Abstract 96: Real time multimodal ctDNA and imaging assessment enables adaptive treatment in HPV related oropharyngeal cancer.

Abstract Purpose: Circulating tumor DNA (ctDNA) has emerged as a sensitive biomarker for minimal residual disease detection, but its potential for real-time adaptation during curative therapy remains unexplored. Integrating ctDNA dynamics with imaging could enable more precise, risk-adapted treatment modifications beyond current radiological monitoring alone. HPV-associated oropharyngeal cancer (OPC) presents an ideal context given high cure rates, active treatment de-escalation efforts, and protracted chemoradiation courses allowing mid-treatment adaptation. We sought to determine whether longitudinal ctDNA profiling integrated with multimodal MRI could inform response-adapted treatment strategies. Methods: A total of 158 patients with HPV OPC were enrolled on a personalized de-escalation trial (NCT03323463). Blood samples for ctDNA analysis were collected pre-treatment and weekly during therapy, with 980 longitudinal samples obtained from 119 patients over up to 126 weeks (mean 8.2 samples/patient). We developed a dual Personalized Cancer Monitoring (PCM)-HPV ctDNA assay combining patient-specific tumor-informed variant detection (average 47 variants/patient) with probes targeting high-risk HPV subtypes, especially E6 and E7 genes of HPV-16 and HPV-18, both using anchored multiplex PCR (AMP) followed by high-throughput sequencing with Invitae (now Labcorp, San Francisco, CA). Weekly MRIs (T2-weighted) were performed concurrently to determine tumor volume. Results: Integrating somatic mutations with viral ctDNA detection increased baseline ctDNA detection from 80.3% (HPV ctDNA only) and 89.4% (PCM ctDNA only) to 93.9%. Baseline circulating HPV levels correlated with tumor volume, apoptotic signaling, necrosis, and primary tumor viral load (combined R2=0.54). During treatment, ctDNA showed broader dynamic range and faster kinetics than volumetric imaging. Critically, absolute ctDNA fraction at week 2 of treatment predicted patients requiring treatment intensification (p=0.0003). A multimodal model integrating on-treatment ctDNA assessment and imaging improved identification of patients with high-risk disease, surpassing either modality alone. Conclusions: Early on-treatment ctDNA dynamics capture aggressive disease biology during a critical window for adaptation. Multimodal integration of molecular and imaging assessments provides superior risk stratification, demonstrating that they capture complementary biology early in therapy and establishing a framework for real-time treatment personalization. Citation Format: Bill H. Diplas, David N. Brown, Xin Pei, Yingjie Zhu, Achraf Shamseddine, Chiharu Graybill, W. Michael Korn, Emily Westheimer, Luc GT Morris, Richard J. Wong, Sean M. McBride, Alan L. Ho, Heiko Schoder, Eric Sherman, Robert Daber, Nora Katabi, Jorge Reis-Filho, Britta Weigelt, Nancy Lee, Nadeem Riaz. Real time multimodal ctDNA and imaging assessment enables adaptive treatment in HPV related oropharyngeal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 96.