Abstract P2-11-07: Endothelial progenitor cells as novel markers of anthracycline induced cardiac injury
Authors: Lustberg MB , Ruppert AS , Carothers S , Bingman A , McCarthy B , Raman S , Das M , Kanji S , Lu J , Das H , Cinar-Akakin H , Gurcan MN , Berger MJ , Wesolowski R , Olson EM , Ramaswamy B , Mrozek E , Layman RM , Binkley P , Shapiro CL 
Published: August 2014

Abstract
Background: Anthracyclines including doxorubicin (DOX) cause myocardial damage that manifests as either subclinical decrements of left ventricular ejection function (LVEF) or overt cardiomyopathy. LVEF changes and cardiac risk factors are insufficient predictors of future DOX cardiotoxicity. Bone marrow derived endothelial progenitor cells (EPCs) are mobilized and are homed to sites of myocardial injury to help with repair of damaged myocardium. We hypothesized that EPC levels would be indicative of early DOX cardiotoxicity. Hence, we prospectively collected serial blood samples to evaluate functional EPCs, Troponin I (Ti) and B-natriuretic peptide (BNP), in patients (pts) receiving DOX-based chemotherapy.
Methods: Eligible pts were initiating adjuvant DOX for early stage breast cancer. Pts underwent cardiac magnetic resonance (CMR), Ti, BNP, and EPC at baseline, after 1 cycle of DOX, and after completion of DOX. CD133+ progenitor cells were isolated from the peripheral blood mononuclear cells (PBMC) using AutoMACS (automated magnetic cell sorting, Miltenyi Biotech). In vitro colony forming unit (CFU) assay was performed for isolated CD133+ progenitor cells on MethoCult (Stemcell Technology). After 8 days of culture, EPC colonies were counted using a two-step image analysis algorithm. Repeated measures analysis of variance modeled changes in cardiac markers over time. Logistic regression was used to correlate variables with abnormal Ti.
Results: Forty two women were enrolled. The average age was 52 years (range 33–68) and stage distribution was I (14%), II (58%) and III (28%). All but one patient received peg-fligrastim after DOX. Thirty six pts had EPC/cardiac biomarkers and twenty nine pts had CMRs at all three time points. LVEF decreased 1.6% following completion of DOX (95% CI: −3.8 to 0.6, p = 0.16). There was a non-linear trend in EPCs over time (p = 0.05), with an initial increase followed by a decrease, with average values of 59 (95% CI: 50–70), 65 (95% CI: 55–75), and 50 (95% CI: 40–60), respectively, across the three time points. By the end of treatment, 54% (95% CI: 0.37–0.71) of women had abnormal troponins (median: 0.03, range: 0.02 to 0.17). Variables associated with abnormal troponins included lower baseline EPCs (p = 0.095), older age (p = 0.075) and initial increase in BNP post cycle 1 (p &lt; 0.03). In a multivariable model, age (p = 0.04) and BNP (p = 0.04) were independent prognostic factors for abnormal troponins, where the odds of abnormal troponins was 65% higher for every 5-year increase in age (OR = 1.65, 95% CI: 1.02–2.66) and 58% higher for every 1.5-fold increase in BNP (OR = 1.58, 95% CI: 1.01–2.46). Baseline EPC did not remain in the final model with p = 0.12.
Conclusions: DOX was well-tolerated with no significant changes in LVEF as measured by serials CMRs. Older age and increased BNP were independent prognostic factors for rise in Ti. We observed an initial increase of EPCs with DOX exposure followed by a decrease after the end of treatment. Although not statistically significant, lower EPCs at baseline, corresponding to lower cardiac reserve, were correlated with abnormal Ti. This is the first study reporting an intriguing association of EPCs with traditional cardiac biomarkers during DOX chemotherapy. Funded by R21 CA143787-02.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-11-07.