Personalized Decision Making in Early Stage Breast Cancer: Applying Clinical Prediction Models for Anthracycline Cardiotoxicity and Breast Cancer Mortality Demonstrates Substantial Heterogeneity of Benefit-Harm Trade-off

Jenica N. Upshaw, R. Ruthazer, Kathy D. Miller, Susan K. Parsons, John K. Erban, Anne M. O'Neill, Biniyam Demissei, George Sledge, L. Wagner, Bonnie Ky, David M. Kent

Research output: Contribution to journalArticle

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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 anthracycline cardiotoxicity was created in 967 patients with human epidermal 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. Anthracycline chemotherapy can cause cardiotoxicity. We derived a multivariable risk prediction model to predict anthracycline cardiotoxicity in 967 participants with human epidermal growth factor receptor 2-negative breast cancer with close cardiac monitoring. We identified a subset of patients at high risk of cardiotoxicity but low predicted benefit from anthracyclines. Multivariable risk models can be used to generate patient-specific estimates of both benefits and harms with specific cancer regimens and with additional model validation and updating, use of these models may improve the shared decision-making process.

Original languageEnglish (US)
Pages (from-to)259-267.e1
JournalClinical breast cancer
Issue number4
StatePublished - Aug 2019



  • Cardio-oncology
  • Cardiomyopathy
  • Chemotherapy
  • Heart failure
  • Prediction model

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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