Prediction of anthracycline-induced cardiotoxicity as assessed by global longitudinal strain in women with early breast cancer: insights from the PRADA trial
Authors: Mecinaj A , Gulati G , Heck S L , Steine K , Geisler J , Omland T 
Published: October 2022

Abstract

Background
Early recognition of anthracycline-induced cardiotoxicity is essential to prevent and treat left ventricular dysfunction before permanent damage ensues. Echocardiographic global longitudinal strain (GLS) may be a more sensitive indicator of decline in left ventricular systolic function than measurement left ventricular ejection fraction (LVEF). Many factors have been associated with cardiotoxicity defined by LVEF criteria, but less is known about predictors of early and late cardiotoxicity expressed as GLS.

Objective
The purpose of this study was to identify factors associated with cardiotoxicity, defined as absolute GLS &lt;18% (a) after completion of anthracycline treatment and (b) at extended follow up after completion of adjuvant therapy for early breast cancer.

Methods
120 women with early breast cancer undergoing adjuvant treatment with anthracyclines and/or trastuzumab, were included in the PRADA (PRevention of cArdiac Dysfunction during Adjuvant breast cancer) trial and randomized in a 2x2 factorial fashion to concomitant treatment with candesartan cilexetil, metoprolol succinate or matching placebo. Serial measurements of cardiovascular biomarkers (high sensitivity cardiac troponin I (hs-cTnI), B-type natriuretic peptide (BNP) and Galectin-3), cardiovascular magnetic resonance and echocardiography were performed at baseline, after anthracycline treatment and at extended follow-up median 23 months (interquartile range 21–28 months) after initiation of adjuvant therapy for early breast cancer. To identify potential predictors of cardiotoxicity defined by GLS criteria, associations between demographic, clinical, cancer therapy and biochemical and imaging biomarker data were evaluated by logistic regression analysis.

Results
89 patients had GLS measurements performed at baseline, 87 at completed anthracycline therapy and 81 at extended follow-up. An overall decline in absolute GLS of 0.75% was observed at extended follow-up. One patient had absolute GLS &lt;18 prior to anthracycline therapy whereas, 7 out of 87 (8.0%) and 7 out of 81 (8.6%) patients had GLS levels &lt;18 after completion of anthracycline treatment and at extended follow up, respectively. Variables associated with absolute GLS &lt;18% after anthracycline treatment and at extended follow-up are summarized in Tables 1a and 1b.

Conclusion
In this subanalysis of the PRADA trial, higher age, higher hs-cTnI, lower LVEF, lower E' and higher GLS at baseline predicted subsequent reduced systolic function expressed as reduced absolute GLS after anthracycline treatment. Higher age, hypertension, higher body mass index and higher hs-cTnI concentrations predicted absolute GLS &lt;18 at extended follow up. Assessment of cardiac troponin I, cardiac imaging biomarkers and patient age may assist in the identification of patients at risk for developing cardiotoxicity.

Funding Acknowledgement
Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by The South-Eastern Norway Regional Health Authority, The University of Oslo, The Extra Foundation for Health and Rehabilitation, The Norwegian Cancer Society, and Akershus University Hospital. Study medications and matching placebos were provided free of charge by AstraZeneca. Reagents for the analysis of high-sensitivity cardiac troponin I on the Architect platform were provided by Abbott Diagnostics.