Shom Goel1, Jia Liu2, Hao Guo3, William Barry3, Richard Bell4, Bronwyn Murray2, Jodi Lynch5, Patricia Bastick6, Lorraine Chantrill7, Belinda E Kiely8, Ehtesham Abdi9, Josie Rutovitz10, Ray Asghari11, Anne Sullivan8, Michelle Harrison2, Maija Kohonen-Corish12, Jane Beith2. 1. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia; Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia. Electronic address: shom.goel@petermac.org. 2. Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, Australia. 3. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. 4. Barwon Health Cancer Services, Andrew Love Cancer Centre, Geelong, Australia. 5. St. George Cancer Care Centre, St. George Hospital, Sydney, Australia; Department of Medical Oncology, Sutherland Hospital, Sydney, Australia. 6. St. George Cancer Care Centre, St. George Hospital, Sydney, Australia. 7. Macarthur Cancer Therapy Centre, Liverpool Hospital, Sydney, Australia. 8. Concord Cancer Centre, Concord Repatriation General Hospital, Sydney, Australia. 9. The Tweed Hospital, Tweed Heads & Griffith University, Gold Coast, Australia. 10. Northern Haematology and Oncology Group, San Integrated Cancer Centre, Sydney, Australia. 11. Bankstown Cancer Centre, Bankstown Hospital, Sydney, Australia. 12. Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia.
Abstract
OBJECTIVES: The aim of CATS (Cardiotoxicity of Adjuvant Trastuzumab Study) was to prospectively assess clinical, biochemical, and genomic predictors of trastuzumab-related cardiotoxicity (TRC). BACKGROUND: Cardiac dysfunction is a common adverse effect of trastuzumab. Studies to identify predictive biomarkers for TRC have enrolled heterogeneous populations and yielded mixed results. METHODS: A total of 222 patients with early-stage human epidermal growth factor receptor 2-positive breast cancer scheduled to receive adjuvant anthracyclines followed by 12 months of trastuzumab were prospectively recruited from 17 centers. Left ventricular ejection fraction (LVEF), troponin T, and N-terminal prohormone of brain natriuretic peptide were measured at baseline, post-anthracycline, and every 3 months during trastuzumab. Germline single-nucleotide polymorphisms in ERBB2, FCGR2A, and FCGR3A were analyzed. TRC was defined as symptomatic heart failure; cardiac death, arrhythmia, or infarction; a decrease in LVEF of >15% from baseline; or a decrease in LVEF of >10% to <50%. RESULTS: TRC occurred in 18 of 217 subjects (8.3%). Lower pre-anthracycline LVEF and greater interval decline in LVEF from pre- to post-anthracycline were each associated with TRC on multivariate analyses (odds ratio: 3.9 [p = 0.0001] and 7.9 [p < 0.0001] for a 5% absolute change in LVEF). Higher post-anthracycline N-terminal prohormone of brain natriuretic peptide level was associated with TRC on univariate but not multivariate analyses. There were no associations between troponin T or ERBB2/FGCR polymorphisms and TRC. Baseline LVEF and LVEF change post-anthracycline were used to generate a "low-risk TRC score" to identify patients with low TRC incidence. CONCLUSIONS: Low baseline LVEF and greater LVEF decline post-anthracycline were both independent predictors of TRC. The other biomarkers did not further improve the ability to predict TRC. (Cardiotoxicity of Adjuvant Trastuzumab [CATS]; NCT00858039).
OBJECTIVES: The aim of CATS (Cardiotoxicity of Adjuvant Trastuzumab Study) was to prospectively assess clinical, biochemical, and genomic predictors of trastuzumab-related cardiotoxicity (TRC). BACKGROUND:Cardiac dysfunction is a common adverse effect of trastuzumab. Studies to identify predictive biomarkers for TRC have enrolled heterogeneous populations and yielded mixed results. METHODS: A total of 222 patients with early-stage humanepidermal growth factor receptor 2-positive breast cancer scheduled to receive adjuvant anthracyclines followed by 12 months of trastuzumab were prospectively recruited from 17 centers. Left ventricular ejection fraction (LVEF), troponin T, and N-terminal prohormone of brain natriuretic peptide were measured at baseline, post-anthracycline, and every 3 months during trastuzumab. Germline single-nucleotide polymorphisms in ERBB2, FCGR2A, and FCGR3A were analyzed. TRC was defined as symptomatic heart failure; cardiac death, arrhythmia, or infarction; a decrease in LVEF of >15% from baseline; or a decrease in LVEF of >10% to <50%. RESULTS: TRC occurred in 18 of 217 subjects (8.3%). Lower pre-anthracycline LVEF and greater interval decline in LVEF from pre- to post-anthracycline were each associated with TRC on multivariate analyses (odds ratio: 3.9 [p = 0.0001] and 7.9 [p < 0.0001] for a 5% absolute change in LVEF). Higher post-anthracycline N-terminal prohormone of brain natriuretic peptide level was associated with TRC on univariate but not multivariate analyses. There were no associations between troponin T or ERBB2/FGCR polymorphisms and TRC. Baseline LVEF and LVEF change post-anthracycline were used to generate a "low-risk TRC score" to identify patients with low TRC incidence. CONCLUSIONS: Low baseline LVEF and greater LVEF decline post-anthracycline were both independent predictors of TRC. The other biomarkers did not further improve the ability to predict TRC. (Cardiotoxicity of Adjuvant Trastuzumab [CATS]; NCT00858039).
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