Neoadjuvant ctDNA-MRD monitoring uncovers occult progression despite radiologic response in locally advanced hypopharyngeal carcinoma: a case report

Background The assessment of treatment response during neoadjuvant therapy for head and neck squamous cell carcinoma (HNSCC) relies largely on radiographic and endoscopic evaluations, which may fail to detect minimal residual disease (MRD). Circulating tumor DNA (ctDNA)-based MRD monitoring has emerged as a sensitive biomarker capable of revealing molecular disease activity that is not captured by imaging. Evidence supporting its use in the neoadjuvant setting of HNSCC remains limited. Case presentation We report a 53-year-old man with locally advanced hypopharyngeal squamous cell carcinoma (cT4N2cM0) who received three cycles of neoadjuvant immunochemotherapy (toripalimab, cisplatin, and nab-paclitaxel). Radiologic and endoscopic assessment demonstrated a partial response with a 71.6% reduction in tumor burden and near-complete mucosal normalization. In contrast, ctDNA-MRD analysis showed elevated ctDNA levels compared with baseline, indicating molecular progression. Despite the favorable imaging response, the patient developed new distant metastases three months after definitive chemoradiotherapy and maintenance immunotherapy, confirming systemic disease progression. Discussion This case highlights the limitations of imaging in differentiating true tumor regression from residual disease during neoadjuvant therapy. Persistent ctDNA-MRD despite radiologic remission may signal occult progression and could influence critical treatment decisions, including the choice between surgery, chemoradiation, or systemic intensification. Accumulating evidence from other tumor types suggests that MRD clearance may predict pathological complete response (pCR), raising the possibility that accurate molecular assessment could help identify patients who may safely avoid surgery. However, MRD applications in neoadjuvant HNSCC—particularly hypopharyngeal carcinoma—remain sparsely studied. Conclusion ctDNA-MRD may provide complementary and potentially earlier insights into treatment response compared with imaging alone. Its incorporation into neoadjuvant strategies for HNSCC warrants further investigation and may ultimately support more personalized and accurate therapeutic decision-making.