Genome-wide association study of cardiotoxicity in the NCCTG N9831 (Alliance) adjuvant trastuzumab trial. Issue 10 (October 2017)

• Record Type: Journal Article
• Authors: Serie, Daniel J.; Crook, Julia E.; Necela, Brian M.; Dockter, Travis J.; Wang, Xue; Asmann, Yan W.; Fairweather, DeLisa; Bruno, Katelyn A.; Colon-Otero, Gerardo; Perez, Edith A.; Thompson, E. Aubrey; Norton, Nadine
• Is Part Of: Pharmaocogenetics and genomics. Volume 27:Issue 10(2017:Oct.)
• Publication Date: 2017-10
• Subjects: ABCB1 -- breast cancer -- cardio-oncology -- cardiotoxicity -- CBR3 -- doxorubicin -- ERBB2 -- trastuzumab; Pharmacogenetics -- Periodicals; Pharmacogenomics -- Periodicals; Genetic toxicology -- Periodicals; Biomedical genetics -- Periodicals; 615.7
• DOI: 10.1097/FPC.0000000000000302
• Languages: English
• ISSNs: 1744-6872

Abstract

Abstract : Objectives: The major clinical side effect of the ERBB2 -targeted breast cancer therapy, trastuzumab, is a decline in the left ventricular ejection fraction (LVEF). Improved markers are needed to better identify patients susceptible to cardiotoxicity. Methods: The NCCTG N9831 trial compared adjuvant doxorubicin and cyclophosphamide followed by either weekly paclitaxel (arm A); paclitaxel then trastuzumab (arm B); or concurrent paclitaxel and trastuzumab (arm C) in patients with HER2-positive breast cancer. A genome-wide association study was performed on all patients with available DNA ( N =1446). We used linear regression to identify single nucleotide polymorphisms (SNPs) associated with decline in LVEF, adjusting for age, baseline LVEF, antihypertensive medications, and the first two principle components. Results: In total, 618 863 SNPs passed quality control and DNA from 1191 patients passed genotyping quality control and were identified as Whites of non-Hispanic origin. SNPs at six loci were associated with a decline in LVEF ( P =7.73×10 −6 to 8.93×10 −8 ), LDB2, BRINP1, chr6 intergenic, RAB22A, TRPC6, and LINC01060, in patients who received chemotherapy plus trastuzumab (arms BC, N =800). None of these loci were significant in patients who received chemotherapy only (arm A, N =391) and did not increase in significance in the combined analysis of all patients. We did not observe association, P <0.05, with SNPs previously associated with trastuzumab-induced cardiotoxicity at ERBB2, I655V, and P1170A. We replicated association, P <0.05, with SNPs previously associated with anthracycline-induced cardiotoxicity at CBR3 and ABCB1 . Conclusion: Our study identified six putative novel cardiotoxicity loci in patients treated with combination chemotherapy and trastuzumab that require further investigation and confirmed known associations of anthracycline-induced cardiotoxicity. Abstract : Supplemental Digital Content is available in the text.