Details

Autor(en) / Beteiligte

• Thompson, Elizabeth W.
• Demissei, Biniyam G.
• Smith, Amanda M.
• Brahmbhatt, Priya
• Wang, Jessica
• Clark, Amy
• DeMichele, Angela
• Narayan, Vivek
• Shah, Payal
• Sun, Lova
• Lefebvre, Benedicte
• Fradley, Michael G.
• Carver, Joseph R.
• Tang, W.H. Wilson
• Ky, Bonnie

Titel

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

Ist Teil von

• JACC. Basic to translational science, 2022-01, Vol.7 (1), p.1-10

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2022

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• [Display omitted] •PON-1 is an HDL-associated cardioprotective enzyme that prevents oxidized-LDL formation and has not previously been studied in cardio-oncology.•To determine the associations between PON-1 and the development of CTRCD, the Pon and Aryl serum enzymatic activity levels of PON-1 were quantified in a cohort of 225 patients with breast cancer receiving doxorubicin with or without trastuzumab.•After doxorubicin completion, the activity levels of both Pon and Aryl were significantly decreased.•Early increases in the Pon enzymatic activity of PON-1 were associated with increased risk of CTRCD.•With further study, PON-1 activity may provide insight into mechanistic risk prediction of CTRCD with doxorubicin chemotherapy. 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.