Prospective Trial Evaluating Post-operative Human Papilloma Virus Circulating Tumor DNA Guided Adjuvant Therapy for Human Papilloma Virus-related Oropharyngeal Carcinoma (PATH study): HPV ctDNA Guided Adjuvant therapy in OPC.

Abstract

Human papillomavirus circulating tumor DNA (HPV ctDNA) is a biomarker which detects minimal residual disease (MRD) for HPV-associated oropharyngeal carcinoma (HPV+ OPC).

Purpose: We conducted the first prospective study using HPV ctDNA as an integral biomarker to select patients for post-operative radiotherapy omission. We tested the hypothesis that undetectable post-operative HPV ctDNA can be used to omit or delay adjuvant radiation until patients develop detectable HPV ctDNA using the NavDx (Naveris, Inc.) tumor-tissue-modified viral (TTMV) HPV DNA score. Eligible HPV+ OPC patients had a preoperative TTMV-HPV DNA Score of ³50 and at least one pathologic risk factor to warrant standard adjuvant radiotherapy.

Methods and materials: Post-operatively, eligible patients had no evidence of disease on post-operative MRI and two negative TTMV-HPV DNA test results. Patients with non-HPV-16 genotype, positive margins, and extranodal extension were excluded. Patients were monitored with TTMV-HPV DNA testing, imaging, and physical exams. Delayed adjuvant radiation was initiated if patients developed detectable TTMV-HPV DNA without radiographic recurrence. The primary endpoint was the proportion of patients without gross recurrent disease.

Results: Fifty-five HPV+ OPC patients were screened; 12 patients were enrolled. The median follow-up was 26.6 months (Range: 18.3-40.3). One patient (8%) developed detectable HPV ctDNA 6 months after surgery without evidence of recurrence and was treated with delayed adjuvant radiotherapy. Three additional patients (25%) developed radiographic recurrence 6 months after surgery. Radiographic recurrence was not preceded by detectable TTMV-HPV DNA. TTMV-HPV DNA detection was synchronous with radiographically evident disease in 2 of 3 patients. Recurrence was associated with N2b disease pre-treatment (p=0.01). The high gross recurrence rate (3 of 12 patients) led to closure of this cohort due to a pre-specified stopping rule.

Conclusion: Deferring adjuvant radiotherapy based on HPV ctDNA using NavDx TTMV-HPV DNA testing resulted in a high rate of disease recurrence.