards assumptions using Schoenfeld residuals, and assumptions were not violated (24). Results from multivariable adjusted models are presented because they did not differ substantially from unadjusted models. We examined the patterns of hazard ratios by latency (time since breast cancer diagnosis: 1 to <5 years, 5 to <10 years, ≥10 years) and age in years at breast cancer diagnosis (20-54, 55-64, 65 years and older), and by both latency and age (1 to <10 years since diagnosis: 20-54, 55-64, 65 years and older; ≥10 years since diagnosis: age 20-54, 55-64, 65 years and older). Results with less than 5 events were suppressed from the tables. To account for subsequent treatment, we conducted a sensitivity analysis censoring at second cancer diagnosis and breast cancer recurrence (defined as ≥4-month gap in chemotherapy courses).
To assess the cumulative burden of cardiovascular disease, we calculated cumulative incidence of cardiovascular disease and cause-specific cardiovascular disease by chemotherapy receipt, accounting for competing events of death, and other incident cardiovascular disease categories for cause-specific cardiovascular disease analyses (25). We estimated the cumulative incidence of cardiovascular disease according to age at breast cancer diagnosis (18-54, 55-64, 65 years and older). Stata 17 was used to conduct statistical analyses. Two-sided P values less than .05 were considered statistically significant.
Results
Among 10 211 breast cancer survivors, women treated with anthracyclines and/or trastuzumab (n = 2712) were younger at breast cancer diagnosis and more likely to be diagnosed at later stages, with estrogen-negative and progesterone-negative breast cancer and to receive mastectomy and radiotherapy but had lower proportions of preexisting cardiovascular disease risk factors (except BMI) compared with women treated with other chemotherapies (n = 1185) and no chemotherapy (n = 6314) (Table 1).
Table 1.
Patient and clinical characteristics of 10 211 women diagnosed with first primary breast cancer at Kaiser Permanente Washington and Colorado, 1993-2016 and followed through 2017, according to chemotherapy regimen type
| Characteristics | Overall No. (%) (n = 10 211) | Anthracyclines and/or trastuzumab, No. (%) (n = 2712) | Other chemotherapies, No. (%) (n = 1185) | No chemotherapy (n = 6314) | ||||
|---|---|---|---|---|---|---|---|---|
| Age at diagnosis, y | ||||||||
| Mean (SD) | 61.97 (12.60) | 53.92 (10.57) | 56.99 (10.92) | 66.37 (11.61) | ||||
| 20-54 | 3184 | 31.18 | 1494 | 55.09 | 543 | 45.82 | 1147 | 18.17 |
| 55-64 | 2766 | 27.09 | 791 | 29.17 | 344 | 29.03 | 1631 | 25.83 |
| 65 and older | 4261 | 41.73 | 427 | 15.74 | 298 | 25.15 | 3536 | 56.00 |
| Year of diagnosis | ||||||||
| 1993-1999 | 1944 | 19.04 | 328 | 12.09 | 265 | 22.36 | 1351 | 21.40 |
| 2000-2004 | 2369 | 23.20 | 718 | 26.47 | 213 | 17.97 | 1438 | 22.77 |
| 2005-2009 | 2553 | 25.00 | 832 | 30.68 | 224 | 18.90 | 1497 | 23.71 |
| 2010-2016 | 3345 | 32.76 | 834 | 30.75 | 483 | 40.76 | 2028 | 32.12 |
| Race and ethnicity | ||||||||
| Non-Hispanic | ||||||||
| American Indian and Alaska Native | 70 | 0.69 | 27 | 1.00 | 11 | 0.93 | 32 | 0.51 |
| Asian | 411 | 4.03 | 132 | 4.87 | 77 | 6.50 | 202 | 3.20 |
| Black | 318 | 3.11 | 116 | 4.28 | 44 | 3.71 | 158 | 2.50 |
| Pacific Islander | 28 | 0.27 | 13 | 0.48 | 5 | 0.42 | 10 | 0.16 |
| White | 8696 | 85.16 | 2201 | 81.16 | 980 | 82.70 | 5515 | 87.35 |
| Hispanic (all races) | 575 | 5.63 | 194 | 7.15 | 65 | 5.49 | 316 | 5.00 |
| Unknown | 113 | 1.11 | 29 | 1.07 | <5 | <1 | 81 | 1.28 |
| Stage at diagnosis | ||||||||
| I | 5957 | 58.34 | 530 | 19.54 | 437 | 36.88 | 4990 | 79.03 |
| II | 3347 | 32.78 | 1499 | 55.27 | 641 | 54.09 | 1207 | 19.12 |
| III | 907 | 8.88 | 683 | 25.18 | 107 | 9.03 | 117 | 1.85 |
| Hormone receptor status | ||||||||
| ER+/PR+ | 7192 | 70.43 | 1473 | 54.31 | 764 | 64.47 | 4955 | 78.48 |
| ER+/PR- | 1027 | 10.06 | 261 | 9.62 | 111 | 9.37 | 655 | 10.37 |
| ER-/PR+ | 104 | 1.02 | 53 | 1.95 | 18 | 1.52 | 33 | 0.52 |
| ER-/PR- | 1529 | 14.97 | 892 | 32.89 | 271 | 22.87 | 366 | 5.80 |
| Unknown | 359 | 3.52 | 33 | 1.22 | 21 | 1.77 | 305 | 4.83 |
| HER2 status, 2010 and aftera | ||||||||
| Negative | 2828 | 84.54 | 493 | 59.11 | 469 | 97.10 | 1866 | 92.01 |
| Positive | 412 | 12.32 | 326 | 39.09 | 6 | 1.24 | 80 | 3.94 |
| Unknown, borderline | 105 | 3.14 | 15 | 1.80 | 8 | 1.66 | 82 | 4.04 |
| Surgery | ||||||||
| Breast-conserving surgery | 6265 | 61.36 | 1193 | 43.99 | 651 | 54.94 | 4421 | 70.02 |
| Mastectomy | 3946 | 38.64 | 1519 | 56.01 | 534 | 45.06 | 1893 | 29.98 |
| Radiotherapy and laterality | ||||||||
| Left radiotherapy | 3491 | 34.19 | 1028 | 37.91 | 380 | 32.07 | 2083 | 32.99 |
| Right radiotherapy | 3248 | 31.81 | 965 | 35.58 | 407 | 34.35 | 1876 | 29.71 |
| None | 3412 | 33.41 | 694 | 25.59 | 389 | 32.83 | 2329 | 36.89 |
| Unknown | 60 | <1 | 25 | <1 | 9 | <1 | 26 | <1 |
| Aromatase inhibitors, ER+b | ||||||||
| Yes | 4094 | 49.41 | 1168 | 67.01 | 539 | 61.04 | 2387 | 42.17 |
| No | 4192 | 50.59 | 575 | 32.99 | 344 | 38.96 | 3273 | 57.83 |
| Tamoxifen, ER+b | ||||||||
| Yes | 4229 | 51.04 | 1102 | 63.22 | 539 | 61.04 | 2588 | 45.72 |
| No | 4057 | 48.96 | 641 | 36.78 | 344 | 38.96 | 3072 | 54.28 |
| Prevalent cardiovascular disease risk factorsc | ||||||||
| Hypertension | ||||||||
| Yes | 3121 | 30.57 | 551 | 20.32 | 294 | 24.81 | 2276 | 36.05 |
| No | 7090 | 69.43 | 2161 | 79.68 | 891 | 75.19 | 4038 | 63.95 |
| Diabetes | ||||||||
| Yes | 1028 | 10.07 | 189 | 6.97 | 100 | 8.44 | 739 | 11.70 |
| No | 9183 | 89.93 | 2523 | 93.03 | 1085 | 91.56 | 5575 | 88.30 |
| Dyslipidemia | ||||||||
| Yes | 1952 | 19.12 | 390 | 14.38 | 205 | 17.30 | 1357 | 21.49 |
| No | 8259 | 80.88 | 2322 | 85.62 | 980 | 82.70 | 4957 | 78.51 |
| Smoking | ||||||||
| Yes | 3569 | 34.95 | 1001 | 36.91 | 384 | 32.41 | 2184 | 34.59 |
| No | 4916 | 48.14 | 1438 | 53.02 | 573 | 48.35 | 2905 | 46.01 |
| Missing | 1726 | 16.90 | 273 | 10.07 | 228 | 19.24 | 1225 | 19.40 |
| Body mass index, kg/m2 | ||||||||
| Mean (SD) | 28.38 (6.50) | 28.93 (6.92) | 28.55 (6.45) | 28.12 (6.30) | ||||
| <18.5 | 129 | 1.26 | 25 | 0.92 | 10 | 0.84 | 94 | 1.49 |
| 18.5 to <25 | 2990 | 29.28 | 795 | 29.31 | 352 | 29.70 | 1843 | 29.19 |
| 25 to <30 | 2948 | 28.87 | 779 | 28.72 | 315 | 26.58 | 1854 | 29.36 |
| ≥30 | 3120 | 30.56 | 908 | 33.48 | 386 | 32.57 | 1826 | 28.92 |
| Unknown | 1024 | 10.03 | 205 | 7.56 | 122 | 10.30 | 697 | 11.04 |
HER2 status was restricted to women diagnosed with breast cancer between 2010 and 2016. “+” = positive; “-” = negative; ER = estrogen receptor; PR = progesterone receptor.
Endocrine therapy restricted to women with estrogen receptor–positive breast cancer.
Prevalent cardiovascular disease risk factors were ascertained 12 months before and after breast cancer diagnosis.
Cardiovascular disease
After 5.79 median years of follow-up (range = 1-24 years), 1316 (14.67%) women developed an incident cardiovascular disease. Breast cancer patients who developed cardiovascular disease were older, diagnosed with breast cancer in earlier calendar periods, and more likely to have preexisting hypertension, diabetes, and obesity compared with women who did not develop cardiovascular disease (Supplementary Table 3, available online). After adjusting for patient characteristics, cardiovascular disease risk factors, and other breast cancer treatments, women treated with anthracyclines and/or trastuzumab were at a 53% higher risk of developing cardiovascular disease (adjusted HR = 1.53, 95% CI = 1.31 to 1.79) compared with women who did not receive chemotherapy (Table 2). Risks were elevated at 5 to less than 10 years (adjusted HR = 1.85, 95% CI = 1.44 to 2.39) and at least 10 years after breast cancer diagnosis (adjusted HR = 1.83, 95% CI = 1.34 to 2.49) but not within 1 to less than 5 years (adjusted HR = 1.04, 95% CI = 0.81 to 1.34). Women treated with other chemotherapies also had an increased risk of developing cardiovascular disease at least 10 years after breast cancer diagnosis (adjusted HR = 1.62, 95% CI = 1.12 to 2.34) compared with women who did not receive chemotherapy.
Table 2.
Multivariable adjusted association of initial chemotherapy regimen type and risk of cardiovascular disease and cause-specific cardiovascular diseases, overall and according to years since breast cancer diagnosis
| Cardiovascular disease outcome | Overall |
1 to <5 years since breast cancer diagnosis |
5 to <10 years since breast cancer diagnosis |
≥10 years since breast cancer diagnosis |
||||
|---|---|---|---|---|---|---|---|---|
| Events | Adjusted HR (95% CI)a,b | Events | Adjusted HR (95% CI)a,b | Events | Adjusted HR (95% CI)a,b | Events | Adjusted HR (95% CI)a,b | |
| Cardiovascular disease | ||||||||
| Anthracyclines and/or trastuzumab | 248 | 1.53 (1.31 to 1.79) | 92 | 1.04 (0.81 to 1.34) | 98 | 1.85 (1.44 to 2.39) | 58 | 1.83 (1.34 to 2.49) |
| Other chemotherapies | 103 | 1.14 (0.93 to 1.41) | 38 | 0.91 (0.64 to 1.28) | 31 | 1.08 (0.74 to 1.57) | 34 | 1.62 (1.12 to 2.34) |
| No chemotherapy | 965 | Referent | 367 | Referent | 330 | Referent | 268 | Referent |
| Cardiomyopathy and/or heart failure | ||||||||
| Anthracyclines and/or trastuzumab | 152 | 1.84 (1.51 to 2.25) | 57 | 1.36 (0.98 to 1.89) | 54 | 1.89 (1.35 to 2.64) | 41 | 2.21 (1.52 to 3.20) |
| Other chemotherapies | 59 | 1.18 (0.89 to 1.55) | 20 | 0.93 (0.58 to 1.49) | 14 | 0.86 (0.49 to 1.49) | 25 | 1.90 (1.23 to 2.94) |
| No chemotherapy | 612 | Referent | 212 | Referent | 216 | Referent | 184 | Referent |
| Ischemic heart disease | ||||||||
| Anthracyclines and/or trastuzumab | 111 | 1.19 (0.96 to 1.49) | 38 | 0.68 (0.47 to 0.98) | 47 | 1.51 (1.06 to 2.14) | 26 | 1.86 (1.18 to 2.93) |
| Other chemotherapies | 57 | 1.03 (0.78 to 1.36) | 15 | 0.52 (0.31 to 0.89) | 19 | 1.05 (0.65 to 1.70) | 23 | 2.18 (1.38 to 3.44) |
| No chemotherapy | 600 | Referent | 239 | Referent | 207 | Referent | 154 | Referent |
| Stroke | ||||||||
| Anthracyclines and/or trastuzumab | 98 | 1.33 (1.05 to 1.69) | 34 | 0.88 (0.59 to 1.30) | 39 | 1.67 (1.14 to 2.45) | 25 | 1.52 (0.96 to 2.39) |
| Other chemotherapies | 48 | 1.14 (0.84 to 1.54) | 18 | 0.97 (0.59 to 1.59) | 17 | 1.27 (0.77 to 2.12) | 13 | 1.15 (0.65 to 2.05) |
| No chemotherapy | 528 | Referent | 197 | Referent | 173 | Referent | 158 | Referent |
Bold indicates statistical significance. CI = confidence interval; HR = hazard ratio.
Adjusted hazard ratios for the association between chemotherapy (exposure) and cardiovascular disease risk (outcome), with attained age as timescale and adjusted for study site (Kaiser Permanente, Washington; Kaiser Permanente, Colorado), radiation and laterality (right-sided radiotherapy, left-sided radiotherapy, no or unknown), any tamoxifen (yes, no), any aromatase inhibitors (yes, no), hypertension (yes, no or unknown), dyslipidemia (yes, no or unknown), diabetes (yes, no or unknown), smoking (ever, never, unknown or missing), body mass index category (<25, 25-<30, ≥30 kg/m2), race and ethnicity (White; Black; American Indian, Alaska Native, and Pacific Islander; Asian; Hispanic; Unknown).
Cardiomyopathy and/or heart failure
After 6.02 median years of follow-up, 823 (8.43%) women developed cardiomyopathy and/or heart failure. The risk of cardiomyopathy and/or heart failure was 84% higher for women treated with anthracyclines and/or trastuzumab than women who did not receive chemotherapy (adjusted HR = 1.84, 95% CI = 1.51 to 2.25). Risks increased with time since breast cancer diagnosis: 1 to less than 5 years (adjusted HR = 1.36, 95% CI = 0.98 to 1.89), 5 to less than 10 years (adjusted HR = 1.89, 95% CI = 1.35 to 2.64), and 10 years or more (adjusted HR = 2.21, 95% CI = 1.52 to 3.20). Women treated with other chemotherapies had an elevated cardiomyopathy and/or heart failure risk only after 10 or more years (adjusted HR = 1.90, 95% CI = 1.23 to 2.94) compared with women not treated with chemotherapy (Table 2).
Ischemic heart disease
After 5.91 median years of follow-up, 768 (8.09%) women developed ischemic heart disease. Initially, 1 to less than 5 years after treatment, ischemic heart disease risk was lower among women treated with anthracyclines and/or trastuzumab (adjusted HR = 0.68, 95% CI = 0.47 to 0.98) and other chemotherapies (adjusted HR = 0.52, 95% CI = 0.31 to 0.89) compared with women who did not receive chemotherapy but was elevated 5 or more years after diagnosis for anthracyclines and/or trastuzumab (5 to less than 10 years: adjusted HR = 1.51, 95% CI = 1.06 to 2.14; ≥10 years: adjusted HR = 1.86, 95% CI = 1.18 to 2.93) and 10 or more years for other chemotherapies (adjusted HR = 2.18, 95% CI = 1.38 to 3.44) (Table 2).
Stroke
After 5.99 median years of follow-up, 674 (6.81%) women developed stroke, and risks were elevated among women treated with anthracyclines and/or trastuzumab (adjusted HR = 1.33, 95% CI = 1.05 to 1.69) compared with women who did not receive chemotherapy, with no clear pattern observed with time since breast cancer diagnosis (Table 2).
Sensitivity analyses
When separating anthracyclines and/or trastuzumab treatment, results were largely driven by anthracyclines only and anthracyclines with trastuzumab. For cardiomyopathy and/or heart failure, risk was elevated for women treated with anthracyclines (adjusted HR = 1.82, 95% CI = 1.47 to 2.25) and greatest for women treated with anthracyclines with trastuzumab (adjusted HR = 3.53, 95% CI = 2.21 to 5.64) compared with women who did not receive chemotherapy (Table 3). When censoring at second cancer or recurrence, the risk patterns for overall and cause-specific cardiovascular disease in relation to anthracyclines and/or trastuzumab were broadly similar but slightly attenuated (Supplementary Table 4, available online).
Table 3.
Multivariable adjusted association of initial chemotherapy regimen type (anthracyclines only, anthracyclines with trastuzumab, trastuzumab only, other chemotherapies, no chemotherapy) and risk of cardiovascular disease and cause-specific cardiovascular disease among 10 211 women diagnosed with first primary breast cancer
| Cardiovascular disease outcome | Events | Adjusted HR (95% CI)a,b | |
|---|---|---|---|
| Cardiovascular disease | |||
| Anthracyclines only | 205 | 1.54 (1.30 to 1.81) | |
| Anthracyclines with trastuzumab | 31 | 2.51 (1.72 to 3.63) | |
| Trastuzumab only | 12 | 0.81 (0.45 to 1.43) | |
| Other chemotherapies | 103 | 1.15 (0.93 to 1.41) | |
| No chemotherapy | 965 | Referent | |
| Cardiomyopathy and/or heart failure | |||
| Anthracyclines only | 123 | 1.82 (1.47 to 2.25) | |
| Anthracyclines with trastuzumab | 20 | 3.53 (2.21 to 5.64) | |
| Trastuzumab only | 9 | 1.08 (0.55 to 2.10) | |
| Other chemotherapies | 59 | 1.18 (0.90 to 1.56) | |
| No chemotherapy | 612 | Referent | |
| Ischemic heart disease | |||
| Anthracyclines only | 92 | 1.21 (0.96 to 1.54) | |
| Anthracyclines with trastuzumab | 13 | 1.76 (1.00 to 3.10) | |
| Trastuzumab only | 6 | 0.65 (0.29 to 1.46) | |
| Other chemotherapies | 57 | 1.03 (0.78 to 1.36) | |
| No chemotherapy | 600 | Referent | |
| Stroke | |||
| Anthracyclines only | 82 | 1.39 (1.08 to 1.78) | |
| Anthracyclines with trastuzumab | 12 | 1.85 (1.03 to 3.34) | |
| Trastuzumab only | <5 | — | |
| Other chemotherapies | 48 | 1.14 (0.84 to 1.54) | |
| No chemotherapy | 528 | Referent |
Bold indicates statistical significance. CI = confidence intervals; HR = hazard ratio.
Adjusted hazard ratios for the association between chemotherapy (exposure) and cardiovascular disease risk (outcome), with attained age as timescale and adjusted for study site (Kaiser Permanente, Washington; Kaiser Permanente, Colorado), radiation and laterality (right-sided radiotherapy, left-sided radiotherapy, no or unknown), any tamoxifen (yes, no or unknown), any aromatase inhibitors (yes, no or unknown), hypertension (yes, no or unknown), dyslipidemia (yes, no or unknown), diabetes (yes, no or unknown), smoking (ever, never, unknown or missing), body mass index category (<25, 25 to <30, ≥30 kg/m2), race and ethnicity (White; Black; American Indian, Alaska Native, or Pacific Islander; Asian; Hispanic; Unknown).
Effect of age at breast cancer diagnosis and time since diagnosis
Elevated risks of cardiovascular disease with anthracyclines and/or trastuzumab (compared with the no chemotherapy group) were highest among women diagnosed with breast cancer at age 20-54 years (adjusted HR = 1.70, 95% CI = 1.19 to 2.45) and 55-64 years (adjusted HR = 1.70, 95% CI = 1.29 to 2.23) and attenuated for women age 65 years and older (adjusted HR = 1.26, 95% CI = 0.99 to 1.61) (Table 4). These increased risks were even greater for cardiomyopathy and/or heart failure; women aged 20-54 years treated with anthracycline and/or trastuzumab had a near threefold increased risk of cardiomyopathy and/or heart failure (adjusted HR = 2.97, 95% CI = 1.72 to 5.12), and women aged 55-64 years had a twofold increased risk (adjusted HR = 2.21, 95% CI = 1.52 to 3.19) compared with women not treated with chemotherapy. There were no clear age patterns for risk of ischemic heart disease or for women treated with other chemotherapies. Results stratified by both age at breast cancer diagnosis and latency (Supplementary Table 5, available online) presented consistent findings.
Table 4.
Multivariable adjusted association of initial chemotherapy regimen type and risk of cardiovascular disease and cause-specific cardiovascular disease, according to age at breast cancer diagnosis
| Cardiovascular disease outcome | Age at breast cancer diagnosis |
|||||
|---|---|---|---|---|---|---|
| 20-54 years |
55-64 years |
65 years and older |
||||
| Events | Adjusted HR (95%CI)a,b | Events | Adjusted HR (95% CI)a,b | Events | Adjusted HR (95% CI)a,b | |
| Cardiovascular disease | ||||||
| Anthracyclines and/or trastuzumab | 83 | 1.70 (1.19 to 2.45) | 88 | 1.70 (1.29 to 2.23) | 77 | 1.26 (0.99 to 1.61) |
| Other chemotherapies | 25 | 1.03 (0.63 to 1.67) | 28 | 1.09 (0.73 to 1.64) | 50 | 1.17 (0.88 to 1.56) |
| No chemotherapy | 59 | Referent | 156 | Referent | 750 | Referent |
| Cardiomyopathy and /or heart failure | ||||||
| Anthracyclines and/or trastuzumab | 50 | 2.97 (1.72 to 5.12) | 53 | 2.21 (1.52 to 3.21) | 49 | 1.32 (0.97 to 1.78) |
| Other chemotherapies | 12 | 1.30 (0.63 to 2.68) | 17 | 1.30 (0.76 to 2.21) | 30 | 1.09 (0.75 to 1.58) |
| No chemotherapy | 22 | Referent | 78 | Referent | 512 | Referent |
| Ischemic heart disease | ||||||
| Anthracyclines and/or trastuzumab | 27 | 0.99 (0.57 to 1.72) | 42 | 1.34 (0.91 to 1.97) | 42 | 1.15 (0.83 to 1.59) |
| Other chemotherapies | 13 | 1.03 (0.53 to 2.01) | 17 | 1.12 (0.66 to 1.89) | 27 | 0.95 (0.64 to 1.41) |
| No chemotherapy | 30 | Referent | 95 | Referent | 475 | Referent |
| Stroke | ||||||
| Anthracyclines and/or trastuzumab | 24 | 1.08 (0.60 to 1.94) | 35 | 1.57 (1.02 to 2.40) | 39 | 1.19 (0.85 to 1.67) |
| Other chemotherapies | 7 | 0.66 (0.28 to 1.52) | 12 | 1.07 (0.58 to 1.99) | 29 | 1.27 (0.87 to 1.85) |
| No chemotherapy | 29 | Referent | 75 | Referent | 424 | Referent |
Bold indicates statistical significance. CI = confidence interval; HR = hazard ratio.
Adjusted hazard ratios for the association between chemotherapy (exposure) and cardiovascular disease risk (outcome), with attained age as timescale and adjusted for study site ((Kaiser Permanente, Washington; Kaiser Permanente, Colorado), radiation and laterality (right-sided radiotherapy, left-sided radiotherapy, no or unknown), any tamoxifen (yes, no or unknown), any aromatase inhibitors (yes, no or unknown), hypertension (yes, no or unknown), dyslipidemia (yes, no or unknown), diabetes (yes, no or unknown), smoking (ever, never, unknown or missing), body mass index category (<25, 25-<30, ≥30 kg/m2), race and ethnicity (White; Black; American Indian, Alaska Native, or Pacific Islander; Asian; Hispanic; Unknown).
Cumulative incidence
At 10 years after breast cancer diagnosis, 17.49% of women developed incident cardiovascular disease, which was 5.85% for women aged 20-54 years, 12.36% for women aged 55-64 years, and 29.92% for women aged 65 years and older. For women diagnosed at age younger than 65 years, the 10-year cumulative incidence of cardiovascular disease was highest for women treated with anthracyclines and/or trastuzumab (20-54 years = 6.91%; 55-64 years = 16.00%) compared with women not treated with chemotherapy (20-54 years = 5.95%; 55-64 years = 11.28%). For women aged 65 years and older, the 10-year cumulative incidence did not differ materially by chemotherapy receipt (Figure 2; Supplementary Table 6, available online). Absolute differences for cardiomyopathy and/or heart failure were even greater for women treated with anthracyclines and/or trastuzumab compared with women who did not receive chemotherapy (3.90% vs 1.81% for women aged 20-54 years; 9.78% vs 4.44% for women aged 55-64 years). The cumulative incidence of ischemic heart disease and stroke were relatively similar by chemotherapy receipt or slightly greater among women who were not treated with chemotherapy.
Figure 2.
Cumulative incidence of cardiovascular disease and cause-specific cardiovascular disease among 10 211 women diagnosed with first primary breast cancer diagnosis accounting for competing events of death and other incident cardiovascular disease categories for cause-specific cardiovascular disease analyses, according to age at breast cancer diagnosis.
Discussion
Across 24 years of follow-up, we observed that breast cancer survivors treated with anthracyclines and/or trastuzumab were at increased risk of developing cardiovascular disease, especially for cardiomyopathy and/or heart failure, compared with women who were not treated with chemotherapy, after adjusting for patient characteristics, cardiovascular disease risk factors, and other potentially cardiotoxic breast cancer treatments. Risks were greatest among women diagnosed with breast cancer aged younger than 65 years. We observed long-term risks that persisted 10 or more years after breast cancer diagnosis; approximately 1 in 26 women aged 20-54 years had developed cardiomyopathy and/or heart failure when treated with anthracyclines and/or trastuzumab compared with 1 in 55 women treated with other chemotherapies. The 10-year cumulative cardiomyopathy and/or heart failure burden was highest for women aged 55-64 years, at 1 in 10 women treated with anthracyclines and/or trastuzumab compared with 1 in 26 women treated with other chemotherapies.
To our knowledge, this is the largest study examining treatment-related cardiovascular disease incidence among breast cancer survivors in a general community setting during the modern treatment era (81% diagnosed and treated from the year 2000 forward), comprising 58% of women diagnosed prior to age 65 years and with the longest-term follow-up (22% with 10 or more years of follow-up). Our study findings of increased cardiomyopathy and/or heart failure risk for women treated with anthracycline and/or trastuzumab are consistent with women aged younger than 65 years in a previous study (16,20) but differed for older women. One prior study (for which a portion of the present study population overlapped) found that heart failure risk was increased among women aged 65 years and older treated with anthracycline with trastuzumab and women aged 75 years and older treated with trastuzumab only (16). Two other studies reported similarly higher risks among women aged 65 years and older when comparing receipt of anthracyclines (14), or anthracycline with trastuzumab and trastuzumab only (but not for anthracyclines only) (17), compared with women who received other chemotherapies. Observed differences may be related to longer follow-up in our study (earlier and later breast cancer diagnoses) and/or our finer adjustment for age (using attained age as the time scale).
Evidence from randomized trials suggests early onset, mostly asymptomatic left ventricular dysfunction but not long-term risk after trastuzumab use (26,27) and long-term cardiac injury susceptibility from anthracyclines but not trastuzumab (8). Two prior studies (19,28) observed increased risk of heart failure after trastuzumab use compared with other chemotherapies especially within the first 18 months after treatment completion, but risk after 18 months was observed only for 1 study (27) and not the other (19), potentially because of the confounding late effects of anthracyclines. In contrast, we did not see an increased risk of cardiomyopathy and/or heart failure within 1-5 years after diagnosis; however, most (76%) women in the anthracyclines and/or trastuzumab group received anthracyclines only, and differing findings could result from treatment regimen differences across settings. The results of our study were largely driven by anthracyclines, with sensitivity analyses demonstrating that the highest risk of cardiomyopathy and/or heart failure observed after receiving anthracyclines with trastuzumab (of which 96% of women had received sequential anthracycline then trastuzumab treatment, consistent with National Comprehensive Cancer Network guidelines to avoid concurrent use) (29), though we had small number of events for trastuzumab only.
Women diagnosed before age 65 years were at the greatest risk for developing cardiovascular disease after anthracycline and/or trastuzumab treatment. Younger women are more likely to be diagnosed with more aggressive tumors and at an advanced stage, which subsequently can lead to a greater proportion of anthracycline receipt (30,31) or higher cumulative dose, which is correlated with a greater risk of cardiomyopathy and/or heart failure (20). Clinicians may expect younger women to have greater recovery from cardiac damage compared with older women and may opt to treat the breast cancer more aggressively or not routinely screen for cardiac dysfunction. Importantly, we did not observe an elevated risk after anthracycline and/or trastuzumab treatment for women aged 65 years and older, which may be related to the longer follow-up within our cohort, potential selection bias if only the healthiest older women receive anthracyclines and/or trastuzumab (31) as only 46% of older women with stage III did in this cohort, or growing awareness of cardiotoxicity and modified treatment plans (eg, chemotherapy alternatives, lower cumulative anthracycline dose) because of the higher risk of age-related cardiovascular disease.
Current US clinical guidelines recommend cardiac function surveillance via ejection fraction using echocardiograms, cardiac magnetic resonance imaging, or multigated acquisition scans, which can identify early markers for cardiomyopathy and/or heart failure among patients treated with anthracyclines and/or trastuzumab in the first 5 years after breast cancer diagnosis (8,10,22,32); however, there are no current long-term cardiac surveillance recommendations for adult cancer survivors in the United States. The European Society of Cardiology guidelines recommend additional surveillance for cardiac dysfunction every 5 years for high-risk patients (eg, high-dose anthracyclines, combination regimens with radiotherapy, and elevated cardiovascular disease risk profile at baseline) (33). Our finding of long-term risk of cardiovascular disease associated with anthracyclines and/or trastuzumab use may suggest the need for long-term cardiac surveillance in the United States, especially for women diagnosed before age 65 years, and thus, early referral to cardiology may promote patients to continue cardiac surveillance long throughout survivorship. Clinical trial (34) and observational data (35) have demonstrated similar disease-free and overall survival for nonanthracycline trastuzumab-based regimens (docetaxel, carboplatin, trastuzumab) and anthracyclines with trastuzumab combined regimens (doxorubicin, cyclophosphamide, docetaxel, trastuzumab) for early-stage HER2-positive breast cancer patients; therefore, implications from our study further reiterate the importance of considering nonanthracycline-based regimens, when possible and safe, to lower the long-term risk of cardiovascular disease.
Long-term risk for stroke and ischemic heart disease after anthracyclines and/or trastuzumab could be related to combination treatment regimens with endocrine therapy (13,36) or radiotherapy (5,37), which were adjusted for in this study. Lower ischemic heart disease risk within the first 5 years of breast cancer diagnosis after anthracycline and/or trastuzumab could be related to confounding by indication if women with other preexisting cardiovascular diseases (eg, cardiomyopathy and/or heart failure or stroke) were less likely to receive anthracyclines and/or trastuzumab. Future studies should assess potential joint effects and underlying biological mechanisms of chemotherapy with endocrine therapy or radiotherapy and investigate the long-term ischemic heart disease risk observed among women who received other chemotherapies as current mechanisms are unclear.
The present study had several strengths including the large sample size, systematic data capture of breast cancer treatment, comorbidity data that are not routinely available within cancer registry–based cohorts, and long-term systematic follow-up for incident cardiovascular disease. These strengths helped minimize systematic and random error. Limitations of our study include lack of anthracycline dose data, limited statistical power to examine detailed risk for trastuzumab only or for concurrent vs sequential anthracycline and trastuzumab receipt as prior evidence has demonstrated increased risk for concurrent treatments (38), reduced generalizability to noninsured populations, and the lack of racial and ethnic diversity in the 2 study centers (85% non-Hispanic White), which meant we could not currently assess possible differences in treatment-related cardiovascular disease risk by race and ethnicity (39-42). We are currently expanding the cohort to include KP Georgia and Hawaii to address this limitation.
Our study demonstrated an increased risk of cardiomyopathy and/or heart failure and ischemic heart disease among breast cancer survivors who were treated with anthracyclines and/or trastuzumab compared with women who did not receive chemotherapy, persisting even after 10 years post breast cancer diagnosis, and risks were heightened among women diagnosed before age 65 years. These findings highlight the importance of increased awareness of cardiovascular disease risk during breast cancer survivorship and the potential need for long-term cardiovascular surveillance among high-risk patients.
Supplementary Material
Acknowledgements
The funding organization had no role in the study design; the collection analysis or interpretation of the data; the writing of the report; or the decision to submit the manuscript for publication.
The authors would like to thank Paloma Mitra for her editorial support. This study abstract was selected for an oral presentation at the 48th Annual Meeting of the American Society of Preventive Oncology in March 2024.
Contributor Information
Jacqueline B Vo, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Cody Ramin, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA; Department of Biomedical Sciences, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Lene H S Veiga, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Carolyn Brandt, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Rochelle E Curtis, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Clara Bodelon, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA; Population Science Department, American Cancer Society, Atlanta, GA, USA.
Ana Barac, Inova Schar Cancer, Inova Schar Heart and Vascular, Fairfax, VA, USA.
Véronique L Roger, Epidemiology and Community Health Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA.
Heather Spencer Feigelson, Institute for Health Research, Kaiser Permanente, Denver, CO, USA; Bernard J. Tyson Kaiser Permanente School of Medicine, Pasadena, CA, USA.
Diana S M Buist, Bernard J. Tyson Kaiser Permanente School of Medicine, Pasadena, CA, USA; Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
Erin J Aiello Bowles, Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA.
Gretchen L Gierach, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
Amy Berrington de González, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA; Clinical Cancer Epidemiology Group, Institute for Cancer Research, London, UK.
Data availability
The data from this study, including individual participant data, are not publicly available because they contain potentially identifiable information that cannot be shared openly without approval and data use agreements. Summary statistical data will be available from the corresponding author on reasonable request with the permission of the contributing Kaiser Permanente centers.
Author contributions
Jacqueline B Vo, PhD, RN, MPH (Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Software; Validation; Visualization; Writing—original draft; Writing—review & editing), Cody Ramin, PhD, SM (Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Validation; Visualization; Writing—original draft; Writing—review & editing), Lene HS Veiga, PhD (Conceptualization; Methodology; Project administration; Resources; Validation; Writing—review & editing), Carolyn Brandt, MPH (Formal analysis; Writing—review & editing), Rochelle E. Curtis, MA (Data curation; Project administration; Resources; Writing—review & editing), Clara Bodelon, PhD, MS (Writing—review & editing), Ana Barac, MD, PhD (Writing—review & editing), Veronique Roger, MD, MPH (Writing—review & editing), Heather Spencer Feigelson, PhD, MPH (Data curation; Project administration; Resources; Writing—review & editing), Diana S. M. Buist, PhD, MPH (Data curation; Project administration; Resources; Writing—review & editing), Erin J. Aiello Bowles, MPH (Data curation; Resources; Software; Writing—review & editing), Gretchen L. Gierach, PhD, MPH (Data curation; Funding acquisition; Project administration; Resources; Writing—review & editing), and Amy Berrington de González, DPhil (Conceptualization; Data curation; Formal analysis; Funding acquisition; Investigation; Methodology; Project administration; Resources; Supervision; Validation; Writing—review & editing)
Funding
This work was supported in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the US National Cancer Institute. Data collected at Kaiser Permanente Colorado was supported by contracts from the National Cancer Institute (HHSN 261201800469P, HHSN 261201700708P, HHSN 261201600711P) and a subcontract with RTI International (HHSN 26120090017C) and Westat (6648-00-S010). Data collected at Kaiser Permanente Washington was supported by grants from NIH (1R01CA1205621 and P01CA154292) and contracts from NCI (HHSN 261201700564P, HHSN75N91019P00076, HHSN 5N91020P00327). Cancer incidence data used in this study was supported by the Cancer Surveillance System of the Fred Hutchinson Cancer Research Center, which is funded by Contract No. N01-CN-67009 and N01-PC-35142 from the Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute with additional support from the Fred Hutchinson Cancer Research Center and the State of Washington. Erin Bowles’s time was also supported by the National Cancer Institute (R50CA211115).
Conflicts of interest
The authors declare that they have no competing interests.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data from this study, including individual participant data, are not publicly available because they contain potentially identifiable information that cannot be shared openly without approval and data use agreements. Summary statistical data will be available from the corresponding author on reasonable request with the permission of the contributing Kaiser Permanente centers.