Shilbayeh Sireen Abdul Rahim, Abd El-Baset Omnia A, Alshabeeb Mohammad A, Alanizi Abdalrhman Hamdan, Khedr Naglaa F, Werida Rehab H
Department of Pharmacy Practice, College of Pharmacy, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.
Clinical Pharmacy and Pharmacy Practice Department, Faculty of Pharmacy, Egyptian Russian University, Cairo, Egypt.
Pharmacol Res Perspect. 2025 Jun;13(3):e70114. doi: 10.1002/prp2.70114.
We investigated the influence of CYP2B6, GSTP1, and SLCO1B1 star allele-predicted phenotypes and CBR1 variants on clinical outcomes in patients with HCC receiving DOX via TACE. A prospective cohort of patients with HCC underwent DOX therapy via TACE. Selected genes were genotyped in germline DNA samples from the final cohort (82 patients) via Axiom Precision Medicine Diversity (PMD) Research Array technology. The Kaplan-Meier (KM) method and Cox proportional hazards (CPH) model were employed to find independent clinical and genetic predictors of overall survival (OS) and progression-free survival (PFS) after TACE. Based on univariate and combined association analyses of genetic factors, the star alleles predicting the phenotypic status of three genes (CYP2B6, GSTP1, and SLCO1B1) did not significantly modify the response potential of DOX via TACE, as indicated by OS or PFS. Conversely, we found a novel association between two CBR1 polymorphisms (rs3787728 and rs1005695) and interindividual differences in OS and PFS. The presence of a heterozygous genotype (TC or CG at either locus, which were highly frequent in our cohort), probably with greater CBR metabolic activity, appeared to have an expressive influence by negatively modulating the consequences of DOX locoregional therapy on HCC by shortening the median OS (KM p = 0.02 and 0.04, respectively) and median PFS (KM p = 0.05 and 0.023, respectively) in comparison to those with other haplotypes. Exploratory PGx studies involving a wider HCC cohort and targeting more DOX-related genes are needed to replicate our findings. Trial Registration: NCT06313047 (Study Details | Pharmacogenetic of Doxorubicin in HCC. | clinicaltrials.gov).
我们研究了CYP2B6、GSTP1和SLCO1B1星等位基因预测的表型以及CBR1变体对接受经动脉化疗栓塞（TACE）的多柔比星（DOX）治疗的肝癌（HCC）患者临床结局的影响。一组HCC患者的前瞻性队列接受了经TACE的DOX治疗。通过Axiom精准医学多样性（PMD）研究阵列技术，对最终队列（82例患者）的种系DNA样本中的选定基因进行基因分型。采用Kaplan-Meier（KM）方法和Cox比例风险（CPH）模型来寻找TACE后总生存期（OS）和无进展生存期（PFS）的独立临床和遗传预测因素。基于遗传因素的单变量和联合关联分析，预测三个基因（CYP2B6、GSTP1和SLCO1B1）表型状态的星等位基因并未如OS或PFS所示，显著改变DOX经TACE的反应潜力。相反，我们发现两个CBR1多态性（rs3787728和rs1005695）与个体间OS和PFS差异之间存在新的关联。杂合基因型（任一基因座处为TC或CG，在我们的队列中频率很高）的存在，可能具有更高的CBR代谢活性，似乎通过缩短中位OS（KM p分别为0.02和0.04）和中位PFS（KM p分别为0.05和0.023），与其他单倍型相比，对DOX局部区域治疗对HCC的影响产生负面调节作用，从而产生显著影响。需要开展涉及更广泛HCC队列并针对更多与DOX相关基因的探索性药物基因组学（PGx）研究来重复我们的发现。试验注册：NCT06313047（研究详情|肝癌中多柔比星的药物遗传学。|clinicaltrials.gov）
