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.