Automated imaging-based tumor burden and pre-treatment circulating tumor DNA in HPV-associated oropharynx cancer

Background Artificial intelligence (AI)-based imaging analysis has applications for the diagnosis of head and neck malignancies, and serum circulating tumor-associated DNA (ctDNA) is an emerging biomarker being evaluated for response assessment and risk stratification in human papilloma virus (HPV)-associated oropharynx squamous cell carcinoma (HPV-OPSCC). The relationship between automated imaging biomarkers and ctDNA has not yet been explored.

To test the association between ctDNA and AI-derived measures of tumor burden among patients with HPV-OPSCC. Design, Setting, and Participants This cross-sectional study included patients who were treated with curative intent for HPV-OPSCC between 2020-2023, prospectively enrolled on a blood collection protocol (Clinical trials.gov identifier: NCT04965792). Exposures Clinical factors including demographics, AJCC 8th edition clinical staging, and HPV genotype. Main Outcomes and Measures Pre-treatment serum measurement of circulating tumor-tissue modified viral (TTMV) HPV-DNA using a commercially available test, measured as a continuous value (fragments/mL). Primary tumor and nodal volumes, total tumor volume, and cystic/necrotic nodal volume were generated on pre-treatment diagnostic or radiation CT- planning scans using a prospectively validated AI auto-segmentation algorithm. Assessments of model fit: Akaike information criterion (AIC) and Bayesian information criterion (BIC).

170 patients with HPV-OPSCC were included in the study. On univariable regression, primary tumor volume (coeff=39.43, p<0.001), nodal volume (coeff=39.54, p<0.001), AJCC 8th edition Tumor (T) stage (coeff = 1031.09, p=0.009), Nodal (N) stage (coeff=1840, p=0.018), HPV subtype 16 (coeff=3072.40, p=0.006), and CCI (coeff=-596.60, p=0.038) were associated with ctDNA. Cystic nodal volume was not associated with ctDNA (coeff=0.31, p=0.11). On multivariable analysis, primary tumor and nodal volumes were associated with ctDNA (coeff=34.79, p=0.001 and coeff=24.68, p=0.022, respectively), but T and N stage were not (coeff=-439.28, p=0.37 and coeff=238.19, p=0.29, respectively). Including automated tumor and nodal volumes improved model fit compared to T and N stage alone (3420.96 vs 3435.88 AIC, 3449.18 vs 3457.83 BIC).

and Relevance AI-automated volumetrics on pretreatment imaging are independently associated with ctDNA, controlling for clinical stage. The association is stronger than staging and improved predictive capacity of regression models. AI-automated volumetrics may provide a practical correlate to ctDNA levels and help risk stratify patients. Competing Interest Statement Mina Bakhtiar: No disclosures. Zezhong Ye: No disclosures. Jonathan D. Schoenfeld: grants from Merck, BMS, Regeneron, and Siemens; grants and personal fees from EMD Serono and Debiopharm; and personal fees from Merck KGA, Immmunitas, LEK, ACI Clinical, Intagrel, Stimit, and SIRPant. Homan Mohammadi: No disclosures. Jeffrey P. Guenette: grants from the National Institute of Biomedical Imaging and Bioengineering, and grants from the Agency for Healthcare Research and Quality and Association of Academic Radiology. Eleni M. Rettig: grants from Dunkin' Donuts Drives Cancer Breakthrough Award and nonfinancial support from Naveris. Glenn J. Hanna: personal fees and nonfinancial support from Naveris and Adela. Benjamin H. Kann: No disclosures. Clinical Protocols https://clinicaltrials.gov/study/NCT04965792?term=NCT04965792&rank=1 Funding Statement This study was funded by the National Institutes of Health NIH/NIDCR K08 DE030216 Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was conducted in accordance with the Declaration of Helsinki guidelines and following Mass General Brigham Institutional Review Board approval. The study is reported in accordance with the TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis) guidelines. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors.