Scholarlink

Introduction <p>Circulating tumor DNA (ctDNA) holds promise for guiding immune checkpoint inhibitor (ICI) therapy and stratifying responders from non-responders. While tumor-informed ctDNA detection approaches are sensitive and mutation-inclusive, they require tumor tissue, which limits applicability in real-world settings. Conversely, tumor-agnostic methods often have limited genomic coverage. In this study, we evaluated a tumor-agnostic, broad-panel ctDNA assay in patients with advanced melanoma treated with ICI.</p> Methods <p>We conducted a prospective analysis of 241 longitudinal samples from 39 patients with unresectable stage III/IV melanoma using a SYSMEX targeted NGS panel covering 1,114 COSMIC mutations. Plasma samples were collected at baseline and during ICI therapy. The assay’s sensitivity reached seven mutant molecules, corresponding to a 0.07% mutation allele frequency (MAF). ctDNA profiles were compared with matched tumor tissue and correlated with clinical features and survival.</p> Results <p>At baseline, ctDNA was detected in 64.5% of patients. Common mutations included <i>BRAF</i><sup>V600E</sup> (43.8%) and <i>NRAS</i><sup>G12D</sup> (36.4%), followed by <i>KRAS, EGFR,</i> and <i>PIK3CA</i> variants. Overall tissue–plasma concordance was 51.6%, with more extended biopsy–plasma intervals associated with discordance (<i>p</i> = 0.0105). Notably, 12.2% of cases exhibited partial concordance, characterized by shared mutations and additional plasma-only alterations, underscoring the complementary value of blood-based profiling. Persistent or re-emerging ctDNA positivity post-therapy correlated with shorter progression-free survival (PFS, <i>p</i> = 0.003), while ctDNA-negative patients showed significantly improved outcomes. Patients that remained ctDNA-negative had significantly longer progression-free survival (median not reached) compared to those with persistent ctDNA positivity (median 3&#xa0;months) or those converting to positive (median 7.5&#xa0;months; <i>p</i> = 0.0073). Early <i>NRAS</i> and <i>KRAS</i> ctDNA levels strongly predicted poor response (<i>p</i> = 0.0069 and <i>p</i> = 0.028). The prognostic impact extended beyond canonical drivers, as non-hotspot variants also correlated with the outcome. Notably, even low-level ctDNA persistence (5–10 MM/mL) carried adverse prognostic implications (<i>p</i> = 0.0054). Concerning a shorter PFS, ctDNA positivity was also associated with elevated S100 levels (<i>p</i> = 0.047). Organ-specific mutation enrichment (e.g., KRAS<sup>G12D</sup> in brain, EGFR<sup>G719A</sup> in lymph nodes) suggested possible metastatic tropism.</p> Conclusion <p>Broad tumor-agnostic ctDNA analysis effectively identified clinically relevant mutations and predicted outcomes in ICI-treated melanoma patients. This approach enables tissue-independent and real-time ctDNA monitoring and may inform patient selection and therapeutic strategies in future interventional trials.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

In-depth assessment of BRAF, NRAS, KRAS, EGFR, and PIK3CA mutations on cell-free DNA in the blood of melanoma patients receiving immune checkpoint inhibition

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月12日

查看全文
  • Isabel Heidrich,
  • Charlotte Rautmann,
  • Cedric Ly,
  • Robin Khatri,
  • Julian Kött,
  • Glenn Geidel,
  • Alessandra Rünger,
  • Antje Andreas,
  • Inga Hansen-Abeck,
  • Finn Abeck,
  • Anne Menz,
  • Stefan Bonn,
  • Stefan W. Schneider,
  • Daniel J. Smit,
  • Christoffer Gebhardt,
  • Klaus Pantel

摘要

Introduction

Circulating tumor DNA (ctDNA) holds promise for guiding immune checkpoint inhibitor (ICI) therapy and stratifying responders from non-responders. While tumor-informed ctDNA detection approaches are sensitive and mutation-inclusive, they require tumor tissue, which limits applicability in real-world settings. Conversely, tumor-agnostic methods often have limited genomic coverage. In this study, we evaluated a tumor-agnostic, broad-panel ctDNA assay in patients with advanced melanoma treated with ICI.

Methods

We conducted a prospective analysis of 241 longitudinal samples from 39 patients with unresectable stage III/IV melanoma using a SYSMEX targeted NGS panel covering 1,114 COSMIC mutations. Plasma samples were collected at baseline and during ICI therapy. The assay’s sensitivity reached seven mutant molecules, corresponding to a 0.07% mutation allele frequency (MAF). ctDNA profiles were compared with matched tumor tissue and correlated with clinical features and survival.

Results

At baseline, ctDNA was detected in 64.5% of patients. Common mutations included BRAFV600E (43.8%) and NRASG12D (36.4%), followed by KRAS, EGFR, and PIK3CA variants. Overall tissue–plasma concordance was 51.6%, with more extended biopsy–plasma intervals associated with discordance (p = 0.0105). Notably, 12.2% of cases exhibited partial concordance, characterized by shared mutations and additional plasma-only alterations, underscoring the complementary value of blood-based profiling. Persistent or re-emerging ctDNA positivity post-therapy correlated with shorter progression-free survival (PFS, p = 0.003), while ctDNA-negative patients showed significantly improved outcomes. Patients that remained ctDNA-negative had significantly longer progression-free survival (median not reached) compared to those with persistent ctDNA positivity (median 3 months) or those converting to positive (median 7.5 months; p = 0.0073). Early NRAS and KRAS ctDNA levels strongly predicted poor response (p = 0.0069 and p = 0.028). The prognostic impact extended beyond canonical drivers, as non-hotspot variants also correlated with the outcome. Notably, even low-level ctDNA persistence (5–10 MM/mL) carried adverse prognostic implications (p = 0.0054). Concerning a shorter PFS, ctDNA positivity was also associated with elevated S100 levels (p = 0.047). Organ-specific mutation enrichment (e.g., KRASG12D in brain, EGFRG719A in lymph nodes) suggested possible metastatic tropism.

Conclusion

Broad tumor-agnostic ctDNA analysis effectively identified clinically relevant mutations and predicted outcomes in ICI-treated melanoma patients. This approach enables tissue-independent and real-time ctDNA monitoring and may inform patient selection and therapeutic strategies in future interventional trials.