Clinical validation of a tissue-agnostic genome-wide methylome enrichment MRD assay for head and neck malignancies
Menée à partir de 1 155 échantillons plasmatiques prélevés au diagnostic ou après traitement sur 325 patients atteints d'un cancer de la tête et du cou de stade I à IVB (durée médiane de suivi : 60 mois), cette étude évalue la performance d'un système de classification, basé sur l'analyse du méthylome de l'ADN tumoral circulant, pour détecter une maladie résiduelle moléculaire et prédire la survie sans récidive
Background : Outcomes for patients with locally advanced head and neck cancer (HNC) treated with curative intent remain disappointing, with 5-year survival rates at 50%. Most recurrences occur within the first two years after treatment, providing a window of opportunity to identify patients with molecular residual disease (MRD). A tissue agnostic test for MRD detection in HNC, where tissue is often scarce, and suitable for HPV-positive and HPV-negative patients, is needed.
Patients and methods : Patients with stage I-IVB HNC, including HPV-positive and HPV-negative patients, were enrolled and peripheral blood plasma was collected longitudinally at diagnosis and approximately 3, 12, and 24 months after curative intent treatment. The full cohort includes 325 patients with 1,155 samples. Samples were split into distinct sets to train and validate a classifier capable of identifying MRD using a tissue-agnostic genome-wide methylome enrichment platform. The primary endpoint was recurrence-free survival (RFS).
Results : With a median follow-up of 60 months, patients in the blinded validation set with MRD positivity experienced significantly worse RFS with a hazard ratio (HR) of 35.7; 95% CI, 10.8 - 117.8; P < 0.0001. For HPV-negative patients, HR was 42.3; 95% CI, 9.8 – 182.3; P < 0.0001; for HPV-positive oropharyngeal cancer patients, HR was 24.1; 95% CI, 3.0 - 196.87; P < 0.0001. Moreover, the lead time between MRD positivity and clinical recurrence was up to 14.9 months, with a mean lead time of 4.1 months. Surveillance sensitivity was 91% (95% CI, 77% - 97%), specificity was 88% (95% CI, 80% - 93%).
Conclusions : Here we validate the clinical performance characteristics of a tissue-agnostic genome-wide methylome enrichment assay for MRD detection in HNC patients. The test showed high sensitivity for MRD detection across different anatomical sites, HPV status and treatment regimens, highlighting the broad applicability for MRD detection in HNC patients.
Annals of Oncology , article en libre accès, 2023