Medical Oncology Unit, R. Dulbecco (Mater Domini facility), Teaching Hospital, Magna Græcia University and Cancer Center, Campus Salvatore Venuta, Catanzaro, Italy; Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
Biomed Pharmacother. 2024 May;174:116478. doi: 10.1016/j.biopha.2024.116478. Epub 2024 Mar 27.
Long-term survival induced by anticancer treatments discloses emerging frailty among breast cancer (BC) survivors. Trastuzumab-induced cardiotoxicity (TIC) is reported in at least 5% of HER2+BC patients. However, TIC mechanism remains unclear and predictive genetic biomarkers are still lacking. Interaction between systemic inflammation, cytokine release and ADME genes in cancer patients might contribute to explain mechanisms underlying individual susceptibility to TIC and drug response variability. We present a single institution case series to investigate the potential role of genetic variants in ADME genes in HER2+BC patients TIC experienced.
We selected data related to 40 HER2+ BC patients undergone to DMET genotyping of ADME constitutive variant profiling, with the aim to prospectively explore their potential role in developing TIC. Only 3 patients ("case series"), who experienced TIC, were compared to 37 "control group" matched patients cardiotoxicity-sparing. All patients underwent to left ventricular ejection fraction (LVEF) evaluation at diagnosis and during anti-HER2 therapy. Each single probe was clustered to detect SNPs related to cardiotoxicity.
In this retrospective analysis, our 3 cases were homogeneous in terms of clinical-pathological characteristics, trastuzumab-based treatment and LVEF decline. We identified 9 polymorphic variants in 8 ADME genes (UGT1A1, UGT1A6, UGT1A7, UGT2B15, SLC22A1, CYP3A5, ABCC4, CYP2D6) potentially associated with TIC.
Real-world TIC incidence is higher compared to randomized clinical trials and biomarkers with potential predictive value aren't available. Our preliminary data, as proof of concept, could suggest a predictive role of pharmacogenomic approach in the identification of cardiotoxicity risk biomarkers for anti-HER2 treatment.
抗癌治疗带来的长期生存揭示了乳腺癌（BC）幸存者中出现的脆弱。曲妥珠单抗诱导的心脏毒性（TIC）在至少 5%的 HER2+BC 患者中报道。然而，TIC 的机制仍不清楚，预测性遗传生物标志物仍然缺乏。癌症患者的全身炎症、细胞因子释放和 ADME 基因之间的相互作用可能有助于解释个体对 TIC 和药物反应变异性的易感性的机制。我们提出了一个单机构病例系列，以研究 ADME 基因中的遗传变异在经历 TIC 的 HER2+BC 患者中的潜在作用。
我们选择了与 40 名 HER2+BC 患者相关的数据，这些患者接受了 ADME 组成型变异谱的 DMET 基因分型，目的是前瞻性地探讨它们在发生 TIC 中的潜在作用。只有 3 名经历 TIC 的患者（“病例系列”）与 37 名免受心脏毒性的“对照组”患者相匹配。所有患者在诊断时和接受抗 HER2 治疗期间都进行了左心室射血分数（LVEF）评估。每个单独的探针被聚类以检测与心脏毒性相关的 SNPs。
在这项回顾性分析中，我们的 3 个病例在临床病理特征、基于曲妥珠单抗的治疗和 LVEF 下降方面是同质的。我们在 8 个 ADME 基因（UGT1A1、UGT1A6、UGT1A7、UGT2B15、SLC22A1、CYP3A5、ABCC4、CYP2D6）中鉴定出 9 个多态性变体，这些变体可能与 TIC 相关。
与随机临床试验相比，真实世界的 TIC 发生率更高，并且没有具有潜在预测价值的生物标志物。我们的初步数据，作为概念验证，可以表明药物基因组学方法在识别抗 HER2 治疗的心脏毒性风险生物标志物方面具有预测作用。
