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

Frontiers in Oncology

Oncology

Nadine Norton¹  Jordan C. Ray²  Joerg Herrmann³  Emily C. Craver⁴  Edith A. Perez⁵  Gerardo Colon-Otero⁵  Pooja P. Advani⁵  Kathryn J. Ruddy⁶  Greg Yothers⁷  Reena S. Cecchini⁷  Huichen Feng⁸  Soonmyung Paik⁸  Katherine L. Pogue-Geile⁸  Corey Lipchik⁸  Sandra M. Swain⁹  Eleftherios P. Mamounas^1,10  Priya Rastogi^1,11  Norman Wolmark^1,11  Charles E. Geyer^1,11 

[1] Department of Cancer Biology, Mayo Clinic, Jacksonville, FL, United States;Department of Cardiovascular Diseases, Mayo Clinic, Jacksonville, FL, United States;Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, United States;Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, United States;Department of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, United States;Department of Oncology, Mayo Clinic, Rochester, MN, United States;NRG Oncology Statistics and Data Management Center, Pittsburgh, PA, United States;Department of Biostatistics, The University of Pittsburgh, Pittsburgh, PA, United States;NRG Oncology/NSABP Foundation, Pittsburgh, PA, United States;NRG Oncology/NSABP Foundation, Pittsburgh, PA, United States;Department of Surgical Oncology, Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, United States;NRG Oncology/NSABP Foundation, Pittsburgh, PA, United States;Department of Surgical Oncology, Orlando Health Cancer Institute, Orlando, FL, United States;NRG Oncology/NSABP Foundation, Pittsburgh, PA, United States;UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, United States;

关键词: anthracycline;    doxorubicin;    trastuzumab;    breast cancer;    cardiomyopathy;    cardiotoxicity;    TRPC6;   

DOI  :  10.3389/fonc.2023.1139347

 received in 2023-01-06, accepted in 2023-05-15,  发布年份 2023

来源: Frontiers

【 摘 要 】

BackgroundThe 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.MethodsUsing the Agena Bioscience MassARRAY system, we genotyped TRPC6 rs77679196, BRINP1 rs62568637, LDB2 rs55756123, RAB22A rs707557, intergenic rs4305714, LINC01060 rs7698718, and CBR3 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 (N = 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.ResultsAssociations of maximum decline in LVEF in the NCCTG N9831 patients did not replicate in the NSABP B-31 patients. However, TRPC6 rs77679196 and CBR3 rs1056892 were significantly associated with congestive heart failure, p < 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.ConclusionsTRPC6 rs77679196 and CBR3 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.

【 授权许可】

Unknown   
Copyright © 2023 Advani, Ruddy, Herrmann, Ray, Craver, Yothers, Cecchini, Lipchik, Feng, Rastogi, Mamounas, Swain, Geyer, Wolmark, Paik, Pogue-Geile, Colon-Otero, Perez and Norton