Dahlstrom Kristina R, Anderson Karen S, Cheng Julia N, Chowell Diego, Li Guojun, Posner Marshall, Sturgis Erich M
Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Center for Personalized Diagnostics, The Biodesign Institute, Arizona State University, Tempe, Arizona.
Clin Cancer Res. 2015 Jun 15;21(12):2861-9. doi: 10.1158/1078-0432.CCR-14-3323.
Oropharyngeal carcinoma positive for human papillomavirus type 16 (HPV16) has a significantly better prognosis than oropharyngeal carcinoma unrelated to HPV. Within HPV16-positive oropharyngeal carcinoma, biomarkers of prognosis are urgently needed to individualize care. We hypothesized that serum antibodies specific to HPV16, the major HPV type causing oropharyngeal carcinoma, have biologic relevance and are potential biomarkers for improved prognosis among patients with HPV16-positive oropharyngeal carcinoma.
IgG antibodies to the HPV16 antigens E1, E4-E7, L1, L2, and the N-terminal and C-terminal fragments of E2 (NE2, CE2) were quantified using a custom programmable enzyme-linked immunosorbent assay. Sera were obtained at diagnosis from 209 oropharyngeal carcinoma patients (96 HPV16-positive). The ratios of median fluorescent intensity (MFI) for each antigen to MFI for control GST protein were determined. Kaplan-Meier survival curves and Cox proportional hazards regression were used to determine survival differences between groups. ROC curves were used to determine the best combination of E antibodies to predict disease recurrence.
E1, NE2, and E6 antibody positivity were all strongly associated with improved overall and progression-free survival in the entire cohort and in patients with known HPV16-positive tumors (P < 0.05). For both overall and progression-free survival among HPV-positive patients, hazard ratios were 0.2 for NE2, 0.3 for E1, and 0.3 for E6 antibody positivity.
We identified three HPV16-specific antibodies that are associated with improved overall and progression-free survival in patients with HPV-related oropharyngeal carcinoma. These results suggest that differential serologic responses in patients may reflect differential biologic processes within the host and tumor and may have prognostic value.
16型人乳头瘤病毒（HPV16）阳性的口咽癌患者的预后明显优于与HPV无关的口咽癌患者。在HPV16阳性的口咽癌患者中，迫切需要预后生物标志物来实现个体化治疗。我们假设，针对导致口咽癌的主要HPV类型HPV16的血清抗体具有生物学相关性，并且是改善HPV16阳性口咽癌患者预后的潜在生物标志物。
使用定制的可编程酶联免疫吸附测定法定量检测针对HPV16抗原E1、E4-E7、L1、L2以及E2的N端和C端片段（NE2、CE2）的IgG抗体。在诊断时从209例口咽癌患者（96例HPV16阳性）中获取血清。确定每种抗原的中位荧光强度（MFI）与对照GST蛋白的MFI之比。采用Kaplan-Meier生存曲线和Cox比例风险回归分析来确定组间生存差异。使用ROC曲线确定E抗体预测疾病复发的最佳组合。
在整个队列以及已知HPV16阳性肿瘤的患者中，E1、NE2和E6抗体阳性均与总体生存率和无进展生存率的提高密切相关（P<0.05）。对于HPV阳性患者的总体生存率和无进展生存率，NE2抗体阳性的风险比为0.2，E1为0.3，E6为0.3。
我们鉴定出三种HPV16特异性抗体，它们与HPV相关口咽癌患者总体生存率和无进展生存率的提高相关。这些结果表明，患者的不同血清学反应可能反映宿主和肿瘤内不同的生物学过程，并且可能具有预后价值。
