AUTHOR=Advani Pooja P. , Ruddy Kathryn J. , Herrmann Joerg , Ray Jordan C. , Craver Emily C. , Yothers Greg , Cecchini Reena S. , Lipchik Corey , Feng Huichen , Rastogi Priya , Mamounas Eleftherios P. , Swain Sandra M. , Geyer Charles E. , Wolmark Norman , Paik Soonmyung , Pogue-Geile Katherine L. , Colon-Otero Gerardo , Perez Edith A. , Norton Nadine 

TITLE=Replication of genetic associations of chemotherapy-related cardiotoxicity in the adjuvant NSABP B-31 clinical trial

JOURNAL=Frontiers in Oncology

VOLUME=13

YEAR=2023

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2023.1139347

DOI=10.3389/fonc.2023.1139347

ISSN=2234-943X

ABSTRACT=<sec><title>Background</title><p>The cardiotoxic effects of doxorubicin, trastuzumab, and other anticancer agents are well known, but molecular genetic testing is lacking for the early identification of patients at risk for therapy-related cardiac toxicity.</p></sec><sec><title>Methods</title><p>Using the Agena Bioscience MassARRAY system, we genotyped <italic>TRPC6</italic> rs77679196, <italic>BRINP1</italic> rs62568637, <italic>LDB2</italic> rs55756123, <italic>RAB22A</italic> rs707557, intergenic rs4305714, <italic>LINC01060</italic> rs7698718, and <italic>CBR3</italic> rs1056892 (V244M) (previously associated with either doxorubicin or trastuzumab-related cardiotoxicity in the NCCTG N9831 trial of anthracycline-based chemotherapy ± trastuzumab) in 993 patients with HER2+ early breast cancer from the NSABP B-31 trial of adjuvant anthracycline-based chemotherapy ± trastuzumab. Association analyses were performed with outcomes of congestive heart failure (<italic>N</italic> = 29) and maximum decline in left ventricular ejection fraction (LVEF) using logistic and linear regression models, respectively, under an additive model with age, baseline LVEF, and previous use of hypertensive medications as covariates.</p></sec><sec><title>Results</title><p>Associations of maximum decline in LVEF in the NCCTG N9831 patients did not replicate in the NSABP B-31 patients. However, <italic>TRPC6</italic> rs77679196 and <italic>CBR3</italic> rs1056892 were significantly associated with congestive heart failure, <italic>p</italic> &lt; 0.05, with stronger associations observed in patients treated with chemotherapy only (no trastuzumab) or in the combined analysis of all patients relative to those patients treated with chemotherapy + trastuzumab.</p></sec><sec><title>Conclusions</title><p><italic>TRPC6</italic> rs77679196 and <italic>CBR3</italic> rs1056892 (V244M) are associated with doxorubicin-induced cardiac events in both NCCTG N9831 and NSABP B-31. Other variants previously associated with trastuzumab-related decline in LVEF failed to replicate between these studies.</p></sec>