{
  "abstract": "ImportanceRecurrence rates in head and neck squamous cell carcinoma (HNSCC) remain high, yet current post-treatment surveillance relies primarily on clinical examination and imaging with known limitations. Circulating tumor DNA (ctDNA) has shown promise for recurrence detection in HPV-positive HNSCC, but less is known about its role in non-virally associated disease.\n\nObjectiveTo evaluate the diagnostic performance of a methylation-based ctDNA assay for detecting recurrence during post-treatment surveillance of non-virally associated HNSCC and to assess its prognostic association with survival outcomes.\n\nDesign, Setting, and ParticipantsThis retrospective single-institution cohort study included patients with non-metastatic non-virally associated HNSCC who underwent definitive therapy and had at least one Guardant360 ctDNA test during post-treatment surveillance between January 2024 and October 2025. Guardant360 identifies tumor-specific DNA methylation patterns via next-generation sequencing of plasma cell-free DNA. A positive result was defined by a methylation signal of 0.05% or greater.\n\nMain Outcomes and MeasuresSensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic curve (AUC). Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method.\n\nResultsFifty patients were included; most had larynx (38%) or oral cavity (36%) primaries, AJCC stage IVA-IVB disease (72%), T3-T4 tumors (69%), and N2-N3 nodal classification (48%). Treatment was chemoradiation (54%) or surgery (46%). At a median follow-up of 18.0 months, 13 patients recurred, and 12 had positive ctDNA results. Sensitivity, specificity, PPV, and NPV were 76.9%, 94.6%, 83.3%, and 92.1%, respectively (AUC, .858; 95% CI, .733-.982). Positive ctDNA was associated with worse PFS (1-year: 25.0% vs 96.4%; P < .001) and OS (1-year: 75.0% vs 100%; P < .001). Among 10 patients with recurrence and positive ctDNA, ctDNA preceded clinical detection in 6 (60%) by a median of 131 days. An exploratory analysis identified TP53, SETD2, and ROBO2 mutations as associated with recurrence.\n\nConclusions and RelevanceA methylation-based ctDNA assay demonstrated high sensitivity and specificity for detecting disease recurrence in non-virally associated HNSCC. Positive post-treatment ctDNA was associated with inferior survival and preceded clinical detection in most cases, supporting ctDNA integration into surveillance strategies, though prospective validation is warranted.\n\nKey PointsO_ST_ABSQuestionC_ST_ABSCan a methylation-based circulating tumor DNA assay detect recurrence during post-treatment surveillance of non-virally associated head and neck squamous cell carcinoma?\n\nFindingsIn this cohort study of 50 patients, the ctDNA assay had a sensitivity of 76.9% and specificity of 94.6% for detecting recurrence (AUC of 0.858). Positive ctDNA preceded clinical detection in 60% of recurrences by a median of 131 days and was associated with worse progression-free and overall survival.\n\nMeaningMethylation-based ctDNA may be a useful tool for surveillance of recurrence in non-virally associated HNSCC.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Radiation Oncology, Montefiore Einstein Comprehensive Cancer Center"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "name": "D. Tomer"
    },
    {
      "name": "P. Brodin"
    },
    {
      "name": "N. Malik"
    },
    {
      "name": "S. Mayat"
    },
    {
      "name": "C. Velten"
    },
    {
      "name": "B.-H. Rhieu"
    },
    {
      "name": "E. Castellucci"
    },
    {
      "name": "B. Schiff"
    },
    {
      "name": "V. Mehta"
    },
    {
      "name": "R. Smith"
    },
    {
      "name": "S. Kalnicki"
    },
    {
      "name": "M. Garg"
    },
    {
      "affs": [
        0
      ],
      "name": "R. Kabarriti"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/3gcqhngngmyd2.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.17.26363361",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.09.17.26363361v1.full",
  "id": "3gcqhngngmyd2",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.09.17.26363361v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "oncology"
    ],
    [
      "openalex",
      "2733|Head and Neck Cancer Studies"
    ]
  ],
  "openalex": "W7213756952",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.09.17.26363361v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-17",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/3gcqhngngmyd2.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:58Z",
      "native_id": "10.64898/2026.09.17.26363361",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.09.17.26363361v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:oncology",
      "subfield": "oncology"
    }
  ],
  "title": "Methylation-Based ctDNA for Post-Treatment Surveillance of Non-Viral Head and Neck Cancer",
  "title_text": "Methylation-Based ctDNA for Post-Treatment Surveillance of Non-Viral Head and Neck Cancer",
  "type": "preprint",
  "updated_at": "2026-10-30T12:18:58Z",
  "url": "https://research.draconitic.com/paper/3gcqhngngmyd2",
  "venue": "medRxiv",
  "versions": []
}