Purpose: Human papillomavirus (HPV) is the cause of the majority of cervical cancers and has been showed to be released as cell-free tumour DNA (ctHPV DNA) into the circulation. We here analyse if ctHPV DNA could be used as a prognostic biomarker and/or to detect relapse earlier than traditional methods in locally advanced cervical cancer (LACC). Experimental Design: 74 patients with LACC were included, 66/74 were positive for 13 high-risk HPV-types using a bead-based assay on tumour biopsies. HPV-type-specific droplet digital PCR (ddPCR) assays were developed. Longitudinal plasma samples were then analysed for the biopsy-verified HPV-type for each patient. 418 plasma samples were analysed. Patients were followed for a median of 37 months. Results were correlated to tumour- and clinical characteristics. Results: 92.4% of pre-treatment plasma samples were positive for ctHPV DNA. Persistent ctHPV DNA in end-of-treatment, early follow-up (1-2 months after end-of-treatment) or tumour evaluation (3-4 months after end-of-treatment) plasma was correlated with worse progression-free survival (p < 0.001) compared to if ctHPV DNA was not found. The positive predictive value of ctHPV-status at early follow-up for predicting disease progression was 87.5% and the negative predictive value was 89.3%. ctHPV DNA was found in plasma before relapse was diagnosed on radiology in all patients (n=10) who experienced relapse after complete clinical response to treatment with a median 315 days lead time. Conclusions: ctHPV DNA in follow-up plasma is a promising prognostic biomarker in patients with LACC, useful for analysis of response to therapy and for early detection of relapse.

中文翻译：

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无细胞人乳头瘤病毒 (HPV) DNA 是局部晚期宫颈癌预后和早期复发检测的敏感生物标志物

目的：人乳头瘤病毒 (HPV) 是大多数宫颈癌的病因，并已被证明以无细胞肿瘤 DNA (ctHPV DNA) 的形式释放到循环系统中。我们在这里分析 ctHPV DNA 是否可以用作局部晚期宫颈癌 (LACC) 的预后生物标志物和/或比传统方法更早地检测复发。实验设计：纳入了 74 名 LACC 患者，使用基于珠子的肿瘤活检检测，其中 66/74 的患者对 13 种高危 HPV 类型呈阳性。开发了 HPV 类型特异性液滴数字 PCR (ddPCR) 检测方法。然后对每位患者的纵向血浆样本进行活检验证的 HPV 类型分析。分析了 418 个血浆样本。患者的随访时间中位数为 37 个月。结果与肿瘤和临床特征相关。结果：92.4% 的治疗前血浆样本 ctHPV DNA 呈阳性。治疗结束、早期随访（治疗结束后 1-2 个月）或肿瘤评估（治疗结束后 3-4 个月）血浆中持续存在 ctHPV DNA 与较差的无进展生存期相关(p＜0.001)与未发现ctHPV DNA的情况相比。早期随访时 ctHPV 状态预测疾病进展的阳性预测值为 87.5%，阴性预测值为 89.3%。所有患者 (n=10) 在放射学诊断复发之前，在血浆中发现了 ctHPV DNA，这些患者在对治疗产生完全临床反应后出现复发，中位时间为 315 天。结论：随访血浆中的 ctHPV DNA 是 LACC 患者有前景的预后生物标志物，可用于分析治疗反应和早期检测复发。