The journal of liquid biopsy · 2026
Prognostic utility of copy number variations in circulating tumor DNA in head and neck cancer.
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Sim Edward S, Ruiz-Torres Daniel A, Du Pan, Huang Yong, Zhang Frank, Jia Shidong, Fisch Adam S, Merkin Ross D, Paly Jonathan J, Faden Daniel L
Аннотация
BACKGROUND: Plasma circulating tumor DNA (ctDNA) is a minimally invasive biomarker in head and neck squamous cell carcinoma (HNSCC). Most commercially available assays for human papillomavirus-unrelated HNSCC are tumor-informed assays that require tissue sampling and may not comprehensively capture tumor heterogeneity. We evaluated a tumor-agnostic approach using genome-wide ctDNA copy-number variation (CNV) profiling to derive blood copy-number burden (CNB) for prognostication in non-surgically treated HNSCC.
METHODS: ctDNA was extracted from 250 longitudinal plasma samples from 33 patients and analyzed using PredicineSCORE low-pass whole-genome sequencing (LP-WGS). CNB was dichotomized as positive (CNB+) or negative (CNB-) using a predefined threshold. Associations with overall survival (OS) and progression-free survival (PFS) were assessed with Kaplan-Meier models.
RESULTS: Median age was 63 years; 67% were male; 67% had recurrent/metastatic disease; 15% were HPV-associated. Treatment included chemoradiation (39%) and immune checkpoint blockade-based regimens (60%). The most frequent CNV was 3q gain. Baseline plasma was available for 30 patients, of whom 17 (56%) were CNB+. Baseline CNB+ was associated with inferior OS (HR 4.38, 95% CI 1.22-15.72; p = 0.01) but not PFS (HR 1.41, 95% CI 0.62-3.20; p = 0.41) over a median follow-up of 23.4 months. CNB + at any post-treatment timepoint occurred in 26/33 (79%) and showed a non-significant trend toward worse OS (HR 3.03; p = 0.12) and PFS (HR 2.70; p = 0.06). Detection rates were modest, highlighting potential utility mainly in CNV-high, HPV-independent tumors over time.
CONCLUSIONS: LP-WGS enables tumor-agnostic detection of CNV signals in plasma from non-surgically treated HNSCC, and baseline CNB stratifies OS. Larger, more homogeneous cohorts with matched tumor sequencing are needed to validate ctDNA-derived CNV metrics and define which molecular subtypes benefit most from blood-based CNB detection and monitoring.
LEVEL OF EVIDENCE: 3.
METHODS: ctDNA was extracted from 250 longitudinal plasma samples from 33 patients and analyzed using PredicineSCORE low-pass whole-genome sequencing (LP-WGS). CNB was dichotomized as positive (CNB+) or negative (CNB-) using a predefined threshold. Associations with overall survival (OS) and progression-free survival (PFS) were assessed with Kaplan-Meier models.
RESULTS: Median age was 63 years; 67% were male; 67% had recurrent/metastatic disease; 15% were HPV-associated. Treatment included chemoradiation (39%) and immune checkpoint blockade-based regimens (60%). The most frequent CNV was 3q gain. Baseline plasma was available for 30 patients, of whom 17 (56%) were CNB+. Baseline CNB+ was associated with inferior OS (HR 4.38, 95% CI 1.22-15.72; p = 0.01) but not PFS (HR 1.41, 95% CI 0.62-3.20; p = 0.41) over a median follow-up of 23.4 months. CNB + at any post-treatment timepoint occurred in 26/33 (79%) and showed a non-significant trend toward worse OS (HR 3.03; p = 0.12) and PFS (HR 2.70; p = 0.06). Detection rates were modest, highlighting potential utility mainly in CNV-high, HPV-independent tumors over time.
CONCLUSIONS: LP-WGS enables tumor-agnostic detection of CNV signals in plasma from non-surgically treated HNSCC, and baseline CNB stratifies OS. Larger, more homogeneous cohorts with matched tumor sequencing are needed to validate ctDNA-derived CNV metrics and define which molecular subtypes benefit most from blood-based CNB detection and monitoring.
LEVEL OF EVIDENCE: 3.