Departments of Otolaryngology and Head and Neck Surgery, University of Pittsburgh School of Medicine and University of Pittsburgh Cancer Institute, PA 15213, USA.
Clin Cancer Res. 2011 Aug 15;17(16):5513-22. doi: 10.1158/1078-0432.CCR-11-0086. Epub 2011 Jul 7.
Tumor-specific biomarkers that predict resistance to DNA damaging agents may improve therapeutic outcomes by guiding the selection of effective therapies and limiting morbidity related to ineffective approaches. XPF (ERCC4) is an essential component of several DNA repair pathways and XPF-deficient cells are exquisitely sensitive to DNA damaging agents. The purpose of this study was to determine whether XPF expression levels predict clinical response to DNA damaging agents in head and neck squamous cell carcinoma (HNSCC).
Quantitative immunohistochemistry was used to measure XPF expression in tumors from a cohort of 80 patients with newly diagnosed HNSCC treated with radiation therapy with or without platinum-based chemotherapy; samples were collected prospectively. Genomic DNA isolated from blood samples was analyzed for nine single nucleotide polymorphisms (SNP) in the XPF gene by using a custom array. The primary endpoint was progression-free survival (PFS).
XPF expression was higher in tumors from the oral cavity than from the other sites (P < 0.01). High XPF expression correlated with early time to progression both by univariate (HR = 1.87, P = 0.03) and multivariate analysis (HR = 1.83, P = 0.05). The one year PFS for high expressers was 47% (95% CI = 31-62) compared with 72% (95% CI = 55-83) for low expressers. In addition, we identified four XPF SNPs that showed marginal association with treatment failure.
Expression level of XPF in HNSCC tumors correlates with clinical response to DNA damaging agents. XPF has potential to guide next generation personalized cancer therapy.
预测对 DNA 损伤药物产生耐药性的肿瘤特异性生物标志物，可能通过指导有效治疗方法的选择，并限制无效方法相关的发病率，从而改善治疗效果。XPF（ERCC4）是几种 DNA 修复途径的重要组成部分，XPF 缺陷细胞对 DNA 损伤药物极其敏感。本研究旨在确定 XPF 表达水平是否可预测头颈部鳞状细胞癌（HNSCC）患者对 DNA 损伤药物的临床反应。
采用定量免疫组织化学方法检测 80 例新诊断的 HNSCC 患者肿瘤组织中的 XPF 表达水平，这些患者接受了放化疗联合或不联合铂类药物化疗；前瞻性收集了这些样本。从血液样本中提取基因组 DNA，使用定制的阵列分析 XPF 基因中的 9 个单核苷酸多态性（SNP）。主要终点为无进展生存期（PFS）。
XPF 表达在口腔肿瘤中的表达高于其他部位（P < 0.01）。单因素（HR = 1.87，P = 0.03）和多因素分析（HR = 1.83，P = 0.05）均显示，高 XPF 表达与早期进展时间相关。高表达者的 1 年 PFS 为 47%（95%CI = 31-62），而低表达者为 72%（95%CI = 55-83）。此外，我们发现 4 个 XPF SNP 与治疗失败有一定的相关性。
HNSCC 肿瘤中 XPF 的表达水平与 DNA 损伤药物的临床反应相关。XPF 有可能指导下一代个体化癌症治疗。
