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<p>In stage 2–3 colon cancer (CC), postsurgery circulating tumor DNA (ctDNA) assessment is crucial for guiding adjuvant chemotherapy (ACT) decisions. While existing assays detect ctDNA and help identify high-risk persons with CC for recurrence, their limited sensitivity after surgery poses challenges in deciding on ACT. Additionally, a substantial portion of persons with CC fail to clear ctDNA after ACT, leading to recurrence. In this study, we performed whole-exome sequencing (WES) of ctDNA at different time points in participants with relapsed CC in two independent cohorts, alongside transcriptomic and proteomic analyses of metastases, to enhance comprehension of progression mechanisms. A plasma WES-based tumor-agnostic assay demonstrated higher sensitivity in detecting minimal residual disease (MRD) compared to current assays. Immune evasion appears to be the primary driver of progression in the localized CC setting, indicating the potential efficacy of immunotherapy for microsatellite stability in persons with CC. Organoid modeling further supports the promising potential of targeted therapy in eradicating MRD, surpassing conventional treatments.</p>

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Whole-exome tumor-agnostic ctDNA analysis enhances minimal residual disease detection and reveals relapse mechanisms in localized colon cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月29日

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  • Jorge Martín-Arana,
  • Francisco Gimeno-Valiente,
  • Tenna Vesterman Henriksen,
  • Blanca García-Micó,
  • Belén Martínez-Castedo,
  • Valentina Gambardella,
  • Carolina Martínez-Ciarpaglini,
  • Brenda Palomar,
  • Marisol Huerta,
  • Daniel G. Camblor,
  • Miguel García Bartolomé,
  • Juan Antonio Carbonell-Asins,
  • Amanda Frydendahl,
  • Kåre Andersson Gotchalck,
  • Tania Fleitas,
  • Roberto Tébar-Martínez,
  • David Moro,
  • Vicente Pla,
  • Leticia Pérez-Santiago,
  • José Martín-Arévalo,
  • David Casado,
  • Stephanie García-Botello,
  • Alejandro Espí,
  • Susana Roselló,
  • Desamparados Roda,
  • Claus Lindbjerg Andersen,
  • Andrés Cervantes,
  • Noelia Tarazona

摘要

In stage 2–3 colon cancer (CC), postsurgery circulating tumor DNA (ctDNA) assessment is crucial for guiding adjuvant chemotherapy (ACT) decisions. While existing assays detect ctDNA and help identify high-risk persons with CC for recurrence, their limited sensitivity after surgery poses challenges in deciding on ACT. Additionally, a substantial portion of persons with CC fail to clear ctDNA after ACT, leading to recurrence. In this study, we performed whole-exome sequencing (WES) of ctDNA at different time points in participants with relapsed CC in two independent cohorts, alongside transcriptomic and proteomic analyses of metastases, to enhance comprehension of progression mechanisms. A plasma WES-based tumor-agnostic assay demonstrated higher sensitivity in detecting minimal residual disease (MRD) compared to current assays. Immune evasion appears to be the primary driver of progression in the localized CC setting, indicating the potential efficacy of immunotherapy for microsatellite stability in persons with CC. Organoid modeling further supports the promising potential of targeted therapy in eradicating MRD, surpassing conventional treatments.