Matevska-Geshkovska Nadica, Staninova-Stojovska Marija, Kapedanovska-Nestorovska Aleksandra, Petrushevska-Angelovska Natalija, Panovski Milco, Grozdanovska Biljana, Mitreski Nenad, Dimovski Aleksandar
Center for Biomolecular Pharmaceutical Analyses, Faculty of Pharmacy, Ss. Cyril and Methodius University in Skopje, Skopje, Macedonia,
University Clinic for Oncology and Radiotherapy, Ss. Cyril and Methodius University in Skopje, Skopje, Macedonia.
Pharmgenomics Pers Med. 2018 Nov 1;11:193-203. doi: 10.2147/PGPM.S172467. eCollection 2018.
The aim of this study was to evaluate whether pretreatment analysis of selected molecular markers can be used for the prediction of disease-free survival (DFS)/overall survival (OS) of capecitabine adjuvant monotherapy in colon cancer patients.
A total of 126 patients enrolled in a capecitabine Phase IV clinical trial were analyzed for microsatellite instability (MSI), 18q loss of heterozygosity (LOH), thymidylate synthase (TYMS) 5' variable number of tandem repeat (VNTR), and methylene tetrahydrofolate reductase (MTHFR) C677T variants. The significance in predicting 5-year DFS/OS was assessed by Kaplan-Meier and Cox regression analyses.
The MSI-high (MSI-H) genotype was significantly associated with DFS (HR 0.205, 95% CI 0.05-0.88, =0.033) and OS (HR 0.208, 95% CI 0.05-0.89, =0.035) compared to the microsatellite stable genotype. In models stratified according to clinicopathologic characteristics, the MSI-H genotype remained a positive predictive factor for DFS/OS only in patients with stage III (=0.023) and patients with tumors localized proximally to the splenic flexure (=0.004). Distal colon cancers with 18q LOH have a greater survival rate when treated with capecitabine than patients with stable tumors (81.3% vs 50.0%, HR for relapse 0.348, 95% CI 0.13-0.97, =0.043). TYMS 5'VNTR and MTHFR C677T variants were not associated with DFS or OS.
MSI and 18q LOH markers have the potential to be utilized in the selection of colon cancer patients eligible for capecitabine adjuvant monotherapy.
本研究旨在评估对选定分子标志物进行预处理分析是否可用于预测结肠癌患者接受卡培他滨辅助单药治疗后的无病生存期（DFS）/总生存期（OS）。
对126例参与卡培他滨IV期临床试验的患者进行微卫星不稳定性（MSI）、18号染色体长臂杂合性缺失（LOH）、胸苷酸合成酶（TYMS）5'端可变串联重复序列（VNTR）以及亚甲基四氢叶酸还原酶（MTHFR）C677T变异分析。通过Kaplan-Meier法和Cox回归分析评估预测5年DFS/OS的意义。
与微卫星稳定基因型相比，微卫星高度不稳定（MSI-H）基因型与DFS（风险比[HR]0.205，95%置信区间[CI]0.05 - 0.88，P = 0.033）和OS（HR 0.208，95% CI 0.05 - 0.89，P = 0.035）显著相关。在根据临床病理特征分层的模型中，MSI-H基因型仅在III期患者（P = 0.023）和肿瘤位于脾曲近端的患者（P = 0.004）中仍是DFS/OS的阳性预测因素。与肿瘤稳定的患者相比，伴有18q LOH的远端结肠癌患者接受卡培他滨治疗后的生存率更高（81.3%对50.0%，复发风险比0.348，95% CI 0.13 - 0.97，P = 0.043）。TYMS 5'VNTR和MTHFR C677T变异与DFS或OS无关。
MSI和18q LOH标志物有潜力用于筛选适合卡培他滨辅助单药治疗的结肠癌患者。
