PO.CL01.18 · 临床研究

在PLCO队列中基于多分析物血液筛查对HPV相关口咽癌和肛门癌的早期检测

Multi-analyte blood-based screening early detection of HPV-associated oropharyngeal and anal cancer within the PLCO cohort

编号 1092 展板 2 时间 4/19 02:00–05:00 区域 Section 43 主讲 Daniel Faden, MD

分会场 Early Detection Biomarkers 1

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作者与单位 Authors & Affiliations

Krystle A. Kuhs¹, Hilary Robbins², Li Chen³, Xiaoshuang Feng⁴, Yana Al-Inaya⁵, Gjystina Lumaj⁶, Samuli Eldorfs⁵, Qin Wang⁵, Tim Waterboer⁷, Dipon Das⁵, Daniel Faden⁸

¹Department of Epidemiology and Environmental Health, University of Kentucky, Lexington, KY,²International Agency for Research on Cancer, World Health Organization, Lyon, France,³University of Kentucky, Lexington, KY,⁴World Health Organization,⁵Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear, Boston, MA,⁶Massachusetts Eye and Ear, Otolaryngology-Head and Neck Surgery, MA,⁷DFKZ-German Cancer Research Center, Heidelberg, Germany,⁸Mass General Brigham, Boston, MA

摘要 Abstract

中文摘要

背景:尽管发病率不断上升,但目前尚无针对HPV+口咽癌(HPV+OPC)和肛门癌(HPV+AC)的早期检测方法。HPV16 E6抗体(E6 Ab)阳性是一个有前景的早期生物标志物,在大多数患者诊断时以及症状出现前数年即出现,但血清转化与癌症之间的长间隔限制了其临床应用价值。还需要其他肿瘤指示性生物标志物。循环肿瘤HPV DNA(ctHPVDNA)在诊断时对检测HPV+癌症具有高度敏感性和特异性。超灵敏HPV全基因组测序(WGS)检测,如HPV-DeepSeek,已在单机构队列中显示出对HPV+OPC早期检测的强大性能。方法:对73例OPC和19例AC病例以及183例具有可用E6 Ab结果的匹配PLCO对照的连续诊断前血浆样本进行了ctHPVDNA检测。样本经过盲法处理,进行cfDNA提取,并如先前所述使用HPV-DeepSeek进行分析。结果:ctHPVDNA检测与未来OPC和AC的发生强烈相关(OR 20.52 [95% CI 4.80-87.59],P<0.0001;OR 33.63 [95% CI 7.05-无穷大],P<0.0001)。在E6 Ab阳性病例中(N=31,作为HPV+的替代标志物),ctHPVDNA对OPC的敏感性为61.3%(95% CI 42.2-78.2),对AC为71.4%(95% CI 29-96.3)。敏感性在接近诊断时最高(OPC在2年内为100%;AC在5年内为100%),并随着提前时间延长而下降。ctHPVDNA读数随着距诊断的提前时间缩短而增加。18例OPC和9例ctHPVDNA阳性的AC病例有连续样本。10例OPC(56%)在所有连续样本中均为阳性(首次ctHPVDNA阳性检测至诊断的中位时间:3.5年),8例(44%)在随访期间从ctHPVDNA阴性转为阳性(转化至诊断的中位时间:4.7年,范围0.6至8.9年)。2例AC(22%)在所有连续样本中均为阳性(首次ctHPVDNA阳性检测至诊断的中位时间:6.6年),6例(67%)在随访期间从ctHPVDNA阴性转为阳性(转化至诊断的中位时间:2.4年,范围1.2至15.4年)。结论:使用超灵敏WGS检测HPV-DeepSeek测量的ctHPVDNA与未来HPV癌症风险强烈相关。在E6 Ab阳性病例中,ctHPVDNA在OPC和AC诊断前的紧邻数年中均达到100%的敏感性。连续采样显示随着诊断临近,检测率和读数不断增加,支持ctHPVDNA作为新发疾病的时间依赖性标志物。将E6 Ab检测与超灵敏ctHPVDNA检测相结合,为HPV+癌症的血液早期检测提供了互补信息,应在前瞻性早期检测试验中进行验证。

查看英文原文 English abstract

Background: Despite rising incidence, there are no early detection methods for HPV+ oropharyngeal (HPV+OPC) and anal (HPV+AC) cancers. HPV16 E6 antibody (E6 Ab) positivity is a promising early biomarker, appearing in most patients at diagnosis and years before symptoms, but the long interval between seroconversion and cancer limits clinical utility. Additional tumor-indicative biomarkers are needed. Circulating tumor HPV DNA (ctHPVDNA) is highly sensitive and specific for detecting HPV+ cancers at diagnosis. Ultrasensitive HPV whole genome sequencing (WGS) assays such as HPV-DeepSeek have shown strong performance for HPV+OPC early detection in a single institution cohort. Methods: ctHPVDNA testing was performed on serial pre-diagnostic plasma samples from 73 OPC and 19 AC cases and 183 matched PLCO controls with available E6 Ab results. Samples were blinded, underwent cfDNA extraction, and were analyzed using HPV-DeepSeek as previously described. Results: ctHPVDNA detection was strongly associated with future OPC and AC development (OR 20.52 [95% CI 4.80-87.59], P<0.0001; OR 33.63 [95% CI 7.05-Infinity], P<0.0001). Among E6 Ab positive cases (N=31, surrogate marker to HPV+), ctHPVDNA sensitivity was 61.3% (95% CI 42.2-78.2) for OPC and 71.4% (95% CI 29-96.3) for AC. Sensitivity was highest near diagnosis (100% for OPC within 2 years; 100% for AC within 5 years) and declined with longer lead time. ctHPVDNA read counts increased as the lead time to diagnosis decreased. Eighteen OPC and nine AC cases positive for ctHPVDNA had serial samples. 10 OPC (56%) were positive in all serial samples (median time between first positive ctHPVDNA test to diagnosis: 3.5 years) and 8 (44%) converted from ctHPVDNA negative to positive over follow-up (median time from conversion to diagnosis: 4.7 years, range 0.6 to 8.9 years). 2 AC (22%) were positive in all serial samples (median time between first positive ctHPVDNA test to diagnosis: 6.6 years) and 6 (67%) converted from ctHPVDNA negative to positive over follow-up (median time from conversion to diagnosis: 2.4 years, range 1.2 to 15.4 years). Conclusions: ctHPVDNA, measured using an ultrasensitive WGS assay, HPV-DeepSeek, was strongly associated with future HPV cancer risk. Among E6 Ab positive cases, ctHPVDNA achieved 100% sensitivity in the years immediately preceding diagnosis in both OPC and AC. Serial sampling showed increasing detection rates and read counts as diagnosis neared, supporting ctHPVDNA as a time-dependent marker of emerging disease. Combining E6 Ab testing with ultrasensitive ctHPVDNA detection provides complementary information for blood-based early detection of HPV+ cancers which should be tested in prospective early detection trials.

利益披露 Disclosure

K. A. Kuhs, None.. H. Robbins, None.. L. Chen, None.. Y. Al-Inaya, None.. G. Lumaj, None.. S. Eldorfs, None.. Q. Wang, None.. T. Waterboer, None.. D. Das, None.. D. Faden, None.

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