Using ctDNA to Guide Treatment in HPV-Positive Oropharyngeal Cancer

Clinical Summary: 

• Design/Population: A prospective analysis of 104 patients with HPV-related oropharyngeal cancer assessing ctDNA levels before and after surgery.
• Key Outcomes: Preoperative ctDNA correlated with nodal burden, while persistent postoperative ctDNA was associated with adverse pathologic features and potential residual disease.
• Clinical Relevance:  ctDNA may serve as a useful adjunct biomarker for risk stratification but should be integrated with clinical and pathologic factors rather than used alone to guide treatment decisions.

Catherine Haring, MD, The Ohio State University, Columbus, Ohio, discusses findings from a study evaluating circulating tumor DNA (ctDNA) as a biomarker in patients with HPV-related oropharyngeal cancer undergoing surgery.

Results demonstrate ctDNA correlates with tumor burden and pathologic risk features and may help identify patients with residual disease, supporting its role in guiding risk-adapted treatment strategies.

Transcript: 

My name is Catherine Haring, I’m an otolaryngologist–head and neck surgeon practicing at The Ohio State University. Today, I wanted to share with you our newly published research findings regarding the use of a circulating tumor DNA test, a blood-based test, for patients with HPV-related throat cancer.

We see that these patients with HPV-related throat cancer have really good responses to treatment. Treatment can include radiation or surgery, but unfortunately, patients experience significant side effects from treatment, especially if they receive radiation. Those side effects can include scarring of the neck and throat, which can result in long-term issues with swallowing, appearance, and their ability to live a normal life. We have recently developed and are using a new blood-based test that is able to detect cancers at an earlier stage and importantly, for patients who have known cancer, it can help us detect if they develop recurrence after treatment.

In this particular study, we were looking at the use of this circulating tumor DNA test in patients who were undergoing surgery for their treatment. We had a cohort of 104 patients, and we analyzed their blood-based test before and after treatment—before and after surgery—and looked at whether any features related to the patient’s tumor on the final pathology report, or any clinical features, were associated with those levels before and after surgery.

When we first looked at the values before surgery, we saw that there were a few factors associated with the degree of elevation. For example, patients with higher nodal burden, or larger lymph nodes in their neck, were associated with higher levels of circulating tumor DNA. This has been shown across other studies, and our findings reinforce that. We also showed, somewhat counterintuitively, that more aggressive tumor features—things like perineural invasion or extranodal extension—were actually associated with lower baseline levels. That may seem counterintuitive, but it is supported by existing literature.

What we see is that HPV circulating tumor DNA levels are highly related to the degree of genomic integration. The HPV genome can integrate into the human genome, and when that occurs, it is associated with more aggressive tumors. At the same time, higher degrees of genomic integration are associated with lower circulating tumor DNA levels. So our findings align with that—patients with perineural invasion or extranodal extension were more likely to have lower preoperative ctDNA levels.

We then looked at postoperative circulating tumor DNA values. We saw that the majority of patients cleared their ctDNA after surgery. All of these measurements were taken before patients started radiation, so this was purely post-surgical ctDNA. However, about 20% of patients still had detectable ctDNA after surgery. So we asked whether there were factors associated with persistent detection. We found that patients with more than 4 positive lymph nodes on final pathology were more likely to have persistently detectable ctDNA. Additionally, patients with aggressive features such as perineural invasion or extranodal extension were also more likely to have persistently elevated ctDNA after surgery.

We then looked at recurrence patterns. We wanted to see whether postoperative ctDNA—detectable versus undetectable—could serve as an early biomarker or prognostic factor. Among patients with persistently detectable ctDNA after surgery, most went on to receive radiation or chemoradiation, and those patients did very well, with only 1 recurrence in that group. Among patients with undetectable postoperative ctDNA, a notable proportion did not receive radiation for various reasons. Unfortunately, some of those patients went on to develop locoregional recurrence. 

When we look at these data together, it suggests a few things. Detectable postoperative ctDNA likely represents molecular residual disease and supports the need for adjuvant radiation or chemoradiation. On the other hand, a negative post-surgical ctDNA result needs to be interpreted in the context of other clinical and pathologic factors. These data suggest that we cannot yet use ctDNA as a standalone marker to guide treatment decisions. Instead, it should be incorporated into a multifactorial risk assessment that includes the patient’s clinical history and final pathology.

In terms of future directions, many institutions, including ours at Ohio State, have ongoing clinical trials using blood-based tests like this to help guide treatment intensity. This includes both surgical patients and those receiving chemoradiation. Overall, these data highlight the promise of circulating tumor DNA testing to help personalize treatment for patients with HPV-related oropharyngeal cancer.

Source:

Birkenbeuel JL, Noel C, Baliga S, et al. Determinants of circulating tumor HPV DNA in surgically treated oropharyngeal cancer. JAMA Otolaryngol Head Neck Surg. Published online: April 2, 2026. doi:10.1001/jamaoto.2026.0015