Paraoxonase-1 Activity in Breast Cancer Patients Treated With Doxorubicin With or Without Trastuzumab

Abstract

The objective of this study was to determine associations of paraoxonase-1 (PON-1) with development of cancer therapy-related cardiac dysfunction (CTRCD). PON-1 is a cardioprotective enzyme associated with high-density lipoprotein that prevents oxidized low-density lipoprotein formation. Given the role of oxidative stress in doxorubicin-induced cardiotoxicity, PON-1 activity may have relevance for the prediction of CTRCD. In 225 patients with breast cancer receiving doxorubicin with or without trastuzumab, we quantified PON-1 activity through its paraoxonase (Pon) and arylesterase (Aryl) enzymatic activity at baseline, during, and after doxorubicin completion. Echocardiograms were performed at baseline, during therapy, and annually. CTRCD was defined as a decrease in left ventricular ejection fraction by ≥10% from baseline to <50%. Associations between baseline biomarkers and clinical variables were determined using multivariable linear regression. Associations between changes in biomarker activity and time to CTRCD were evaluated using Cox regression. Pon was directly associated with Black race and inversely associated with Stage 2 cancer. Aryl was inversely associated with body mass index. After doxorubicin completion, activity levels of Pon and Aryl were significantly decreased (median ratio compared with baseline for Pon: 0.95 [Q1-Q3: 0.81-1.07, P < 0.001]; for Aryl: 0.97 [Q1-Q3: 0.85-1.08, P = 0.010]). A total of 184 patients had an available quantitated echocardiogram at baseline and at least 1 follow-up visit. Increases from baseline in Pon at doxorubicin completion were independently associated with increased CTRCD risk (per 10% increase: hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.05-1.39; P = 0.007). Associations between increases in Aryl and CTRCD tended in the same direction but were of borderline statistical significance (HR: 1.17; 95% CI: 0.99-1.38; P = 0.071). In patients with breast cancer treated with doxorubicin with or without trastuzumab, increases in the Pon enzymatic activity level of PON-1 were associated with increased CTRCD risk. PON-1 activity may be relevant to mechanistic risk prediction of cardiotoxicity with anthracyclines.

Keywords: Aryl, arylesterase; BMI, body mass index; CTRCD, cancer therapy–related cardiac dysfunction; CVD, cardiovascular disease; HDL, high-density lipoprotein; HER2, human epidermal growth factor receptor 2; LDL, low-density lipoprotein; LVEF, left ventricular ejection fraction; PON-1, paraoxonase-1; Pon, paraoxonase; cardiac dysfunction; cardiotoxicity; doxorubicin; heart failure; paraoxonase-1.

Graphical abstract

Figure 1

Risk of CTRCD According to Pon and Aryl Activity Ratios at Doxorubicin Completion CTRCD-free survival curves comparing highest versus lowest tertiles of Pon and Aryl ratios at 2 months relative to baseline; models adjusted for baseline LVEF, cancer therapy regimen, age, race, hypertension, smoking, BMI, disease stage, diabetes, and statin use at baseline. Aryl = arylesterase; BMI = body mass index; CTRCD = cancer therapy–related cardiac dysfunction; LVEF = left ventricular ejection fraction; Pon = paraoxonase.