Jamila Mammadova, Alicia Richards, Adriana Gonzalez-Torriente, Evan R Adler, Rachel J Cruz, Stefanie Palfi, Dae Hyun Lee, Christine Sam, Mohammed Al-Jumayli, Anders Berglund, Jong Y Park, Mohammed Alomar, Jacob K Kresovich
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Discovering biomarkers that assess cardiotoxicity risk before trastuzumab therapy is essential for protecting the cardiovascular health of cancer patients.</p><p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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).</p><p><strong>Conclusions: </strong>Pre-treatment epigenetic age acceleration appears to be a novel biomarker for cardiotoxicity risk that improves cardiotoxicity risk prediction.</p>","PeriodicalId":9804,"journal":{"name":"Cardio-oncology","volume":"11 1","pages":"44"},"PeriodicalIF":3.2000,"publicationDate":"2025-05-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12065287/pdf/","citationCount":"0","resultStr":"{\"title\":\"Methylation-based biological age and cardiotoxicity risk in breast cancer patients treated with trastuzumab.\",\"authors\":\"Jamila Mammadova, Alicia Richards, Adriana Gonzalez-Torriente, Evan R Adler, Rachel J Cruz, Stefanie Palfi, Dae Hyun Lee, Christine Sam, Mohammed Al-Jumayli, Anders Berglund, Jong Y Park, Mohammed Alomar, Jacob K Kresovich\",\"doi\":\"10.1186/s40959-025-00340-7\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Objective: </strong>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.</p><p><strong>Methods: </strong>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.</p><p><strong>Results: </strong>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). 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引用次数: 0
摘要
背景：曲妥珠单抗是已知具有心脏毒性的her2阳性癌症的有效治疗方法。在曲妥珠单抗治疗前发现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系。方法：在Moffitt癌症中心接受曲妥珠单抗治疗的her2阳性乳腺癌患者的回顾性队列中，我们分析了血液DNA甲基化和遗传谱。表观遗传时钟和循环白细胞亚群来自MethylationEPIC BeadChip数据，并使用Global Screening Array测量候选snp。心脏毒性事件（即左心室射血分数降低，症状性心力衰竭）在医疗记录中得到确认。经传统危险因素调整后的Logistic回归模型，估计了生物标志物与心脏毒性风险相关的比值比（ORs）。结果：157例患者中，39例（25%）在治疗开始一年内出现心脏毒性。rs776746与心脏毒性风险呈负相关（OR: 0.38, 95% CI: 0.14, 1.00, P = 0.05）。在调整传统危险因素和白细胞组成后，Hannum AgeAccel、Horvath AgeAccel和Horvath Skin and Blood AgeAccel指标与心脏毒性风险显著正相关（or范围在1.62至1.89之间）。在传统的心脏毒性危险因素中加入Horvath Skin and Blood AgeAccel可显著提高心脏毒性风险预测(AUC: 0.75 vs. 0.79；P-diff = 0.04)。结论：治疗前表观遗传年龄加速似乎是一种新的心脏毒性风险生物标志物，可以改善心脏毒性风险预测。
Methylation-based biological age and cardiotoxicity risk in breast cancer patients treated with trastuzumab.
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.
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