Early clearance of circulating tumor DNA as a determinant of induction therapy response in human papillomavirus-associated oropharyngeal squamous cell carcinoma

The management of human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) largely mirrors that of other head and neck squamous cell carcinomas (HNSCC), despite its distinctly favorable prognosis. Consequently, a substantial proportion of long-term survivors continue to experience chronic toxicities, such as dysphagia and xerostomia, which significantly impair their quality of life. These concerns have intensified interest in treatment de-intensification strategies, particularly for low-risk HPV-OPSCC (1). Accurate risk stratification is essential to maintain excellent oncologic outcomes while reducing the treatment burden. Many ongoing de-intensification trials use tumor (T) and node (N) classifications, smoking history, and—most prominently—response to induction therapy as the major determinants of treatment intensity. Traditionally, radiographic evaluation using computed tomography (CT) or magnetic resonance imaging (MRI) has been employed to assess the response to induction chemotherapy (IC) and guide subsequent therapy decisions. However, radiographic changes often lag behind the true biological response and may not accurately correlate with oncologic outcomes, as noted in prior studies (2). Functional imaging, such as fluorodeoxyglucose-positron emission tomography, offers improved metabolic information but is still limited by false positivity caused by inflammation and treatment-induced changes. These challenges underscore the need for a reliable, biologically meaningful marker of early treatment response.

In this regard, the study by Tang et al. provides noteworthy insights (3). By evaluating circulating tumor tissue-modified HPV DNA (TTMV-HPV DNA) kinetics during IC or chemoimmunotherapy, they reported that complete clearance of TTMV-HPV DNA after the first cycle of induction therapy was strongly associated with favorable clinical outcomes. Importantly, the absence of detectable TTMV-HPV DNA at this early time point corresponded to complete freedom from recurrence during the follow-up period. In contrast, persistent detectability, even among patients who later achieved clearance after the second or third cycle, was associated with a substantially higher risk of relapse. This finding suggests that early complete clearance may represent a sensitive surrogate of biological treatment response and may offer distinct advantages over conventional imaging methods, which are susceptible to confounding by post-therapeutic changes. These observations also broaden the context of the evolving role of induction therapy in HNSCC.

While concurrent chemoradiation remains the standard of care for locoregionally advanced HNSCC, induction therapy continues to be used for selected patients, particularly for response-adapted strategies in HPV-OPSCC, where robust induction responders may be directed toward reduced-intensity chemoradiation. Similarly, emerging evidence from trials evaluating induction immunotherapy has renewed interest in pre-radiation systemic modulation, particularly in light of the disappointing outcomes of concurrent immunoradiotherapy (4). However, morphological response assessment in these trials remains vulnerable to pseudoprogression and immune-related inflammatory effects, further strengthening the appeal of circulating biomarkers such as TTMV-HPV DNA.

The clinical implications of Tang et al.’s findings are significant. Early identification of patients who achieve complete TTMV-HPV DNA clearance may enable the rational implementation of de-intensified treatment approaches designed to reduce long-term toxicity without compromising disease control. Conversely, persistent detection of TTMV-HPV DNA after the initial cycle may help identify a subset of patients at an elevated risk of treatment failure. Notably, metastatic recurrence was the predominant pattern of failure in the present cohort; among the six recurrences, one was locoregional, and five were metastatic. This raises the possibility that such patients may benefit from systemic therapy intensification beyond the use of conventional cytotoxic agents. The induction therapy regimen used in their study was cisplatin and docetaxel in combination with either 5-fluorouracil or anti-programmed death 1 antibody, which are the most intensive regimens under current practice. Therefore, patients with persistent TTMV-HPV DNA after one induction cycle may be appropriate candidates for emerging systemic therapies currently under investigation, including HPV-targeted therapeutic vaccines, antibody-drug conjugates, and bispecific antibodies (5). These novel treatments could improve systemic disease control in patients with high-risk HPV-OPSCC.

Although these initial findings are promising, several limitations should be acknowledged. This retrospective study was conducted at a single institution and included a small sample size with heterogeneity in both the induction regimens and subsequent treatments. Because of the limited sample size, Tang et al. were unable to perform multivariate analyses to adjust for potential confounders. In addition, the low incidence of recurrence, attributable to the favorable prognosis of HPV-OPSCC, limited the ability to draw definitive conclusions regarding the predictive value of TTMV-HPV DNA clearance. These factors necessitate a cautious interpretation of the results. Nevertheless, the consistent and clearly delineated association between early complete TTMV-HPV DNA clearance and improved outcomes provides a compelling justification for further studies. Prospective trials designed to evaluate response-adapted therapeutic strategies based on TTMV-HPV DNA kinetics are essential to validate these observations and determine their applicability in routine clinical practice.

Tang et al. meaningfully advanced the growing body of literature evaluating the applications of liquid biopsy in head and neck cancer. Their findings support the concept that real-time molecular monitoring has the potential to surpass traditional imaging modalities in assessing early therapeutic responses. As the field continues to progress toward biologically informed personalized treatment paradigms, the integration of TTMV-HPV DNA dynamics may help refine both de-escalation and escalation strategies in HPV-OPSCC. Continued research in this domain holds promise for improving treatment selection, reducing toxicity, and enhancing the survival of patients with this increasingly curable disease.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2605/prf

Funding: This work was supported by JSPS KAKENHI (grant No. JP25K12742).

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-1-2605/coif). The authors have no conflicts of interest to declare.

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References

1. Patel RR, Ludmir EB, Augustyn A, et al. De-intensification of therapy in human papillomavirus associated oropharyngeal cancer: A systematic review of prospective trials. Oral Oncol 2020;103:104608. [Crossref] [PubMed]
2. de Bree R, Wolf GT, de Keizer B, et al. Response assessment after induction chemotherapy for head and neck squamous cell carcinoma: From physical examination to modern imaging techniques and beyond. Head Neck 2017;39:2329-49. [Crossref] [PubMed]
3. Tang M, Dougherty M, Worona L, et al. Predictive value of circulating tumor tissue-modified HPV DNA kinetics in induction therapy for oropharyngeal squamous cell carcinoma. Oral Oncol 2025;169:107608. [Crossref] [PubMed]
4. Sim ES, Nguyen HCB, Hanna GJ, et al. Current Progress and Future Directions of Immunotherapy in Head and Neck Squamous Cell Carcinoma: A Narrative Review. JAMA Otolaryngol Head Neck Surg 2025;151:521-8. [Crossref] [PubMed]
5. Gauduchon T, Neidhardt EM, Fayette J. Therapeutic perspectives for recurrent or metastatic head and neck squamous cell carcinoma. Curr Opin Oncol 2025;37:175-83. [Crossref] [PubMed]