接受曲妥珠单抗治疗的乳腺癌患者中基于甲基化的生物学年龄与心脏毒性风险
Methylation-based biological age and cardiotoxicity risk in breast cancer patients treated with trastuzumab.
作者信息
Mammadova Jamila, Richards Alicia, Gonzalez-Torriente Adriana, Adler Evan R, Cruz Rachel J, Palfi Stefanie, Lee Dae Hyun, Sam Christine, Al-Jumayli Mohammed, Berglund Anders, Park Jong Y, Alomar Mohammed, Kresovich Jacob K
机构信息
Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
出版信息
Cardiooncology. 2025 May 10;11(1):44. doi: 10.1186/s40959-025-00340-7.
BACKGROUND
Trastuzumab is an effective treatment for HER2-positive cancers that has known cardiotoxic properties. Discovering biomarkers that assess cardiotoxicity risk before trastuzumab therapy is essential for protecting the cardiovascular health of cancer patients.
OBJECTIVE
To examine the associations between pre-treatment epigenetic age acceleration, circulating leukocyte composition, and candidate single nucleotide polymorphisms (SNPs) with cardiotoxicity risk in breast cancer patients receiving trastuzumab.
METHODS
Among a retrospective cohort of HER2-positive breast cancer patients treated with trastuzumab at Moffitt Cancer Center, we profiled blood DNA methylation and genetic profiles. Epigenetic clocks and circulating leukocyte subsets were derived from MethylationEPIC BeadChip data, and candidate SNPs were measured using the Global Screening Array. Cardiotoxicity events (i.e., reductions in left ventricular ejection fraction, symptomatic heart failure), were identified in medical records. Logistic regression models, adjusted for traditional risk factors, estimated odds ratios (ORs) for biomarker associations with cardiotoxicity risk.
RESULTS
Among 157 patients selected for this study, 39 (25%) experienced cardiotoxicities within one year of treatment initiation. rs776746 was inversely associated with cardiotoxicity risk (OR: 0.38, 95% CI: 0.14, 1.00, P = 0.05). After adjusting for traditional risk factors and leukocyte composition, the Hannum AgeAccel, Horvath AgeAccel, and Horvath Skin and Blood AgeAccel metrics were significantly positively associated with cardiotoxicity risk (ORs ranging between 1.62 and 1.89). Adding Horvath Skin and Blood AgeAccel to traditional cardiotoxicity risk factors significantly improved cardiotoxicity risk prediction (AUC: 0.75 vs. 0.79; P-diff = 0.04).
CONCLUSIONS
Pre-treatment epigenetic age acceleration appears to be a novel biomarker for cardiotoxicity risk that improves cardiotoxicity risk prediction.
背景
曲妥珠单抗是治疗HER2阳性癌症的一种有效药物，但具有已知的心脏毒性。在曲妥珠单抗治疗前发现可评估心脏毒性风险的生物标志物对于保护癌症患者的心血管健康至关重要。
目的
研究接受曲妥珠单抗治疗的乳腺癌患者治疗前的表观遗传年龄加速、循环白细胞组成和候选单核苷酸多态性（SNP）与心脏毒性风险之间的关联。
方法
在莫菲特癌症中心接受曲妥珠单抗治疗的HER2阳性乳腺癌患者回顾性队列中，我们分析了血液DNA甲基化和基因图谱。表观遗传时钟和循环白细胞亚群来自MethylationEPIC BeadChip数据，候选SNP使用全球筛查阵列进行检测。在医疗记录中识别心脏毒性事件（即左心室射血分数降低、有症状的心衰）。经传统风险因素调整的逻辑回归模型估计生物标志物与心脏毒性风险关联的比值比（OR）。
结果
在本研究入选的157例患者中，39例（25%）在开始治疗的一年内发生了心脏毒性。rs776746与心脏毒性风险呈负相关（OR：0.38，95%CI：0.14，1.00，P = 0.05）。在调整传统风险因素和白细胞组成后，汉纳姆年龄加速、霍瓦斯年龄加速和霍瓦斯皮肤与血液年龄加速指标与心脏毒性风险显著正相关（OR在1.62至1.89之间）。将霍瓦斯皮肤与血液年龄加速纳入传统心脏毒性风险因素可显著改善心脏毒性风险预测（AUC：0.75对0.79；P差异 = 0.04）。
结论
治疗前的表观遗传年龄加速似乎是一种用于心脏毒性风险的新型生物标志物，可改善心脏毒性风险预测。
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