Marret Grégoire, Lamy Constance, Vacher Sophie, Cabel Luc, Séné Mathieu, Ahmanache Ladidi, Courtois Laura, El Beaino Zakhia, Klijanienko Jerzy, Martinat Charlotte, Servant Nicolas, Kamoun Choumouss, Halladjian Maral, Bronzini Thierry, Balsat Cédric, Laes Jean-François, Prévot Aubray, Sauvage Sébastien, Lienard Maxime, Martin Emmanuel, Genin Bérengère, Badois Nathalie, Lesnik Maria, Dubray-Vautrin Antoine, Choussy Olivier, Ghanem Wahib, Taouachi Rabah, Planchon Julien Masliah, Bièche Ivan, Le Tourneau Christophe, Kamal Maud
Department of Drug Development and Innovation (D3i), Institut Curie, Paris-Saclay University, Paris, France.
Genetics Department, Institut Curie, Paris, France.
Oral Oncol. 2025 Jan;160:107111. doi: 10.1016/j.oraloncology.2024.107111. Epub 2024 Nov 29.
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.
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.
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).
ctDNA detection is a useful biomarker for ITH and MRD in resectable HNSCC patients.
头颈部鳞状细胞癌（HNSCC）具有显著的肿瘤内基因异质性（ITH），这可能会阻碍依赖单个肿瘤活检标本结果的精准医学策略。治疗反应评估依赖于放射影像学检查，而放射影像学检查无法检测到微小残留病（MRD）。我们评估了循环肿瘤DNA（ctDNA）作为HNSCC中ITH和MRD生物标志物的相关性。
在前瞻性生物样本库SCANDARE研究（NCT03017573）中，我们招募了41例接受 upfront 根治性手术治疗的非转移性可切除HNSCC患者。31例患者（76%）在中位随访41个月时出现疾病复发。对切除的肿瘤组织以及手术时、术后14周内、6个月时和复发时采集的系列血样进行靶向二代测序。
手术时在21/41例患者中检测到ctDNA（敏感性：51%；95%CI，35 - 67%），复发时在15/22例患者中检测到ctDNA（敏感性：68%；95%置信区间[CI]，45 - 86%）。在纵向血浆样本中鉴定出突变的患者中，3/21例患者（14%）报告了肿瘤组织中遗漏的其他突变，而9/21例患者（43%）报告了新出现的突变。在术后监测中，基于ctDNA的MRD检测在17/27例患者（63%）中预测临床复发的中位提前期为9.9个月（四分位间距，8.0 - 14.5个月）。在术后14周内检测到MRD时，在调整经典预后变量后，MRD与疾病复发相关（HR = 3.0；95%CI，1.1 - 7.9；p = 0.03）。
ctDNA检测是可切除HNSCC患者中ITH和MRD的有用生物标志物。
