Rosenberg Ari J, Izumchenko Evgeny, Juloori Aditya, Katipally Rohan, Cursio John, Choudhury Noura, Gooi Zhen, Blair Elizabeth, Chin Jeffrey, Hasina Rifat, Vannier Augustin, Starus Anna, Jones Frederick S, Gramiccioni Emily L, Miao Yuxuan, Haraf Daniel J, Vokes Everett E, Pearson Alexander T, Agrawal Nishant
Department of Medicine, Section of Hematology and Oncology, University of Chicago, Chicago, Illinois.
University of Chicago Comprehensive Cancer Center, Chicago, Illinois.
Clin Cancer Res. 2025 Aug 1;31(15):3150-3159. doi: 10.1158/1078-0432.CCR-25-0152.
Human papillomavirus-associated (HPV+) oropharyngeal carcinoma is associated with excellent survival, yet treatment drives substantial toxicity. Improved biomarkers are needed to select patients for de-escalated treatment. Circulating tumor HPV DNA (ctHPV-DNA) represents a promising noninvasive biomarker to gauge treatment response and surveil for disease recurrence.
A prospective biomarker clinical trial of response-stratified de-escalation was conducted. Eligible patients with non-metastatic HPV+ oropharyngeal carcinoma received neoadjuvant chemotherapy, followed by risk/response-stratified de-escalation with transoral robotic surgery, de-escalated radiation with or without chemotherapy to 50 Gy, or standard chemoradiation to 70 Gy. Deep response (≥50% tumor shrinkage per RECIST v1.1) qualified patients for de-escalation. ctHPV-DNA was measured using HPV-SEQ in plasma at baseline, during neoadjuvant chemotherapy, radiation, and following treatment. The primary endpoint was the correlation of ctHPV-DNA kinetics and radiographic response.
Forty-six eligible patients were enrolled, and 488 ctHPV-DNA samples were analyzed (median 11 per patient). The median follow-up was 30 months, and five recurrences were observed (10.9%). Baseline ctHPV-DNA was detected in 95% of evaluable patients. Rapid early ctHPV-DNA clearance after one cycle of neoadjuvant therapy (≥95% reduction) predicted radiographic deep response (P = 0.04). Detection of ctHPV-DNA 3 months or later after treatment was associated with worse progression-free and overall survival (P < 0.001). Sensitivity, specificity, and positive and negative predictive values of longitudinal ctHPV-DNA were 100%. The longest lead time from positive ctHPV-DNA to detection of recurrent disease was 25 months.
Rapid early clearance of ctHPV-DNA during neoadjuvant therapy demonstrates utility in predicting response to treatment. Detectable ctHPV-DNA following treatment is predictive of both disease recurrence and worse survival.
人乳头瘤病毒相关（HPV+）口咽癌患者生存率良好，但治疗会带来严重毒性。需要改进生物标志物以选择适合降阶梯治疗的患者。循环肿瘤HPV DNA（ctHPV-DNA）是一种很有前景的非侵入性生物标志物，可用于评估治疗反应和监测疾病复发。
开展了一项反应分层降阶梯的前瞻性生物标志物临床试验。符合条件的非转移性HPV+口咽癌患者接受新辅助化疗，随后根据风险/反应分层进行降阶梯治疗，采用经口机器人手术、降阶梯放疗（有或无化疗，剂量为50 Gy）或标准放化疗（剂量为70 Gy）。深度反应（根据RECIST v1.1标准，肿瘤缩小≥50%）使患者有资格接受降阶梯治疗。在基线、新辅助化疗期间、放疗期间及治疗后，使用HPV-SEQ检测血浆中的ctHPV-DNA。主要终点是ctHPV-DNA动力学与影像学反应的相关性。
46例符合条件的患者入组，共分析了488份ctHPV-DNA样本（每位患者中位数为11份）。中位随访时间为30个月，观察到5例复发（10.9%）。95%的可评估患者检测到基线ctHPV-DNA。新辅助治疗一个周期后ctHPV-DNA快速早期清除（降低≥95%）可预测影像学深度反应（P = 0.04）。治疗后3个月或更晚检测到ctHPV-DNA与无进展生存期和总生存期较差相关（P < 0.001）。纵向ctHPV-DNA的敏感性、特异性、阳性和阴性预测值均为100%。从ctHPV-DNA阳性到检测到复发疾病的最长提前期为25个月。
新辅助治疗期间ctHPV-DNA的快速早期清除在预测治疗反应方面具有实用性。治疗后可检测到的ctHPV-DNA可预测疾病复发和较差的生存率。
