Circulating tumor DNA (ctDNA) monitoring with Signatera, a personalized liquid biopsy test, demonstrated prognostic and predictive value in head and neck squamous cell carcinoma (HNSCC), with 3 newly reported studies highlighting its potential to inform adjuvant treatment decisions and detect disease recurrence during surveillance.^1-3

The findings include data from institutional cohorts and a retrospective analysis evaluating the personalized, tumor-informed molecular residual disease (MRD) assay across human papillomavirus (HPV)-positive and HPV-negative disease subtypes. Across the studies, serial testing demonstrated high sensitivity and negative predictive value, with recurrence detected a median of 4.3 months before radiographic progression in 1 analysis.

“Head and neck cancer is difficult to treat and carries high recurrence rates, underscoring the importance of catching relapse as early as possible,” Michael Krainock, MD, PhD, MBA, medical director, oncology at Natera, stated in a news release. “Collectively, these new studies demonstrate Signatera’s ability to detect recurrence well in advance of clinical signs and predict which patients were likely to benefit from adjuvant chemotherapy.”

Identifying Adjuvant Chemotherapy Benefit

In an institutional cohort study published in npj Precision Oncology, investigators prospectively evaluated Signatera following curative-intent surgical resection in patients with mucosal HNSCC. Postoperative, pre-adjuvant ctDNA status was predictive of benefit from adjuvant chemotherapy.

Among patients with detectable ctDNA, adjuvant chemotherapy was associated with a 35-percentage-point absolute reduction in 2-year locoregional recurrence compared with no adjuvant chemotherapy (28.6% vs 63.3%, respectively).¹ In contrast, patients with undetectable ctDNA experienced no differences in disease-free survival, locoregional recurrence, or distant metastases regardless of whether they received adjuvant chemotherapy.

Signatera also outperformed clinicopathologic risk factors in prognosticating disease-free survival risk, suggesting that ctDNA status could provide additional information beyond traditional factors when assessing postoperative recurrence risk.

High Sensitivity Across HPV Subtypes

A second study, published in JAMA Otolaryngology–Head & Neck Surgery, evaluated Signatera in the pretreatment and surveillance settings among 168 patients with HNSCC. At baseline, 92.2% of pretreatment samples tested positive for ctDNA. During surveillance, serial testing demonstrated 95.2% sensitivity and a 99.4% negative predictive value. Specificity and positive predictive value were both 100%.²

These findings demonstrated assay performance across both HPV-positive and HPV-negative disease, addressing an important consideration in HNSCC surveillance given the distinct biological subtypes associated with HPV status.

Earlier Detection of Recurrence During Surveillance

A third publication in Advances in Radiation Oncology retrospectively evaluated 97 patients with stage I to IV HNSCC to assess the clinical utility of Signatera following definitive treatment. Serial ctDNA testing detected recurrence a median of 4.3 months before radiographic progression, with 91.7% sensitivity and 96.4% specificity.³ In the HPV-positive subgroup, the assay achieved 100% sensitivity, outperforming tumor tissue-modified viral HPV DNA assays commonly used to monitor recurrence in this population.

Additionally, multivariate analysis identified Signatera positivity as the only independent predictor of progression-free survival, outperforming clinical stage, p16 status, and tumor location.

Implications for Posttreatment Monitoring

Together, the 3 studies highlight potential applications for ctDNA monitoring in postoperative risk assessment, adjuvant treatment selection, and posttreatment surveillance. These findings are particularly relevant in HNSCC, where recurrence rates can reach 60%, depending on disease stage, and conventional imaging-based surveillance can be limited by false-positive findings and low sensitivity.

The ability to identify patients with detectable postoperative ctDNA who may derive greater benefit from adjuvant chemotherapy could help refine treatment decisions, while serial monitoring may provide an earlier indication of recurrence than radiographic assessment alone. Further prospective evaluation will be important to determine how these results translate into clinical decision-making and patient outcomes.

FAQs

What is Signatera, and how does it work in head and neck squamous cell carcinoma (HNSCC)?

Signatera is a personalized, tumor-informed liquid biopsy test that detects circulating tumor DNA (ctDNA) in the blood. It is used as a molecular residual disease (MRD) assay, and 3 newly reported studies evaluated it in HNSCC for postoperative risk assessment, adjuvant treatment decisions, and surveillance for recurrence.

Can ctDNA status help determine who benefits from adjuvant chemotherapy?

Possibly. In an institutional cohort study published in npj Precision Oncology, postoperative, pre-adjuvant ctDNA status predicted benefit from adjuvant chemotherapy in patients with mucosal HNSCC who underwent curative-intent resection. Among patients with detectable ctDNA, adjuvant chemotherapy was associated with a lower 2-year locoregional recurrence rate than no adjuvant chemotherapy (28.6% vs 63.3%). Patients with undetectable ctDNA had no differences in disease-free survival, locoregional recurrence, or distant metastases, regardless of whether they received adjuvant chemotherapy.

How accurate is Signatera during surveillance?

In a study of 168 patients published in JAMA Otolaryngology–Head & Neck Surgery, serial testing during surveillance showed 95.2% sensitivity and a 99.4% negative predictive value. Specificity and positive predictive value were both 100%. At baseline, 92.2% of pretreatment samples were ctDNA positive.

Does the test work in both HPV-positive and HPV-negative disease?

Yes. The studies showed assay performance across both HPV-positive and HPV-negative HNSCC. In a retrospective analysis of 97 patients published in Advances in Radiation Oncology, the assay reached 100% sensitivity in the HPV-positive subgroup, outperforming tumor tissue-modified viral HPV DNA assays commonly used to monitor recurrence in this population.

How much earlier can ctDNA detect recurrence than imaging?

In the Advances in Radiation Oncology analysis, serial ctDNA testing detected recurrence a median of 4.3 months before radiographic progression. Sensitivity was 91.7% and specificity was 96.4%.

How does ctDNA compare with traditional prognostic factors?

In the institutional cohort, Signatera outperformed clinicopathologic risk factors in prognosticating disease-free survival. In the retrospective analysis, multivariate analysis identified Signatera positivity as the only independent predictor of progression-free survival, ahead of clinical stage, p16 status, and tumor location.

Why does earlier detection matter in HNSCC?

Recurrence rates can reach 60%, depending on disease stage. Imaging-based surveillance can also be limited by false-positive findings and low sensitivity, so earlier and more specific signals of relapse could help guide care.

Is ctDNA monitoring ready to change clinical practice in HNSCC?

Not yet. The findings point to potential uses in postoperative risk assessment, adjuvant treatment selection, and posttreatment surveillance. Further prospective evaluation is needed to determine how these results translate into clinical decision-making and patient outcomes.

REFERENCES

1. Clark P, Woody N, Karasik N, et al. Tumor-informed molecular residual disease in resected mucosal and cutaneous squamous cell carcinomas of the head and neck. npj Precision Oncology. Published online October 18, 2026. doi:10.1038/s41698-026-01757-8

2. Sicard RM, Cooke PV, Steinbaum A, et al. Tissue-Informed ctDNA Assay Performance in Head and Neck Squamous Cell Carcinoma. JAMA Otolaryngology–Head & Neck Surgery. 2026;152(10):962. doi:10.1001/jamaoto.2026.2469

3. Denney SF, Laliotis G, Palsuledesai CC, et al. Tumor-Informed Circulating Tumor DNA Monitoring for Predicting Outcomes in Patients With Head and Neck Squamous Cell Carcinoma. Advances in Radiation Oncology. 2027;12(1):102205. doi:10.1016/j.adro.2026.102205