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, Robin Ruthazer, Kathy Miller, Susan K. Parsons, John K. Erban, Anne M. O'Neill, Biniyam Demissei, George Sledge, Lynne Wagner, Bonnie Ky, David M. Kent

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
JournalClinical Breast Cancer
DOIs
StatePublished - Jan 1 2019

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Anthracyclines
Decision Making
Breast Neoplasms
Mortality
Stroke Volume
Cardiotoxicity
Epidermal Growth Factor Receptor
Doxorubicin
Body Mass Index
Drug Therapy

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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. / Upshaw, Jenica N.; Ruthazer, Robin; Miller, Kathy; Parsons, Susan K.; Erban, John K.; O'Neill, Anne M.; Demissei, Biniyam; Sledge, George; Wagner, Lynne; Ky, Bonnie; Kent, David M.

In: Clinical Breast Cancer, 01.01.2019.

Research output: Contribution to journalArticle

Upshaw, Jenica N. ; Ruthazer, Robin ; Miller, Kathy ; Parsons, Susan K. ; Erban, John K. ; O'Neill, Anne M. ; Demissei, Biniyam ; Sledge, George ; Wagner, Lynne ; Ky, Bonnie ; Kent, David M. / 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. In: Clinical Breast Cancer. 2019.
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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 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.",
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author = "Upshaw, {Jenica N.} and Robin Ruthazer and Kathy Miller and Parsons, {Susan K.} and Erban, {John K.} and O'Neill, {Anne M.} and Biniyam Demissei and George Sledge and Lynne Wagner and Bonnie Ky and Kent, {David M.}",
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T2 - Applying Clinical Prediction Models for Anthracycline Cardiotoxicity and Breast Cancer Mortality Demonstrates Substantial Heterogeneity of Benefit-Harm Trade-off

AU - Upshaw, Jenica N.

AU - Ruthazer, Robin

AU - Miller, Kathy

AU - Parsons, Susan K.

AU - Erban, John K.

AU - O'Neill, Anne M.

AU - Demissei, Biniyam

AU - Sledge, George

AU - Wagner, Lynne

AU - Ky, Bonnie

AU - Kent, David M.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Cardio-oncology

KW - Cardiomyopathy

KW - Chemotherapy

KW - Heart failure

KW - Prediction model

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