title: Biomarkers for Presymptomatic Doxorubicin-Induced Cardiotoxicity in Breast Cancer Patients.
abstract: Cardiotoxicity of doxorubicin (DOX) remains an important health concern. DOX cardiotoxicity is cumulative-dose-dependent and begins with the first dose of chemotherapy. No biomarker for presymptomatic detection of DOX cardiotoxicity has been validated. Our hypothesis is that peripheral blood cells (PBC) gene expression induced by the early doses of DOX-based chemotherapy could identify potential biomarkers for presymptomatic cardiotoxicity in cancer patients. PBC gene expression of 33 breast cancer patients was conducted before and after the first cycle of DOX-based chemotherapy. Cardiac function was evaluated before the start of chemotherapy and at its completion. Differentially expressed genes (DEG) of patients who developed DOX-associated cardiotoxicity after the completion of chemotherapy were compared with DEG of patients who did not. Ingenuity database was used for functional analysis of DEG. Sixty-sevens DEG (P<0.05) were identified in PBC of patients with DOX-cardiotoxicity. Most of DEG encode proteins secreted by activated neutrophils. The functional analysis of the DEG showed enrichment for immune- and inflammatory response. This is the first study to identify the PBC transcriptome signature associated with a single dose of DOX-based chemotherapy in cancer patients. We have shown that PBC transcriptome signature associated with one dose of DOX chemotherapy in breast cancer can predict later impairment of cardiac function. This finding may be of value in identifying patients at high or low risk for the development of DOX cardiotoxicity during the initial doses of chemotherapy and thus to avoid the accumulating toxic effects from the subsequent doses during treatment.
authors.affiliation: Department of Surgery/Breast Surgical Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
authors.forename: Valentina K
authors.initials: VK
authors.lastname: Todorova
authors.affiliation: Department of Hematology/Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
authors.forename: Issam
authors.initials: I
authors.lastname: Makhoul
authors.affiliation: Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Siegel
authors.affiliation: Department of Geriatrics, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Wei
authors.affiliation: Pharmacogenomics Analysis Laboratory, Research and Development Service, Central Arkansas Veterans Healthcare System, Little Rock, AR, United States of America.
authors.forename: Annjanette
authors.initials: A
authors.lastname: Stone
authors.affiliation: Pharmacogenomics Analysis Laboratory, Research and Development Service, Central Arkansas Veterans Healthcare System, Little Rock, AR, United States of America.
authors.forename: Weleetka
authors.initials: W
authors.lastname: Carter
authors.affiliation: Nephropath, Little Rock, AR, United States of America.
authors.forename: Marjorie L
authors.initials: ML
authors.lastname: Beggs
authors.affiliation: Department of Surgery/Breast Surgical Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
authors.forename: Aaron
authors.initials: A
authors.lastname: Owen
authors.affiliation: Department of Surgery/Breast Surgical Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America.
authors.forename: V Suzanne
authors.initials: VS
authors.lastname: Klimberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D004317:Doxorubicin / Q000009:adverse effects / Q000627:therapeutic use / Q000633:toxicity*; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism; D059467:Transcriptome; D016277:Ventricular Function, Left / Q000187:drug effects; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; D015415:Biomarkers; D004317:Doxorubicin