Jenica N Upshaw1, Robin Ruthazer2, Kathy D Miller3, Susan K Parsons4, John K Erban5, Anne M O'Neill6, Biniyam Demissei7, George Sledge8, Lynne Wagner9, Bonnie Ky10, David M Kent2. 1. Division of Cardiology, Tufts Medical Center, Boston, MA; The Predictive Analytics and Comparative Effectiveness Center Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA. Electronic address: jupshaw@tuftsmedicalcenter.org. 2. The Predictive Analytics and Comparative Effectiveness Center Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA. 3. Indiana University Simon Cancer Center, Indianapolis, IN. 4. The Predictive Analytics and Comparative Effectiveness Center Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, MA; Division of Hematology/Oncology, Tufts Medical Center, Boston, MA. 5. Division of Hematology/Oncology, Tufts Medical Center, Boston, MA. 6. Dana Farber Cancer Institute - ECOG-ACRIN Biostatistics Center, Boston, MA. 7. Division of Cardiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA. 8. Stanford University Medical Center, Palo Alto, CA. 9. Wake Forest University Health Services, Winston-Salem, NC. 10. Division of Cardiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA; Department of Biostatistics, Epidemiology & Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
Abstract
BACKGROUND:Anthracycline agents can cause cardiotoxicity. We used multivariable risk prediction models to identify a subset of patients with breast cancer at high risk of cardiotoxicity, for whom the harms ofanthracycline chemotherapy may balance or exceed the benefits. PATIENTS AND METHODS: A clinical prediction model for anthracyclinecardiotoxicity was created in 967 patients with human epidermal growth factor receptor-negative breast cancer treated withdoxorubicin in the ECOG-ACRIN study E5103. Cardiotoxicity was defined as left ventricular ejection fraction (LVEF) decline of ≥ 10% to < 50% and/or a centrally adjudicated clinical heart failure diagnosis. Patient-specific incremental absolute benefit of anthracyclines (compared with non-anthracycline taxane chemotherapy) was estimated using the PREDICT model to assess breast cancer mortality risk. RESULTS: Of the 967 women who initiated therapy, 51 (5.3%) developed cardiotoxicity (12 with clinical heart failure). In a multivariate model, increasing age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01-1.08), higher body mass index (OR, 1.06; 95% CI, 1.02-1.10), and lower baseline LVEF (OR, 0.93; 95% CI, 0.89-0.98) at baseline were significantly associated with cardiotoxicity. The concordance statistic of the risk model was 0.70 (95% CI, 0.63-0.77). In patients with low anticipated treatment benefit (n = 176) from the addition of anthracycline (< 2% absolute risk difference of breast cancer mortality at 10 years), 16 (9%) of 176 had a > 10% risk of cardiotoxicity and 61 (35%) of 176 had a 5% to 10% risk of cardiotoxicity at 1 year. CONCLUSION: Older age, higher body mass index, and lower baseline LVEF were associated with increased risk of cardiotoxicity. We identified a subgroup with low predicted absolute benefit of anthracyclines but with high predicted risk of cardiotoxicity. Additional studies are needed incorporating long-term cardiac outcomes and cardiotoxicity model external validation prior to implementation in routine clinical practice.
RCT Entities:
BACKGROUND:Anthracycline agents can cause cardiotoxicity. We used multivariable risk prediction models to identify a subset of patients with breast cancer at high risk of cardiotoxicity, for whom the harms of anthracycline chemotherapy may balance or exceed the benefits. PATIENTS AND METHODS: A clinical prediction model for anthracyclinecardiotoxicity was created in 967 patients with humanepidermal growth factor receptor-negative breast cancer treated with doxorubicin in the ECOG-ACRIN study E5103. Cardiotoxicity was defined as left ventricular ejection fraction (LVEF) decline of ≥ 10% to < 50% and/or a centrally adjudicated clinical heart failure diagnosis. Patient-specific incremental absolute benefit of anthracyclines (compared with non-anthracycline taxane chemotherapy) was estimated using the PREDICT model to assess breast cancer mortality risk. RESULTS: Of the 967 women who initiated therapy, 51 (5.3%) developed cardiotoxicity (12 with clinical heart failure). In a multivariate model, increasing age (odds ratio [OR], 1.04; 95% confidence interval [CI], 1.01-1.08), higher body mass index (OR, 1.06; 95% CI, 1.02-1.10), and lower baseline LVEF (OR, 0.93; 95% CI, 0.89-0.98) at baseline were significantly associated with cardiotoxicity. The concordance statistic of the risk model was 0.70 (95% CI, 0.63-0.77). In patients with low anticipated treatment benefit (n = 176) from the addition of anthracycline (< 2% absolute risk difference of breast cancer mortality at 10 years), 16 (9%) of 176 had a > 10% risk of cardiotoxicity and 61 (35%) of 176 had a 5% to 10% risk of cardiotoxicity at 1 year. CONCLUSION: Older age, higher body mass index, and lower baseline LVEF were associated with increased risk of cardiotoxicity. We identified a subgroup with low predicted absolute benefit of anthracyclines but with high predicted risk of cardiotoxicity. Additional studies are needed incorporating long-term cardiac outcomes and cardiotoxicity model external validation prior to implementation in routine clinical practice.
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