SERUM AND PLASMA SPHINGOLIPIDS AS BIOMARKERS OF CHEMOTHERAPY-INDUCED CARDIOTOXICITY IN FEMALE BREAST CANCER PATIENTS.

Abstract

Although effective as a chemotherapeutic, the utility of Doxorubicin (Dox) is hampered by cardiotoxicity. Despite this, the ability to predict and guide monitoring of patients receiving Dox is hampered by a lack of effective biomarkers to identify susceptible patients and detect early signs of subclinical cardiotoxicity. Based on their well-established roles in the response to Dox and other chemotherapies, we performed a retrospective analysis of serum and plasma sphingolipids (SLs) from female breast cancer (BC) patients undergoing anthracycline-containing therapy, correlating with cardiac parameters assessed by echocardiography. Results showed substantial changes in both plasma and serum SL species during therapy including ceramide (Cer), deoxydihydroCer, and dihydrosphingosine with reversion towards baseline after treatment. Linear mixed-effects model analysis revealed that baseline levels of a number of SLs correlated with adverse cardiac outcomes. Here, serum sphingosine-1-phosphate (S1P) and dihydroS1P, and plasma Cer performed comparably to the prognostic value of pro-NT-BNP, an established biomarker of cardiotoxicity. Intriguingly, while pro-NT-BNP had no predictive value at mid- and post-therapy timepoints, serum S1P and dihydroS1P and plasma Cer levels showed correlation with adverse outcomes, particularly at the post-therapy timepoint. Finally, analysis of plasma and serum C16:C24-Cer ratios - previously linked with adverse cardiac outcomes - showed no correlation in the context of chemotherapy treatment. Overall, this pilot study provides initial evidence that plasma and serum SLs may have benefit as both prognostic and diagnostic biomarkers for female BC patients undergoing anthracycline-containing chemotherapy. Consequently, diagnostic SL measurements - recently implemented for metabolic-associated cardiac disorders - could have wider utility.