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Background <p>The poor prognosis of resectable esophageal squamous cell carcinoma (ESCC) poses an unmet need to identify early predictive and prognostic genomic biomarkers to improve treatment outcome and risk stratification.</p> Methods <p>Mutational profiling was performed for 171 ESCC patients receiving curative neoadjuvant chemoradiation treatment (nCRT). The discovery cohort included 100 ESCC formalin-fixed paraffin-embedded (FFPE) tumor specimens; the validation FFPE cohort consisted of serial ctDNA samples from 71 patients.</p> Results <p>The discovery cohort identified hot-spot oncogenic <i>NFE2L2</i> mutations exclusively localized at DLG and ETGE KEAP1-binding motifs in poor responders associated with incomplete pathological response (<i>P</i> = 0.004). Patients with <i>NFE2L2</i> mutations in two independent FFPE cohorts had about 2-fold higher risk of death and recurrence. Serial ctDNA analysis further demonstrated oncogenic <i>NFE2L2</i> mutations detected at post-nCRT were independent prognosticators for recurrence (HR = 5.90; <i>P</i> = 0.005) and survival (HR = 4.75; <i>P</i> = 0.013). Risk stratification based on pathological T and N stages, positive FFPE (HR = 4.50) and ctDNA <i>NFE2L2</i> mutations (HR = 8.50) identified high-risk groups for recurrence (<i>P</i> = 0.001). Combined FFPE and ctDNA <i>NFE2L2</i> mutation status predicted nCRT responses (<i>P</i> = 0.05) by ROC analysis.</p> Conclusions <p>Tracking oncogenic <i>NFE2L2</i> mutations at pre-treatment and post-surgery or serial ctDNA monitoring during treatment are useful nCRT predictors and independent prognosticators of survival for locally advanced ESCC.</p>

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Oncogenic NFE2L2 mutations in plasma ctDNA and tumors are predictors and prognosticators of chemoradiation therapy in resectable esophageal squamous cell carcinoma

  • 期刊论文

  • 发表日期：

    2025年8月8日

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  • Josephine Mun-Yee Ko,
  • Chen Guo,
  • Alvin Ka-Kiu Leung,
  • Steve Chun-Yin Chan,
  • Anthony Wing-Ip Lo,
  • Lihua Tao,
  • Hoi-Yan Ng,
  • Carissa Wing-Yan Wong,
  • Simon Law,
  • Ian Yu-Hong Wong,
  • Claudia Lai-Yin Wong,
  • Fion Siu-Yin Chan,
  • Kwan Kit Chan,
  • Tsz Ting Law,
  • Ka-On Lam,
  • Dora Lai-Wan Kwong,
  • Wei Dai,
  • Alfred King-Yin Lam,
  • Maria Li Lung

摘要

Background

The poor prognosis of resectable esophageal squamous cell carcinoma (ESCC) poses an unmet need to identify early predictive and prognostic genomic biomarkers to improve treatment outcome and risk stratification.

Methods

Mutational profiling was performed for 171 ESCC patients receiving curative neoadjuvant chemoradiation treatment (nCRT). The discovery cohort included 100 ESCC formalin-fixed paraffin-embedded (FFPE) tumor specimens; the validation FFPE cohort consisted of serial ctDNA samples from 71 patients.

Results

The discovery cohort identified hot-spot oncogenic NFE2L2 mutations exclusively localized at DLG and ETGE KEAP1-binding motifs in poor responders associated with incomplete pathological response (P = 0.004). Patients with NFE2L2 mutations in two independent FFPE cohorts had about 2-fold higher risk of death and recurrence. Serial ctDNA analysis further demonstrated oncogenic NFE2L2 mutations detected at post-nCRT were independent prognosticators for recurrence (HR = 5.90; P = 0.005) and survival (HR = 4.75; P = 0.013). Risk stratification based on pathological T and N stages, positive FFPE (HR = 4.50) and ctDNA NFE2L2 mutations (HR = 8.50) identified high-risk groups for recurrence (P = 0.001). Combined FFPE and ctDNA NFE2L2 mutation status predicted nCRT responses (P = 0.05) by ROC analysis.

Conclusions

Tracking oncogenic NFE2L2 mutations at pre-treatment and post-surgery or serial ctDNA monitoring during treatment are useful nCRT predictors and independent prognosticators of survival for locally advanced ESCC.