Prospective Trial Evaluating Post-operative Human Papilloma Virus Circulating Tumor DNA Guided Adjuvant Therapy for Human Papilloma Virus-related Oropharyngeal Carcinoma (PATH study): HPV ctDNA Guided Adjuvant therapy in OPC

Linda Chen; Marc Cohen; Vaios Hatzglou; Zhigang Zhang; Nadeem Riaz; Achraf A Shamseddine; Luc G T Morris; Sean M McBride; Daphna Y Gelblum; Kaveh Zakeri; Yao Yu; Ian Ganly; Jennifer Cracchiolo; Richard J Wong; Noah S Kalman; Andrew B Tassler; David Kutler; Winston Wong; Anuja Kriplani; Lara Dunn; Alan L Ho; Loren S Michel; James Fetten; David G Pfister; Nora Katabi; Eric J Sherman; Nancy Y Lee

doi:10.1016/j.ijrobp.2025.09.044

Prospective Trial Evaluating Post-operative Human Papilloma Virus Circulating Tumor DNA Guided Adjuvant Therapy for Human Papilloma Virus-related Oropharyngeal Carcinoma (PATH study): HPV ctDNA Guided Adjuvant therapy in OPC

Linda Chen
, Marc Cohen
, Vaios Hatzglou
, Zhigang Zhang
, Nadeem Riaz
, Achraf A Shamseddine
, Luc G T Morris
, Sean M McBride
, Daphna Y Gelblum
, Kaveh Zakeri
, Yao Yu
, Ian Ganly
, Jennifer Cracchiolo
, Richard J Wong
, Noah S Kalman
, Andrew B Tassler
, David Kutler
, Winston Wong
, Anuja Kriplani
, Lara Dunn

Alan L Ho, Loren S Michel, James Fetten, David G Pfister, Nora Katabi, Eric J Sherman, Nancy Y Lee

Research output: Contribution to journal › Article › peer-review

Abstract

UNLABELLED: Human papillomavirus circulating tumor DNA (HPV ctDNA) is a biomarker which detects minimal residual disease (MRD) for HPV-associated oropharyngeal carcinoma (HPV+ OPC).

PURPOSE: We conducted the first prospective study using HPV ctDNA as an integral biomarker to select patients for post-operative radiotherapy omission. We tested the hypothesis that undetectable post-operative HPV ctDNA can be used to omit or delay adjuvant radiation until patients develop detectable HPV ctDNA using the NavDx (Naveris, Inc.) tumor-tissue-modified viral (TTMV) HPV DNA score. Eligible HPV+ OPC patients had a preoperative TTMV-HPV DNA Score of ³50 and at least one pathologic risk factor to warrant standard adjuvant radiotherapy.

METHODS AND MATERIALS: Post-operatively, eligible patients had no evidence of disease on post-operative MRI and two negative TTMV-HPV DNA test results. Patients with non-HPV-16 genotype, positive margins, and extranodal extension were excluded. Patients were monitored with TTMV-HPV DNA testing, imaging, and physical exams. Delayed adjuvant radiation was initiated if patients developed detectable TTMV-HPV DNA without radiographic recurrence. The primary endpoint was the proportion of patients without gross recurrent disease.

RESULTS: Fifty-five HPV+ OPC patients were screened; 12 patients were enrolled. The median follow-up was 26.6 months (Range: 18.3-40.3). One patient (8%) developed detectable HPV ctDNA 6 months after surgery without evidence of recurrence and was treated with delayed adjuvant radiotherapy. Three additional patients (25%) developed radiographic recurrence 6 months after surgery. Radiographic recurrence was not preceded by detectable TTMV-HPV DNA. TTMV-HPV DNA detection was synchronous with radiographically evident disease in 2 of 3 patients. Recurrence was associated with N2b disease pre-treatment (p=0.01). The high gross recurrence rate (3 of 12 patients) led to closure of this cohort due to a pre-specified stopping rule.

CONCLUSION: Deferring adjuvant radiotherapy based on HPV ctDNA using NavDx TTMV-HPV DNA testing resulted in a high rate of disease recurrence.

Original language	English
Journal	International Journal of Radiation Oncology, Biology, Physics
DOIs	https://doi.org/10.1016/j.ijrobp.2025.09.044
State	E-pub ahead of print - Oct 1 2025
Externally published	Yes

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10.1016/j.ijrobp.2025.09.044

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Chen, L., Cohen, M., Hatzglou, V., Zhang, Z., Riaz, N., Shamseddine, A. A., Morris, L. G. T., McBride, S. M., Gelblum, D. Y., Zakeri, K., Yu, Y., Ganly, I., Cracchiolo, J., Wong, R. J., Kalman, N. S., Tassler, A. B., Kutler, D., Wong, W., Kriplani, A., ... Lee, N. Y. (2025). Prospective Trial Evaluating Post-operative Human Papilloma Virus Circulating Tumor DNA Guided Adjuvant Therapy for Human Papilloma Virus-related Oropharyngeal Carcinoma (PATH study): HPV ctDNA Guided Adjuvant therapy in OPC. International Journal of Radiation Oncology, Biology, Physics. Advance online publication. https://doi.org/10.1016/j.ijrobp.2025.09.044

Prospective Trial Evaluating Post-operative Human Papilloma Virus Circulating Tumor DNA Guided Adjuvant Therapy for Human Papilloma Virus-related Oropharyngeal Carcinoma (PATH study): HPV ctDNA Guided Adjuvant therapy in OPC. / Chen, Linda; Cohen, Marc; Hatzglou, Vaios et al.
In: International Journal of Radiation Oncology, Biology, Physics, 01.10.2025.

Research output: Contribution to journal › Article › peer-review

Chen, L, Cohen, M, Hatzglou, V, Zhang, Z, Riaz, N, Shamseddine, AA, Morris, LGT, McBride, SM, Gelblum, DY, Zakeri, K, Yu, Y, Ganly, I, Cracchiolo, J, Wong, RJ, Kalman, NS, Tassler, AB, Kutler, D, Wong, W, Kriplani, A, Dunn, L, Ho, AL, Michel, LS, Fetten, J, Pfister, DG, Katabi, N, Sherman, EJ & Lee, NY 2025, 'Prospective Trial Evaluating Post-operative Human Papilloma Virus Circulating Tumor DNA Guided Adjuvant Therapy for Human Papilloma Virus-related Oropharyngeal Carcinoma (PATH study): HPV ctDNA Guided Adjuvant therapy in OPC', International Journal of Radiation Oncology, Biology, Physics. https://doi.org/10.1016/j.ijrobp.2025.09.044

Chen L, Cohen M, Hatzglou V, Zhang Z, Riaz N, Shamseddine AA et al. Prospective Trial Evaluating Post-operative Human Papilloma Virus Circulating Tumor DNA Guided Adjuvant Therapy for Human Papilloma Virus-related Oropharyngeal Carcinoma (PATH study): HPV ctDNA Guided Adjuvant therapy in OPC. International Journal of Radiation Oncology, Biology, Physics. 2025 Oct 1. Epub 2025 Oct 1. doi: 10.1016/j.ijrobp.2025.09.044

@article{90725c2fab44456bbdcb8076f4eaf8df,

title = "Prospective Trial Evaluating Post-operative Human Papilloma Virus Circulating Tumor DNA Guided Adjuvant Therapy for Human Papilloma Virus-related Oropharyngeal Carcinoma (PATH study): HPV ctDNA Guided Adjuvant therapy in OPC",

abstract = "UNLABELLED: Human papillomavirus circulating tumor DNA (HPV ctDNA) is a biomarker which detects minimal residual disease (MRD) for HPV-associated oropharyngeal carcinoma (HPV+ OPC).PURPOSE: We conducted the first prospective study using HPV ctDNA as an integral biomarker to select patients for post-operative radiotherapy omission. We tested the hypothesis that undetectable post-operative HPV ctDNA can be used to omit or delay adjuvant radiation until patients develop detectable HPV ctDNA using the NavDx (Naveris, Inc.) tumor-tissue-modified viral (TTMV) HPV DNA score. Eligible HPV+ OPC patients had a preoperative TTMV-HPV DNA Score of ³50 and at least one pathologic risk factor to warrant standard adjuvant radiotherapy.METHODS AND MATERIALS: Post-operatively, eligible patients had no evidence of disease on post-operative MRI and two negative TTMV-HPV DNA test results. Patients with non-HPV-16 genotype, positive margins, and extranodal extension were excluded. Patients were monitored with TTMV-HPV DNA testing, imaging, and physical exams. Delayed adjuvant radiation was initiated if patients developed detectable TTMV-HPV DNA without radiographic recurrence. The primary endpoint was the proportion of patients without gross recurrent disease.RESULTS: Fifty-five HPV+ OPC patients were screened; 12 patients were enrolled. The median follow-up was 26.6 months (Range: 18.3-40.3). One patient (8\%) developed detectable HPV ctDNA 6 months after surgery without evidence of recurrence and was treated with delayed adjuvant radiotherapy. Three additional patients (25\%) developed radiographic recurrence 6 months after surgery. Radiographic recurrence was not preceded by detectable TTMV-HPV DNA. TTMV-HPV DNA detection was synchronous with radiographically evident disease in 2 of 3 patients. Recurrence was associated with N2b disease pre-treatment (p=0.01). The high gross recurrence rate (3 of 12 patients) led to closure of this cohort due to a pre-specified stopping rule.CONCLUSION: Deferring adjuvant radiotherapy based on HPV ctDNA using NavDx TTMV-HPV DNA testing resulted in a high rate of disease recurrence.",

author = "Linda Chen and Marc Cohen and Vaios Hatzglou and Zhigang Zhang and Nadeem Riaz and Shamseddine, \{Achraf A\} and Morris, \{Luc G T\} and McBride, \{Sean M\} and Gelblum, \{Daphna Y\} and Kaveh Zakeri and Yao Yu and Ian Ganly and Jennifer Cracchiolo and Wong, \{Richard J\} and Kalman, \{Noah S\} and Tassler, \{Andrew B\} and David Kutler and Winston Wong and Anuja Kriplani and Lara Dunn and Ho, \{Alan L\} and Michel, \{Loren S\} and James Fetten and Pfister, \{David G\} and Nora Katabi and Sherman, \{Eric J\} and Lee, \{Nancy Y\}",

note = "Copyright {\textcopyright} 2025. Published by Elsevier Inc.",

year = "2025",

month = oct,

day = "1",

doi = "10.1016/j.ijrobp.2025.09.044",

language = "English",

journal = "International Journal of Radiation Oncology, Biology, Physics",

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TY - JOUR

T1 - Prospective Trial Evaluating Post-operative Human Papilloma Virus Circulating Tumor DNA Guided Adjuvant Therapy for Human Papilloma Virus-related Oropharyngeal Carcinoma (PATH study)

T2 - HPV ctDNA Guided Adjuvant therapy in OPC

AU - Chen, Linda

AU - Cohen, Marc

AU - Hatzglou, Vaios

AU - Zhang, Zhigang

AU - Riaz, Nadeem

AU - Shamseddine, Achraf A

AU - Morris, Luc G T

AU - McBride, Sean M

AU - Gelblum, Daphna Y

AU - Zakeri, Kaveh

AU - Yu, Yao

AU - Ganly, Ian

AU - Cracchiolo, Jennifer

AU - Wong, Richard J

AU - Kalman, Noah S

AU - Tassler, Andrew B

AU - Kutler, David

AU - Wong, Winston

AU - Kriplani, Anuja

AU - Dunn, Lara

AU - Ho, Alan L

AU - Michel, Loren S

AU - Fetten, James

AU - Pfister, David G

AU - Katabi, Nora

AU - Sherman, Eric J

AU - Lee, Nancy Y

PY - 2025/10/1

Y1 - 2025/10/1

N2 - UNLABELLED: Human papillomavirus circulating tumor DNA (HPV ctDNA) is a biomarker which detects minimal residual disease (MRD) for HPV-associated oropharyngeal carcinoma (HPV+ OPC).PURPOSE: We conducted the first prospective study using HPV ctDNA as an integral biomarker to select patients for post-operative radiotherapy omission. We tested the hypothesis that undetectable post-operative HPV ctDNA can be used to omit or delay adjuvant radiation until patients develop detectable HPV ctDNA using the NavDx (Naveris, Inc.) tumor-tissue-modified viral (TTMV) HPV DNA score. Eligible HPV+ OPC patients had a preoperative TTMV-HPV DNA Score of ³50 and at least one pathologic risk factor to warrant standard adjuvant radiotherapy.METHODS AND MATERIALS: Post-operatively, eligible patients had no evidence of disease on post-operative MRI and two negative TTMV-HPV DNA test results. Patients with non-HPV-16 genotype, positive margins, and extranodal extension were excluded. Patients were monitored with TTMV-HPV DNA testing, imaging, and physical exams. Delayed adjuvant radiation was initiated if patients developed detectable TTMV-HPV DNA without radiographic recurrence. The primary endpoint was the proportion of patients without gross recurrent disease.RESULTS: Fifty-five HPV+ OPC patients were screened; 12 patients were enrolled. The median follow-up was 26.6 months (Range: 18.3-40.3). One patient (8%) developed detectable HPV ctDNA 6 months after surgery without evidence of recurrence and was treated with delayed adjuvant radiotherapy. Three additional patients (25%) developed radiographic recurrence 6 months after surgery. Radiographic recurrence was not preceded by detectable TTMV-HPV DNA. TTMV-HPV DNA detection was synchronous with radiographically evident disease in 2 of 3 patients. Recurrence was associated with N2b disease pre-treatment (p=0.01). The high gross recurrence rate (3 of 12 patients) led to closure of this cohort due to a pre-specified stopping rule.CONCLUSION: Deferring adjuvant radiotherapy based on HPV ctDNA using NavDx TTMV-HPV DNA testing resulted in a high rate of disease recurrence.

AB - UNLABELLED: Human papillomavirus circulating tumor DNA (HPV ctDNA) is a biomarker which detects minimal residual disease (MRD) for HPV-associated oropharyngeal carcinoma (HPV+ OPC).PURPOSE: We conducted the first prospective study using HPV ctDNA as an integral biomarker to select patients for post-operative radiotherapy omission. We tested the hypothesis that undetectable post-operative HPV ctDNA can be used to omit or delay adjuvant radiation until patients develop detectable HPV ctDNA using the NavDx (Naveris, Inc.) tumor-tissue-modified viral (TTMV) HPV DNA score. Eligible HPV+ OPC patients had a preoperative TTMV-HPV DNA Score of ³50 and at least one pathologic risk factor to warrant standard adjuvant radiotherapy.METHODS AND MATERIALS: Post-operatively, eligible patients had no evidence of disease on post-operative MRI and two negative TTMV-HPV DNA test results. Patients with non-HPV-16 genotype, positive margins, and extranodal extension were excluded. Patients were monitored with TTMV-HPV DNA testing, imaging, and physical exams. Delayed adjuvant radiation was initiated if patients developed detectable TTMV-HPV DNA without radiographic recurrence. The primary endpoint was the proportion of patients without gross recurrent disease.RESULTS: Fifty-five HPV+ OPC patients were screened; 12 patients were enrolled. The median follow-up was 26.6 months (Range: 18.3-40.3). One patient (8%) developed detectable HPV ctDNA 6 months after surgery without evidence of recurrence and was treated with delayed adjuvant radiotherapy. Three additional patients (25%) developed radiographic recurrence 6 months after surgery. Radiographic recurrence was not preceded by detectable TTMV-HPV DNA. TTMV-HPV DNA detection was synchronous with radiographically evident disease in 2 of 3 patients. Recurrence was associated with N2b disease pre-treatment (p=0.01). The high gross recurrence rate (3 of 12 patients) led to closure of this cohort due to a pre-specified stopping rule.CONCLUSION: Deferring adjuvant radiotherapy based on HPV ctDNA using NavDx TTMV-HPV DNA testing resulted in a high rate of disease recurrence.

U2 - 10.1016/j.ijrobp.2025.09.044

DO - 10.1016/j.ijrobp.2025.09.044

M3 - Article

C2 - 41043558

SN - 0360-3016

JO - International Journal of Radiation Oncology, Biology, Physics

JF - International Journal of Radiation Oncology, Biology, Physics

ER -