Prognostic significance of undetectable baseline HPV circulating tumor DNA in oropharyngeal cancer.

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Background: Patients with p16-associated oropharyngeal squamous cell carcinomas (OPSCC) generally experience favorable treatment outcomes; however, 10-25% develop progression despite favorable clinical staging. Some reports have posited that undetectability of tumor tissue-modified viral (TTMV)-HPV circulating tumor DNA (ctDNA) may be an unfavorable prognostic feature. We examined for the presence of relationships between baseline HPV ctDNA positivity, anatomic staging, tumor volume, and early progression risk. Methods: We retrospectively analyzed 89 patients with OPSCC who underwent baseline HPV ctDNA testing between August 2021 and December 2025 at a single institution. ctDNA levels were quantified in fragments/mL and analyzed as log10 transformed values using a commercially available HPV ctDNA assay (NavDx; Naveris, Waltham, MA). Clinical stage (AJCC 8 ^th edition), CT or MRI-derived gross tumor volume (GTV), and survival outcomes were collected. Progression-free survival (PFS) was assessed using the Kaplan-Meier method. Pearson correlation was used to determine statistical association. Multivariable logistic regression models with TNM Stage and ctDNA covariates evaluated the incremental prognostic contribution of HPV ctDNA beyond anatomic disease burden. Results: Of the 89 patients, 75 (84%) had HPV16, 2 (2%) had HPV18, 2 (2%) had HPV33, 2 (2%) had HPV35, and 8 (9%) had no identified high-risk HPV subtype. Median follow-up was 15.9 months (IQR 11.1-21.0). Baseline ctDNA was detectable in 79 patients (89%) and across all AJCC group stages (Stage I: 87%, Stage II: 95%, Stage III: 93%, Stage IV: 100%). Baseline ctDNA levels increased numerically with advancing stage but substantial intra-stage heterogeneity was observed. A weak positive association with GTV (r = 0.19) was observed with rising ctDNA levels. Five patients (5.6%) experienced disease progression at a median of 3.5 months from baseline ctDNA test (IQR 2.2-8.2); all had detectable baseline ctDNA. Two-year PFS did not significantly differ by ctDNA positivity (93% vs. 100%, p = 0.43). Addition of ctDNA positivity to AJCC TNM staging did not significantly improve discrimination for progression (AUC 0.91 vs. 0.92). Conclusions: In this single institution cohort, undetectability of baseline TTMV-HPV ctDNA did not demonstrate prognostic value beyond AJCC staging. A weak correlation with tumor volume and intra-stage heterogeneity suggests that ctDNA may reflect biological features beyond anatomic disease burden. Further investigation is needed to determine if alternative testing methods would produce a closer association with prognosis.