Early dynamics of circulating tumor HPV-DNA with neoadjuvant chemotherapy and response-adapted de-escalation in human papillomavirus-associated oropharyngeal cancer.

PURPOSE Human papillomavirus-associated (HPV+) oropharyngeal carcinoma (OPC) 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 non-invasive biomarker to gauge treatment response and surveil for disease recurrence. PATIENTS AND METHODS A prospective biomarker clinical trial of response-stratified de-escalation was conducted. Eligible patients with non-metastatic HPV+ OPC received neoadjuvant chemotherapy followed by risk/response-stratified de-escalation with transoral robotic surgery, de-escalated (chemo)radiation to 50Gy, or standard chemoradiation to 70Gy. 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. Primary endpoint was correlation of ctHPV-DNA kinetics and radiographic response. RESULTS Forty-six eligible patients were enrolled, and 488 ctHPV-DNA samples were analyzed (median 11 per patient). Median follow-up was 30 months, and five recurrences were observed (10.9%). Baseline ctHPV-DNA was detected in 96% 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, positive and negative predictive value of longitudinal ctHPV-DNA was 100%. The longest lead-time from positive ctHPV-DNA to detection of recurrent disease was 25 months. CONCLUSIONS 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.