Liquid biopsy is emerging as a potential way to detect and monitor cancer without repeatedly removing tissue from a tumor. In a study scheduled for publication in JAMA Otolaryngology–Head & Neck Surgery, researchers examine the promise of viral circulating tumor DNA, or ctDNA, as a biomarker across several types of head and neck cancer. The approach focuses on fragments of tumor-derived genetic material found in blood, particularly DNA that contains sequences from cancer-associated viruses.
The concept is especially relevant to virus-related head and neck malignancies, in which viral genetic material can become integrated into tumor cells or persist as part of the cancer’s molecular identity. When tumor cells die, they release short DNA fragments into the bloodstream. These fragments can be isolated from plasma and analyzed using molecular techniques such as polymerase chain reaction, digital PCR, and next-generation sequencing. If viral DNA is present in the tumor, its detection in blood may provide a highly specific signal that cancer cells remain in the body.
The study describes liquid biopsy targeting viral ctDNA as a promising tool in both diagnosis and post-treatment surveillance. Conventional diagnosis generally depends on physical examination, imaging, endoscopy, and tissue biopsy. Although these methods remain central to clinical care, they can be invasive, costly, or limited in their ability to capture the full molecular diversity of a tumor. A blood-based assay could provide a repeatable measurement that can be collected during initial evaluation, treatment, and follow-up.
One of the most important potential applications is monitoring response to therapy. Patients with head and neck cancer may undergo surgery, radiation, chemotherapy, immunotherapy, or combinations of these treatments. Imaging performed soon after therapy can be difficult to interpret because inflammation and tissue injury may resemble persistent disease. Viral ctDNA could offer a molecular readout that changes more quickly than visible anatomical abnormalities. A falling or disappearing signal might indicate a response, while persistent or rising levels could suggest residual disease or renewed tumor activity.
The technology may also help identify minimal residual disease, commonly abbreviated as MRD. MRD refers to a small number of cancer cells that remain after treatment but are below the detection threshold of standard imaging or clinical examination. These cells can eventually give rise to recurrence. Because viral ctDNA may be linked directly to the malignant cell population, researchers are investigating whether its presence after treatment can identify patients at elevated risk before a recurrence becomes clinically apparent.
Such information could support a more adaptive approach to treatment. If a blood test indicates that disease-associated viral DNA has been cleared, clinicians might eventually use that result alongside imaging and pathology to refine surveillance or reduce unnecessary interventions. Conversely, a persistent molecular signal could prompt closer monitoring, additional imaging, or consideration of further treatment. The study emphasizes that these possibilities remain dependent on evidence from ongoing clinical trials rather than being established standards of care.
A major technical challenge is the extremely small quantity of tumor-derived DNA circulating in blood. Plasma contains abundant cell-free DNA released by normal tissues, while ctDNA may represent only a tiny fraction of the total. Viral ctDNA assays must therefore distinguish genuine tumor-associated sequences from background DNA, laboratory contamination, and biological variation. Assay sensitivity, specificity, sample handling, timing of blood collection, and the choice of viral genomic targets can all influence results.
Another challenge is that head and neck cancer is not a single disease. Tumors differ according to their anatomical site, genetic profile, viral association, stage, and treatment history. A test designed for one viral subtype or cancer population may not perform equally well in another. Researchers must establish validated thresholds for detecting clinically meaningful disease and determine how test results should be interpreted when viral DNA levels are low or fluctuate over time.
Clinical trials will be essential for determining whether viral ctDNA improves outcomes rather than simply providing an additional measurement. Studies must assess how accurately the biomarker detects recurrence, how early it provides warning, and whether acting on its results leads to better survival or quality of life. Trials will also need to evaluate false-positive and false-negative results, the psychological effects of molecular surveillance, and the cost and accessibility of repeated testing.
The work by Sagar Kansara, MD, of the Department of Otolaryngology–Head and Neck Surgery at Louisiana State University Health Sciences Center, frames viral ctDNA as part of a broader shift toward precision oncology. Instead of relying solely on anatomical examinations performed at fixed intervals, future care could combine imaging, pathology, symptoms, and real-time molecular data from blood. For patients with virus-associated head and neck cancer, that strategy could make diagnosis and surveillance more individualized, provided ongoing research confirms that the technology is reliable, clinically useful, and ready for routine practice.
Subject of Research: Viral circulating tumor DNA as a liquid biopsy biomarker for diagnosis, treatment-response monitoring, minimal residual disease assessment, and surveillance in head and neck cancer.
Web References: https://doi.org/10.1001/jamaoto.2026.2045
References: Kansara S. JAMA Otolaryngology–Head & Neck Surgery. DOI: 10.1001/jamaoto.2026.2045.
Keywords: Viral ctDNA, circulating tumor DNA, liquid biopsy, head and neck cancer, oncology, cancer surveillance, minimal residual disease, treatment response, precision oncology, clinical trials, otolaryngology, cancer diagnosis.
