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Background <p>Only a minority of patients with advanced gastric cancer (GC) or esophagogastric junction (EGJ) adenocarcinoma derive durable benefit from anti-programmed cell death 1 (PD-1) therapy. However, reliable biomarkers for real-world clinical decision-making remain limited.</p> Objective <p>To identify tumor site-specific genomic alterations associated with outcomes of nivolumab monotherapy in a nationwide real-world cohort.</p> Methods <p>We conducted a retrospective nationwide analysis using Japan’s Center for Cancer Genomics and Advanced Therapeutics (C-CAT) registry, including patients with GC and EGJ cancer adenocarcinoma treated with nivolumab monotherapy (July 2019–April 2024). Primary endpoints were time to treatment failure (TTF) and overall survival (OS), defined as the interval from nivolumab initiation to death from any cause; objective response rate (ORR) was secondary. Gene-level alteration indicators were derived from vendor-reported tumor-only panel calls across multiple platforms and filtered for clonal hematopoiesis of indeterminate potential (CHIP)-like variants (variant allele frequency &lt; 0.05). Multivariable models adjusted for age and sex were fitted separately for GC and EGJ cancer. Variant pathogenicity was based on available panel annotations; therefore, gene-level results should be interpreted as exploratory findings.</p> Results <p>Among 798 patients with GC and 114 patients with EGJ cancer adenocarcinoma, median TTF/OS/ORR were 3.98 months/20.2 months/11.7% in GC and 4.80 months/24.7 months/14.9% in EGJ cancer adenocarcinoma. In GC, <i>ASXL1</i> mutation remained independently associated with longer TTF (hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.37–0.94) after adjustment and CHIP filtering. For OS, microsatellite instability-high [MSI-H] (HR 0.16, 95% CI 0.04–0.70) and <i>FANCG</i> (HR 0.37, 95% CI 0.16–0.87) were associated with longer OS, whereas <i>CDH1</i> (HR 1.51, 95% CI 1.10–2.05) was associated with shorter OS. In EGJ cancer adenocarcinoma, <i>NTRK1</i> mutation correlated with longer TTF (HR 0.31, 95% CI 0.10–0.98) and <i>MUTYH</i> with shorter OS (HR 5.68, 95% CI 2.04–15.81), both exploratory.</p> Conclusions <p>In this large Japanese real-world cohort, genomic associations with nivolumab outcomes differed by tumor site. In gastric cancer, <i>ASXL1</i> mutation was associated with prolonged treatment benefit under PD-1 blockade, while <i>CDH1</i> and <i>FANCG</i> showed exploratory associations with OS. These findings warrant further validation in prospective and platform-controlled analyses.</p>

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Site-Specific Genomic Markers Associated with Outcomes of PD-1 Blockade in Gastric and Esophagogastric Junction Cancer: Analysis of Japan’s C-CAT Registry

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月27日

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  • Yasuyoshi Sato,
  • Koichi Yagi,
  • Kazunaga Ishigaki,
  • Raito Asaoka,
  • Kotaro Sugawara,
  • Shuichiro Oya,
  • Asami Okamoto,
  • Yoshiyuki Miwa,
  • Shoh Yajima,
  • Yoshifumi Baba,
  • Kousuke Watanabe,
  • Katsutoshi Oda,
  • Mitsuhiro Fujishiro

摘要

Background

Only a minority of patients with advanced gastric cancer (GC) or esophagogastric junction (EGJ) adenocarcinoma derive durable benefit from anti-programmed cell death 1 (PD-1) therapy. However, reliable biomarkers for real-world clinical decision-making remain limited.

Objective

To identify tumor site-specific genomic alterations associated with outcomes of nivolumab monotherapy in a nationwide real-world cohort.

Methods

We conducted a retrospective nationwide analysis using Japan’s Center for Cancer Genomics and Advanced Therapeutics (C-CAT) registry, including patients with GC and EGJ cancer adenocarcinoma treated with nivolumab monotherapy (July 2019–April 2024). Primary endpoints were time to treatment failure (TTF) and overall survival (OS), defined as the interval from nivolumab initiation to death from any cause; objective response rate (ORR) was secondary. Gene-level alteration indicators were derived from vendor-reported tumor-only panel calls across multiple platforms and filtered for clonal hematopoiesis of indeterminate potential (CHIP)-like variants (variant allele frequency < 0.05). Multivariable models adjusted for age and sex were fitted separately for GC and EGJ cancer. Variant pathogenicity was based on available panel annotations; therefore, gene-level results should be interpreted as exploratory findings.

Results

Among 798 patients with GC and 114 patients with EGJ cancer adenocarcinoma, median TTF/OS/ORR were 3.98 months/20.2 months/11.7% in GC and 4.80 months/24.7 months/14.9% in EGJ cancer adenocarcinoma. In GC, ASXL1 mutation remained independently associated with longer TTF (hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.37–0.94) after adjustment and CHIP filtering. For OS, microsatellite instability-high [MSI-H] (HR 0.16, 95% CI 0.04–0.70) and FANCG (HR 0.37, 95% CI 0.16–0.87) were associated with longer OS, whereas CDH1 (HR 1.51, 95% CI 1.10–2.05) was associated with shorter OS. In EGJ cancer adenocarcinoma, NTRK1 mutation correlated with longer TTF (HR 0.31, 95% CI 0.10–0.98) and MUTYH with shorter OS (HR 5.68, 95% CI 2.04–15.81), both exploratory.

Conclusions

In this large Japanese real-world cohort, genomic associations with nivolumab outcomes differed by tumor site. In gastric cancer, ASXL1 mutation was associated with prolonged treatment benefit under PD-1 blockade, while CDH1 and FANCG showed exploratory associations with OS. These findings warrant further validation in prospective and platform-controlled analyses.