A Biomarker-Based Diagnostic Model for Cardiac Dysfunction in Childhood Cancer Survivors

Jan M Leerink; Elizabeth A M Feijen; Esmee C de Baat; Remy Merkx; Helena J H van der Pal; Wim J E Tissing; Marloes Louwerens; Marry M van den Heuvel-Eibrink; A Birgitta Versluys; Elvira C van Dalen; Margriet van der Heiden-van der Loo; Dorine Bresters; Cécile M Ronckers; Andrica C H de Vries; Sebastian Neggers; Livia Kapusta; Jacqueline Loonen; Yigal M Pinto; Leontien C M Kremer; Annelies M C Mavinkurve-Groothuis; Wouter E M Kok

doi:10.1016/j.jaccao.2024.02.008

A Biomarker-Based Diagnostic Model for Cardiac Dysfunction in Childhood Cancer Survivors

JACC CardioOncol. 2024 Apr 16;6(2):236-247. doi: 10.1016/j.jaccao.2024.02.008. eCollection 2024 Apr.

Authors

Jan M Leerink^{1

2}, Elizabeth A M Feijen², Esmee C de Baat², Remy Merkx³, Helena J H van der Pal², Wim J E Tissing^{2

4}, Marloes Louwerens⁵, Marry M van den Heuvel-Eibrink^{2

6

7}, A Birgitta Versluys², Elvira C van Dalen², Margriet van der Heiden-van der Loo², Dorine Bresters^{2

8}, Cécile M Ronckers^{2

9}, Andrica C H de Vries^{2

6}, Sebastian Neggers^{2

10}, Livia Kapusta^{11

12}, Jacqueline Loonen¹³, Yigal M Pinto¹, Leontien C M Kremer^{2

7

14}, Annelies M C Mavinkurve-Groothuis², Wouter E M Kok¹

Affiliations

¹ Amsterdam UMC, University of Amsterdam, Heart Center, Department of Cardiology, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands.
² Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands.
³ Radboud University Medical Center, Department of Medical Imaging, Nijmegen, the Netherlands.
⁴ Beatrix Children's Hospital, Department of Pediatric Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.
⁵ Department of Internal Medicine, Leiden University Medical Center, Leiden, the Netherlands.
⁶ Department of Pediatric Oncology, Erasmus Medical Center, Rotterdam, the Netherlands.
⁷ University Medical Center Utrecht, Wilhelmina Children's Hospital, Utrecht, the Netherlands.
⁸ Willem Alexander Children's Hospital/Leiden University Medical Center, Leiden, the Netherlands.
⁹ Carl von Ossietzky University of Oldenburg, Oldenburg, Germany.
¹⁰ Department of Medicine, Section Endocrinology, Erasmus Medical Center, Rotterdam, the Netherlands.
¹¹ Radboud University Medical Center, Department of Pediatric Cardiology, Amalia Children's Hospital, Nijmegen, the Netherlands.
¹² Pediatrics, Pediatric Cardiology Unit, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
¹³ Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁴ Amsterdam UMC, University of Amsterdam, Emma Children's Hospital, Amsterdam, the Netherlands.

Abstract

Background: Childhood cancer survivors at risk for heart failure undergo lifelong echocardiographic surveillance. Previous studies reported the limited diagnostic accuracy of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T (hs-cTnT) in detecting left ventricular (LV) dysfunction. However, potential enhanced diagnostic accuracy through the combination of biomarkers and clinical characteristics has been suggested.

Objectives: The aim of this study was to develop and internally validate a diagnostic model that combines cardiac biomarkers with clinical characteristics for effectively ruling in or ruling out LV dysfunction in childhood cancer survivors.

Methods: A multicenter cross-sectional study included 1,334 survivors (median age 34.2 years) and 278 siblings (median age 36.8 years). Logistic regression models were developed and validated through bootstrapping, combining biomarkers with clinical characteristics.

Results: Abnormal NT-proBNP levels were observed in 22.1% of survivors compared with 5.4% of siblings, whereas hs-cTnT levels exceeding 10 ng/L were uncommon in both survivors (5.9%) and siblings (5.0%). The diagnostic models demonstrated improvement upon the addition of NT-proBNP and hs-cTnT to clinical characteristics, resulting in an increased C statistic from 0.69 to 0.73 for LV ejection fraction (LVEF) <50% and a more accurate prediction of more severe LV dysfunction, with the C statistic increasing from 0.80 to 0.86 for LVEF <45%. For LVEF <50% (prevalence 10.9%), 16.9% of survivors could be effectively ruled out with high sensitivity (95.4%; 95% CI: 90.4%-99.3%) and negative predictive value (97.5%; 95% CI: 94.6%-99.7%). Similarly, for LVEF <45% (prevalence 3.4%), 53.0% of survivors could be ruled out with moderate to high sensitivity (91.1%; 95% CI: 79.2%-100%) and high negative predictive value (99.4%; 95% CI: 98.7%-100%).

Conclusions: The biomarker-based diagnostic model proves effective in ruling out LV dysfunction, offering the potential to minimize unnecessary surveillance echocardiography in childhood cancer survivors. External validation is essential to confirm these findings. (Early Detection of Cardiac Dysfunction in Childhood Cancer Survivors; A DCOG LATER Study; https://onderzoekmetmensen.nl/nl/trial/23641).

Keywords: biomarkers; cardio-oncology; childhood cancer survivors; diagnostic accuracy.