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Location: Marriott Marquis
Location: Marriott Marquis
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Main Session

SS 37 - H&N 1: Envisioning the Future: Leading Edge Research in HPV-Associated Oropharyngeal Cancer

315 - HPV-Seq is Prognostic in p16-Positive Oropharyngeal Cancer (OPC): Independent Validation on a Large Prospective Cohort and a Secondary Analysis of NRG-HN002

Tuesday, October 1, 2024
4:30 PM – 4:40 PM ET
Location: Room 145
E. Y. Stutheit-Zhao1, J. Harris2, J. Zou1, Z. Zhao1, Y. Zheng1, S. A. Koyfman3, J. Chan4, M. W. McDonald5, P. Lang6, D. Blakaj7, R. Banerjee8, M. R. Young9, S. H. Huang10, K. Han1, J. N. Waldron1, R. Jordan11, P. Torres-Saavedra12, Q. T. Le13, S. S. Yom11, and S. Bratman1; 1Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, 2American College of Radiology, Philadelphia, PA, 3Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, 4University of California San Francisco, Department of Radiation Oncology, San Francisco, CA, 5Winship Cancer Institute of Emory University, Atlanta, GA, 6Department of Radiation Oncology, London Health Sciences Centre, London, ON, Canada, 7Ohio State University, Columbus, OH, 8Tom Baker Cancer Centre, Calgary, AB, Canada, 9Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, 10Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada, 11University of California San Francisco, San Francisco, CA, 12Biometric Research Program, Division of Cancer Treatment and Diagnosis, NCI, Bethesda, MD, 13Stanford University, Stanford, CA

Purpose/Objective(s): HPV circulating tumor DNA (ctDNA) is a liquid biopsy biomarker that could evaluate treatment response and risk stratify patients after (chemo)radiotherapy ([C]RT). However, HPV ctDNA is undetectable at baseline in up to 15% of pts and needs prospective validation. HPV next-generation sequencing (HPV-seq) offers both genotyping and ultrasensitive quantification of HPV ctDNA. We validated HPV-seq, testing pre-specified hypotheses: (1) pre-RT HPV ctDNA correlates with gross tumor volume (GTV); (2) undetectable post-RT HPV ctDNA predicts favorable 2-year locoregional control (LRC) and progression-free survival (PFS). Materials/Methods: We analyzed pre- and post-RT HPV ctDNA in 2 cohorts of non-metastatic p16+ OPC. Cohort 1 (n=237): single-institution prospective study, standard RT/CRT; HPV ctDNA at pre-RT and ~3 mo post-RT. Cohort 2 (n=126): secondary endpoint of NRG-HN002, a phase II trial of low-risk p16+ OPC (AJCC 7e T1-T2 N1-N2b or T3 N0-N2b, =10 pack-year) randomized to de-escalated RT vs. CRT to 60 Gy; HPV ctDNA at pre-RT and ~4 wk post-RT. HPV ctDNA was measured by HPV-seq, targeting 38 HPV types. Correlations were assessed by Spearman coefficient (r). Associations with LRC/PFS were assessed by Fisher exact test (2-sided a=0.05). Results: Pre-RT HPV ctDNA was detected in 228/237 (96.2%) of Cohort 1 and 126/126 (100%) of Cohort 2 (range: 0.2 to 408147 copies/mL). Across both cohorts, dominant HPV types were HPV-16 (87.1%), 33 (5.0%), 35 (4.8%), 18 (2.0%), 26 (0.6%), 38 (0.3%), and 59 (0.3%). Pre-RT HPV ctDNA was correlated with GTV in both Cohort 1 (r=0.46 [0.34, 0.56]) and Cohort 2 (r=0.25 [0.08, 0.41]). In a multivariable model, baseline HPV ctDNA was associated with N category in both Cohort 1 (p<0.001) and Cohort 2 (p=0.0125) and not with T category or site (tonsil vs. other). At post-RT, HPV ctDNA clearance occurred in 189/237 (79.7% [74.2-84.4]) in Cohort 1 and 88/126 (69.8% [61.3, 77.2]) in Cohort 2. Pts who demonstrated post-RT HPV ctDNA clearance had better 2-yr LRC and PFS (Table) with negative predictive value (NPV) > 96% for LRC and > 94% for PFS. Conclusion: This study provides prospective clinical validation of the prognostic value of HPV-seq in two high quality independent cohorts. Pre-RT HPV ctDNA was detected in >96% of pts with p16+ OPC and correlated with GTV and N-category. Post-RT HPV ctDNA clearance was associated with favorable outcomes. Cohort 1 showed more clearance and stronger association with LRC and PFS, possibly due to test timing (3 vs. 1 month post-RT) and sample size. Abstract 315 – Table 1
2-yr LRC 2-yr PFS
Post-RT HPV ctDNA Non-event Event Non-event Event
Cohort 1 n 210 12 198 33
Cleared 178 (98%) 4 (2%) 174 (94%) 11 (6%)
Detected 32 (80%) 8 (20%) 24 (52%) 22 (48%)
p-value < 0.001 < 0.001
NPV 97.8% [94.5-99.1] 94.1% [89.7-96.6]
Cohort 2 n 117 8 115 10
Cleared 84 (97%) 3 (3%) 83 (95%) 4 (5%)
Detected 33 (87%) 5 (13%) 32 (84%) 6 (16%)
p-value 0.0550 0.0659
NPV 96.6% [90.3-99.3] 95.4% [88.6-98.7]