Deciphering molecular relapse and intra-tumor heterogeneity in non-metastatic resectable head and neck squamous cell carcinoma using circulating tumor DNA

Abstract

Objectives

Head and neck squamous cell carcinoma (HNSCC) is characterized by significant genetic intra-tumor heterogeneity (ITH), which may hinder precision medicine strategies that depend on results from single tumor-biopsy specimens. Treatment response assessment relies on radiologic imaging, which cannot detect minimal residual disease (MRD). We assessed the relevance of circulating tumor DNA (ctDNA) as a biomarker for ITH and MRD in HNSCC.

Materials and methods

We recruited 41 non-metastatic resectable HNSCC patients treated with upfront curative-intent surgery in the prospective biobanking SCANDARE study (NCT03017573). Thirty-one patients (76 %) showed recurrent disease at a median follow-up of 41 months. Targeted next-generation sequencing was performed on resected tumor tissues, as well as on serial blood samples obtained at surgery, within 14 weeks after surgery, at six months and at recurrence.

Results

ctDNA was detected in 21/41 patients at surgery (sensitivity: 51 %; 95 % CI, 35–67 %) and 15/22 patients at recurrence (sensitivity: 68 %; 95 % confidence interval [CI], 45–86 %). Among patients with mutations identified in longitudinal plasma samples, additional mutations missed in tumor tissues were reported in 3/21 patients (14 %), while emerging mutations were reported in 9/21 patients (43 %). In the postoperative surveillance setting, ctDNA-based MRD detection anticipated clinical recurrence with a median lead-time of 9.9 months (interquartile range, 8.0–14.5 months) in 17/27 patients (63 %). When detected within 14 weeks after surgery, MRD correlated with disease recurrence after adjusting for classical prognostic variables (HR = 3.0; 95 % CI, 1.1–7.9; p = 0.03).

Conclusions

ctDNA detection is a useful biomarker for ITH and MRD in resectable HNSCC patients.