背景:抗癌治疗诱导的长期存活揭示了乳腺癌(BC)幸存者中出现的脆弱。在至少5%的HER2+BC患者中报道曲妥珠单抗诱导的心脏毒性(TIC)。然而,TIC机制尚不清楚,预测遗传生物标志物仍然缺乏。全身炎症之间的相互作用,癌症患者的细胞因子释放和ADME基因可能有助于解释个体对TIC易感性和药物反应变异性的潜在机制。我们提出了一个单一的机构病例系列,以研究遗传变异在HER2BC患者TIC经历的ADME基因中的潜在作用。
方法:我们选择了40例HER2+BC患者的相关数据,目的是前瞻性地探索它们在发展TIC中的潜在作用。只有3名患者(“病例系列”),谁经历了TIC,与37名“对照组”匹配的心脏毒性保留患者进行比较。所有患者在诊断和抗HER2治疗期间均接受左心室射血分数(LVEF)评估。对每个单个探针进行聚类以检测与心脏毒性相关的SNP。
结果:在本回顾性分析中,我们的3例病例在临床病理特征方面是同质的,以曲妥珠单抗为基础的治疗和LVEF下降。我们在8个ADME基因(UGT1A1,UGT1A6,UGT1A7,UGT2B15,SLC22A1,CYP3A5,ABCC4,CYP2D6)中鉴定了9个多态性变异,可能与TIC相关。
结论:与随机临床试验相比,真实世界的TIC发病率更高,并且没有潜在预测价值的生物标志物。我们的初步数据,作为概念的证明,可能提示药物基因组学方法在鉴定抗HER2治疗的心脏毒性风险生物标志物中的预测作用。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.