Targeting Molecular Residual Disease Using Novel Technologies and Clinical Trials Design in Head and Neck Squamous Cell Cancer

Abstract High-risk human papillomavirus (HPV)-related and most cases of HPV-negative locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC) have substantial risks of relapse despite definitive therapy, and thus represent conditions of unmet clinical need. The ability now exists to detect molecular residual disease (MRD) in these patients post-definitive treatment such as surgery or (chemo)radiotherapy using novel and highly sensitive and specific technologies to measure cancer-derived circulating biomarkers. The positive and negative predictive values of these assays to forecast cancer recurrence, as well as the lead time of circulating tumor DNA (ctDNA) detection before clinical relapse, are relevant as these parameters rationalize the design of clinical trials for cancer interception in the MRD setting. Currently, there is evidence that interception in the MRD setting yields benefit in clinical outcome in some cancers, but such data do not yet exist in LA-HNSCC and will require prospective testing via clinical trials.