Development of a Clinical Assay to Guide Patient Therapy in HPV-Associated Head and Neck Cancer

PURPOSE: Patients with HPV+ HNSCC have relatively favorable outcomes, standard treatments like radiation or chemoradiation frequently result in long-term toxic side effects. Appropriate patient selection has been a barrier to effectively de-escalate therapy for HPV+ HNSCC and the absence of accurate biomarkers likely contributed to failure of recent promising de-escalation trials that rely on histologic tumor characteristics, history of tobacco use, or tumor response to chemotherapy; This deficiency underlines the need to develop and validate an assay to accurately detect two subtypes of HPV+ HNSCC-one with good prognosis and one with poor prognosis. EXPERIMENTAL DESIGN: These two subtypes are distinguished by the activity of NF-κB in tumors. We first developed a DNA-based marker panel consisting of genes that when mutated would lead to NF-κB activation. Additionally, we developed a custom Nanostring assay to determine the expression of NF-κB target genes. These assays were tested to determine their accuracy in detecting tumor subtype. RESULTS: We demonstrate that the NF-κB gene signature score, as determined using the nanostring assay, could more accurately classify HPV+ HNSCC as compared to the DNA-based marker panel. Patients with a high NF-κB gene signature score demonstrated significantly increased overall survival, indicating more sensitivity to (chemo)radiation treatment. CONCLUSIONS: The NF-κB gene signature score can accurately predict response to standard (chemo)radiation in HPV+ HNSCC. This molecular biomarker holds promise for clinical use in identifying patients who are likely to benefit from treatment de-escalation strategies, potentially reducing long-term side effects without compromising therapeutic efficacy.

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Publication Details

Journal
Clinical Cancer Research
Published
2026-04-01
DOI
https://doi.org/10.1158/1078-0432.ccr-25-2159
Primary Topic
Head and Neck Cancer Studies
Type
article
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article

Development of a Clinical Assay to Guide Patient Therapy in HPV-Associated Head and Neck Cancer

Natalia Issaeva, Wendell Gray Yarbrough, T. Hackman, Travis P. Schrank et al.
Clinical Cancer Research
Head and Neck Cancer Studies
article

Development of a Clinical Assay to Guide Patient Therapy in HPV-Associated Head and Neck Cancer

Natalia Issaeva, Wendell Gray Yarbrough, T. Hackman, Travis P. Schrank, Siddharth Sheth, Bart Singer, Barbara Ann Burtness, Yael Flamand, L. Zheng, Tito Poli, Hina Rehmani, J. Hakim, Andrew Sewell, Loris De Cecco, Kathrin Scheckenbach, Ruud H. Brakenhoff, Evan M. Graboyes, Lori Ramkissoon, Yasine Mirmozaffari, René C. Leemans, Sri Vemulamanda, C. Courtine, Pragati Upadhyay, Robert L. Ferris, Jennifer Dorth, Xuguang Chen, Sulgi Kim, Quintin Pan, Yue Xie, Stefano Cavalieri, Bhishamjit Chera, Lisa Licitra, Aditi Kothari, Frank Hoebers, Yan Li
article en

Abstract

PURPOSE: Patients with HPV+ HNSCC have relatively favorable outcomes, standard treatments like radiation or chemoradiation frequently result in long-term toxic side effects. Appropriate patient selection has been a barrier to effectively de-escalate therapy for HPV+ HNSCC and the absence of accurate biomarkers likely contributed to failure of recent promising de-escalation trials that rely on histologic tumor characteristics, history of tobacco use, or tumor response to chemotherapy; This deficiency underlines the need to develop and validate an assay to accurately detect two subtypes of HPV+ HNSCC-one with good prognosis and one with poor prognosis. EXPERIMENTAL DESIGN: These two subtypes are distinguished by the activity of NF-κB in tumors. We first developed a DNA-based marker panel consisting of genes that when mutated would lead to NF-κB activation. Additionally, we developed a custom Nanostring assay to determine the expression of NF-κB target genes. These assays were tested to determine their accuracy in detecting tumor subtype. RESULTS: We demonstrate that the NF-κB gene signature score, as determined using the nanostring assay, could more accurately classify HPV+ HNSCC as compared to the DNA-based marker panel. Patients with a high NF-κB gene signature score demonstrated significantly increased overall survival, indicating more sensitivity to (chemo)radiation treatment. CONCLUSIONS: The NF-κB gene signature score can accurately predict response to standard (chemo)radiation in HPV+ HNSCC. This molecular biomarker holds promise for clinical use in identifying patients who are likely to benefit from treatment de-escalation strategies, potentially reducing long-term side effects without compromising therapeutic efficacy.

Clinical Cancer Research
University of North Carolina at Chapel Hill (US), University of Parma (IT), United States Food and Drug Administration (US), Center for Drug Evaluation and Research (US), Harvard University (US), Medical University of South Carolina (US), Harvard University Press (US), Yale University (US), University of Massachusetts Boston (US), Amsterdam Neuroscience (NL), University Hospitals Seidman Cancer Center (US), University of North Carolina Hospitals (US), Dana-Farber/Harvard Cancer Center (US), Amsterdam University Medical Centers (NL), Fondazione IRCCS Istituto Nazionale dei Tumori (IT), Dana-Farber Brigham Cancer Center (US), Heinrich Heine University Düsseldorf (DE), Case Western Reserve University (US), Vrije Universiteit Amsterdam (NL)
Good health and well-being
Openalex Percentile: Top 32%
Head and Neck Cancer Studies
DOIOpen Access PDFOpenAlex
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