Early circulating tumor DNA changes predict outcomes in head and neck cancer patients under re‐radiotherapy

• Published in: International journal of cancer 2025-02, Vol.156 (4), p.853-864
• Main Authors: Janke, Florian, Stritzke, Florian, Dvornikovich, Katharina, Franke, Henrik, Angeles, Arlou Kristina, Riediger, Anja Lisa, Ogrodnik, Simon, Gerhardt, Sabrina, Regnery, Sebastian, Schröter, Philipp, Bauer, Lukas, Weusthof, Katharina, Görtz, Magdalena, Harrabi, Semi, Herfarth, Klaus, Neelsen, Christian, Paech, Daniel, Schlemmer, Heinz‐Peter, Abdollahi, Amir, Adeberg, Sebastian, Debus, Jürgen, Sültmann, Holger, Held, Thomas
• Format: Article
• Language: English
• Subjects: Adult; Aged; Biomarkers; Biomarkers, Tumor - blood; Biomarkers, Tumor - genetics; circulating tumor DNA; Circulating Tumor DNA - blood; Circulating Tumor DNA - genetics; Copy number; copy number variations; Disease control; Disease Progression; DNA Copy Number Variations; DNA fingerprinting; DNA sequencing; Female; Head & neck cancer; Head and neck; head and neck cancer; Head and Neck Neoplasms - blood; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - mortality; Head and Neck Neoplasms - radiotherapy; Humans; Male; Middle Aged; Neoplasm Recurrence, Local - blood; Neoplasm Recurrence, Local - genetics; Observational studies; Patients; Plasma; predictive biomarker; Prognosis; Radiation therapy; Re-Irradiation - methods; RESEARCH ARTICLE; re‐radiotherapy; Tumors; Whole genome sequencing
• ISSN: 0020-7136; 1097-0215; 1097-0215
• DOI: 10.1002/ijc.35152

Local recurrence after radiotherapy is common in locally advanced head and neck cancer (HNC) patients. Re‐irradiation can improve local disease control, but disease progression remains frequent. Hence, predictive biomarkers are needed to adapt treatment intensity to the patient's individual risk. We quantified circulating tumor DNA (ctDNA) in sequential plasma samples and correlated ctDNA levels with disease outcome. Ninety four longitudinal plasma samples from 16 locally advanced HNC patients and 57 healthy donors were collected at re‐radiotherapy baseline, after 5 and 10 radiation fractions, at irradiation end, and at routine follow‐up visits. Plasma DNA was subjected to low coverage whole genome sequencing for copy number variation (CNV) profiling to quantify ctDNA burden. CNV‐based ctDNA burden was detected in 8/16 patients and 25/94 plasma samples. Ten additional ctDNA‐positive samples were identified by tracking patient‐specific CNVs found in earlier sequential plasma samples. ctDNA‐positivity after 5 and 10 radiation fractions (both: log‐rank, p = .050) as well as at the end of irradiation correlated with short progression‐free survival (log‐rank, p = .006). Moreover, a pronounced decrease of ctDNA toward re‐radiotherapy termination was associated with worse treatment outcome (log‐rank, p = .005). Dynamic ctDNA tracking in serial plasma beyond re‐radiotherapy reflected treatment response and imminent disease progression. In five patients, molecular progression was detected prior to tumor progression based on clinical imaging. Our findings emphasize that quantifying ctDNA during re‐radiotherapy may contribute to disease monitoring and personalization of adjuvant treatment, follow‐up intervals, and dose prescription. What's new? Head and neck cancer frequently returns after radiation therapy, and re‐irradiation is commonly used to control locally advanced disease. Here, the authors analyzed circulating tumor DNA (ctDNA) as a predictive marker of disease progression after initial radiation treatment. They tested plasma samples from 16 patients at four timepoints during re‐irradiation and at follow‐up visits. In five cases, molecular progression was detected before tumor progression based on imaging. Detection of ctDNA in plasma samples during and after re‐irradiation correlated with short progression‐free survival. Quantitative ctDNA analysis may therefore be an effective way to monitor disease progression and personalize follow‐up treatment.