Breast cancer and cardiovascular-specific mortality are higher among blacks compared with whites, but disparities in cancer therapy-related adverse cardiovascular outcomes have not been well studied. We assessed for the contribution of race and socioeconomic status on cardiotoxicity among women with HER2-positive breast cancer. This retrospective cohort analysis studied women diagnosed with stage I-III HER2-positive breast cancer from 2004-2013. All underwent left ventricular ejection fraction assessment at baseline and at least one follow-up after beginning trastuzumab. Multivariable logistic regression was used to assess the association between race and socioeconomic status (SES) on cardiotoxicity, defined by clinical heart failure (New York Heart Association class III or IV) or asymptomatic left ventricular ejection fraction decline (absolute decrease ≥ 10% to < 53%, or ≥ 16%). Blacks had the highest prevalence of hypertension, diabetes, and increased BMI. Neighborhood-level SES measures including household income and educational attainment were lower for blacks compared with whites and others. The unadjusted cardiotoxicity risk was significantly higher in black compared with white women (OR, 2.10; 95% CI, 1.42 to 3.10). In a multivariable analysis, this disparity persisted after controlling for relevant cardiovascular risk factors (adjusted OR, 1.88; 95% CI, 1.25 to 2.84). Additional models adjusting for SES factors of income, educational attainment, and insurance status did not significantly alter the association between race and cardiotoxicity. In conclusion, black women are at increased risk of cardiotoxicity during HER2-targeted breast cancer therapy. Future etiologic analyses, particularly studies exploring biologic or genetic mechanisms, are needed to further elucidate and reduce racial disparities in cardiotoxicity.
Advances in breast cancer research and improvements in breast cancer surveillance and treatment have led to significant survival gains for women diagnosed with breast cancer. Despite these advances, racial disparities in breast cancer screening, diagnosis, and treatment have been well established in the literature, with black women more likely to be diagnosed with more advanced stages of disease and up to 40% more likely to die from breast cancer compared with white women. , Treatment for human epidermal growth factor receptor 2 (HER2) positive breast cancer with HER2-targeted therapies such as trastuzumab is associated with risk for cardiotoxicity, manifest as a decline in left ventricular ejection fraction (LVEF) or heart failure that is most commonly observed during the 12-month HER2-targeted treatment period. There is limited data on whether racial or other social determinants of health (e.g. socioeconomic status, education, or access to healthcare) influence the risk of developing cardiotoxicity from breast cancer treatment. , To address this important knowledge gap, the primary objective of the current study was to evaluate for racial disparities in cardiotoxicity associated with HER2-positive breast cancer treatment. Secondary objectives were to determine whether socioeconomic factors including income, educational attainment, and insurance status account for observed racial differences in cardiotoxicity.
Methods
Women with stage I-III HER2 – positve breast cancer who received trastuzumab at Memorial Sloan Kettering Cancer Center (MSKCC) between September 1, 2004 and July 1, 2013 were identified from an institutional breast cancer database of all newly diagnosed breast cancer patients. HER2 – positive disease was defined by an immunohistochemical score of 3+ or by a fluorescent in‐situ hybridization ratio of ≥ 2.0. Only patients who underwent a LVEF assessment at baseline and at least 1 follow-up timepoint after beginning breast cancer treatment were included in the analysis. Women of all races were included. Of 1,443 women treated at MSKCC with trastuzumab-based therapy, 44 (39 white, 3 black, 2 other) were excluded due to insufficient LVEF assessments. This study was approved by the institutional review board of MSKCC and a waiver of informed consent was granted.
Self-reported race was categorized into three nonoverlapping groups: white, black, or other. Basic demographic information, tumor characteristics, cancer treatment, and cardiovascular history were collected by retrospective chart review. The HER2-targeted treatment period was defined by the start and end dates of trastuzumab and was ascertained from pharmacy administration records. Socioeconomic data was based upon income and education level available through the United States Census 2013-2017 American Community Survey. The following neighborhood-level variables linked by zip-code were collected for each patient: median household income, percentage living below the poverty level, and percentage of adults (25 years and over) attaining less than a high school diploma. Patients were categorized into quartiles of median household income for the entire cohort in ascending order from lowest (Q1) to highest (Q4). Neighborhoods with a poverty rate ≥ 20% were classified as low-income. Insurance type (Medicaid, Medicare, or private/other) was ascertained from institutional billing records.
A cardiotoxicity event included: (1) clinical heart failure, defined by symptoms such as dyspnea, decreased exercise tolerance, or fatigue during less than ordinary activity or at rest (New York Heart Association class III or IV) with evidence of new or worsening heart failure on physical examination (e.g. peripheral edema, crackles, increased jugular venous pressure, or rapid weight gain related to fluid retention) or diagnostic testing (e.g. increased B-type natriuretic peptide, pulmonary congestion on chest x-ray, or abnormal left ventricular systolic function); or (2) asymptomatic decline in LVEF, defined as an absolute decrease of ≥ 10% points from baseline to below 53% or an absolute decrease of ≥ 16% occurring during the HER2-targeted treatment period. All cardiotoxicity events were confirmed by a cardiologist based upon data abstracted from the medical record for each patient, including the following: internal and external cardiac imaging procedures (i.e. echocardiogram, multigated acquisition scan, or cardiac magnetic resonance imaging), outpatient and inpatient clinical documentation, laboratory findings, and review of pharmacy administration data to identify early interruption of HER2-targeted therapy due to cardiotoxicity.
Continuous data are summarized as mean and standard deviation or median and interquartile range as appropriate, and categorical measures as frequency and percentage. Differences in characteristics between groups were assessed using the Kruskal-Wallis test for continuous variables and Pearson’s chi squared test for categorical variables. Univariable and multivariable logistic regression were used to model cardiotoxicity with race and socioeconomic variables including education, income, and insurance status. Adjusted odds ratios (ORs) with 95% confidence intervals were reported. The following covariates for which there was a plausible biological or epidemiological association with cardiotoxicity were included in the multivariable analysis: Age, body mass index (BMI), baseline LVEF, anthracycline exposure, hypertension, diabetes, coronary artery disease (CAD), and baseline beta-blocker (BB) or angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blocker (ARB) treatment. All statistical analyses were performed using STATA 16.1 (StataCorp, College Station, Texas). A p value (2-tailed) of <0.05 was considered statistically significant.
Results
A total of 1,399 women with HER2-positive breast cancer were included in this analysis: 169 (12%) were black, 1,064 (76%) were white, 166 (12%) were other (120 Asian, 1 American Indian/Alaska Native, 1 Native Hawaiian/Pacific Islander, 44 other or refused to answer). The median age was 51 (interquartile range, 44-59) years and 1,086 (78%) received an anthracycline-based chemotherapy regimen. Table 1 lists tumor and primary treatment characteristics by race.
| Characteristic | Black (n = 169) | White (n = 1,064) | Other (n = 166) | p |
|---|---|---|---|---|
| Age (years) | 51.6 (44.6, 59.3) | 51.0 (43.5, 59.2) | 50.9 (42.7, 57.5) | 0.420 |
| BMI (kg/m 2 ) | 29.3 (25.8, 32.2) | 25.3 (22.5, 29.3) | 23.9 (21.8, 27.5) | <0.001 |
| <25 | 34 (20%) | 506 (48%) | 96 (58%) | |
| 25-29.9 | 63 (37%) | 325 (31%) | 50 (30%) | |
| ≥ 30 | 72 (43%) | 233 (22%) | 20 (12%) | |
| Cancer Stage | 0.052 | |||
| I | 54 (32%) | 402 (38%) | 54 (33%) | |
| II | 61 (36%) | 424 (40%) | 74 (45%) | |
| III | 54 (32%) | 238 (22%) | 38 (23%) | |
| ER-positive | 114 (67%) | 684 (64%) | 88 (53%) | 0.010 |
| PR-positive | 86 (51%) | 519 (49%) | 66 (40%) | 0.080 |
| Chemotherapy regimen | 0.179 | |||
| Anthracycline | 128 (76%) | 820 (77%) | 138 (83%) | |
| Non-anthracycline | 41 (24%) | 244 (23%) | 28 (17%) | |
| Trastuzumab dose, cumulative (mg/kg) | 106 (102, 110) | 106 (104, 110) | 108 (104, 110) | 0.001 |
| Radiation therapy | 123 (73%) | 721 (68%) | 113 (68%) | 0.426 |
| Baseline LVEF (%) | 65 (63, 70) | 65 (62, 70) | 67 (64, 70) | 0.438 |
| Hypertension | 68 (40%) | 229 (22%) | 33 (20%) | <0.001 |
| Diabetes mellitus | 28 (17%) | 56 (5%) | 17 (10%) | <0.001 |
| Hyperlipidemia | 31 (18%) | 180 (17%) | 29 (17%) | 0.895 |
| Coronary artery disease | 5 (3%) | 14 (1%) | 4 (2%) | 0.210 |
| Smoker | 37 (22%) | 414 (39%) | 21 (13%) | <0.001 |
| BB at baseline | 21 (12%) | 84 (8%) | 11 (7%) | 0.099 |
| ACEI/ARB at baseline | 38 (22%) | 147 (14%) | 25 (15%) | 0.014 |
At baseline, black women had a higher prevalence of cardiovascular risk factors including hypertension, diabetes, and elevated BMI (≥ 25 kg/m 2 ). Treatment with renin angiotensin aldosterone system antagonists (but not beta-blockers) at baseline prior to initiating HER2-targeted therapy was more common among black participants. There was no significant difference in baseline LVEF between racial groups.
Table 2 summarizes the distribution of socioeconomic characteristics by race. The median household income (by neighborhood) was lowest for black patients. The poverty rate was approximately two times higher in neighborhoods of black compared with white or other women (15.9% vs. 6.7% vs 8.2%, p < 0.001). Thirty-three percent of black, 9% of white, and 8% of other patients lived in a low-income neighborhood (p < 0.001). Neighborhood-level educational attainment was lower for black patients, with 14.3% attaining less than a high school degree compared with 6.9% for white and 8.5% for other patients (p < 0.001). The proportion of patients with Medicaid insurance was 12% for black, 7% for white, and 8% for other patients.
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