JAMA Oncol. 2026;12(6):572-580.
Clonal Hematopoiesis and Risk of Trastuzumab-Related Cardiotoxic Effects.
제1저자 박찬순, 류강표 · 교신저자 고영일, 박준빈
소속 (10)
- Department of Cardiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
- Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.
- Department of Pathology, Stanford University School of Medicine, Stanford, California.
- Cardiovascular Center, Seoul National University Hospital, Seoul, Republic of Korea.
- Department of Internal Medicine, Seoul National University Hospital and Seoul National University College of Medicine, Seoul, Republic of Korea.
- NOBO MEDICINE Incorporation, Seoul, Republic of Korea.
- Department of Surgery, Kangnam Sacred Heart Hospital, Seoul, Republic of Korea.
- Department of Surgery, Seoul National University Hospital and Seoul National University College of Medicine, Seoul, Republic of Korea.
- Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California.
- The Phil & Penny Knight Initiative for Brain Resilience at the Wu Tsai Neurosciences Institute, Stanford University, Stanford, California.
Abstract
IMPORTANCE Clonal hematopoiesis of indeterminate potential (CHIP) is linked to an increased incidence of cardiovascular and malignant diseases.
OBJECTIVE To determine whether CHIP is associated with cardiotoxic effects in patients with breast cancer receiving trastuzumab.
DESIGN, SETTING, AND PARTICIPANTS Analyses of human cohorts with complementary animal experimentation were performed using a nationwide population-based cohort (UK Biobank), 1 tertiary referral center (Seoul National University Hospital [SNUH]), and a controlled laboratory setting. UK Biobank participants were enrolled between 2006 and 2010, and SNUH patients were enrolled from January 2004 to March 2024. Data were analyzed from March 2021 to February 2026.
MAIN OUTCOME MEASURES Incident heart failure (HF) in the UK Biobank cohort and trastuzumab-related cardiotoxic effects in the SNUH cohort were the main outcome measures. Trastuzumab-related cardiotoxic effects were defined using established clinical criteria (European Society of Cardiology [ESC], Canadian Trastuzumab Working Group, and Cardiac Review and Evaluation Committee [CREC]). Fine-Gray competing risk models were used to account for death and myocardial infarction; multivariable models were adjusted for age and cardiovascular risk factors in both cohorts, with additional adjustment for anthracycline use in the SNUH cohort. Changes in left ventricular ejection fraction (LVEF) were assessed in Tet2-deficient bone marrow chimeric mice following trastuzumab exposure.
RESULTS Overall, 15 729 patients with breast cancer from the UK Biobank cohort (mean [SD] age, 58.8 [7.3] years; 107 [0.68%] male) and 454 female patients with breast cancer who received trastuzumab from the SNUH cohort (mean [SD] age, 52.0 [9.6] years) were included. The corresponding 2-year cumulative incidence values for trastuzumab-related cardiotoxic effects were 15.7% vs 5.0% by ESC criteria (Gray test P = .001), 19.9% vs 10.8% by Canadian criteria (P = .01), and 20.9% vs 11.3% by CREC criteria (P = .02). Using the ESC definition, CHIP positivity (variant allele frequency ≥1.0%) was associated with cardiotoxic effects in multivariable competing risk analysis (adjusted subdistribution hazard ratio, 1.91; 95% CI, 1.32-2.76). Tet2-deficient mice demonstrated a significant LVEF reduction following trastuzumab treatment (effect size, -4.2%; 95% CI, -7.91 to -0.49; P = .03); other experimental groups showed no significant change.
CONCLUSIONS AND RELEVANCE In this cohort study, the presence of CHIP was associated with increased susceptibility to trastuzumab-related cardiotoxic effects.
Conflict of interest statement
Conflict of Interest Disclosures: Dr C. Park reported grants from National Research Foundation of Korea during the conduct of the study. Dr H. Lee reported being co-founder and a member of the board of directors at DCGen, Co, and grants from Devicor Medical Product, Inc, outside the submitted work; and consulting fees and honoraria from Alvogen, Boryung, Hologic, Intuitive, Lilly, Need, Novartis, Roche, and Takeda. Dr Moon reported grants from government of Korea and other from L’imagin and stocks for CMO outside the submitted work. Dr K. Lee reported grants from Roche for research funding, and personal fees from AstraZeneca, Eisai, Lilly, Novartis, Roche, and Pfizer for advisory roles outside the submitted work. Dr S. Han reported personal fees from AstraZeneca, Natera, and AbbVie, grants from Boryung, stock options from IMBdx, grants from Hanmi, Genentech, Mirati, Arcus Biosciences, Janssen, Loxo Oncology, MSD, Leap Therapeutics, AbbVie, Astellas, AstraZeneca, and Cell Biotech outside the submitted work. Dr Im reported grants from AstraZeneca, Boryung Pharm, Eisai, Roche, Pfizer, and Daiichi Sankyo, advisory roles from AstraZeneca , Daiichi Sankyo, MSD, Novartis, Pfizer, Roche, Lilly, and SK Biopharm outside the submitted work. Dr Jaiswal reported equity from Bitteroot Bio and Big Sur Bio outside the submitted work. Dr Koh reported nonfinancial support from NOBO Medicine outside the submitted work. No other disclosures were reported.
그 밖의 정보
- 출판 형태
- Journal Article
- 저널
- JAMA oncology · eISSN 2374-2445
- MeSH
- Trastuzumab* / adverse effects · Humans · Female · Middle Aged · Animals · Breast Neoplasms* / drug therapy · Clonal Hematopoiesis* / drug effects · Cardiotoxicity* / etiology · Aged · Mice · Risk Factors · Heart Failure* / chemically induced / epidemiology · Antineoplastic Agents, Immunological* / adverse effects · Adult
- Substances
- Trastuzumab · Antineoplastic Agents, Immunological
- 참고문헌
- 32편