Journal
CANCER DISCOVERY
Volume 11, Issue 9, Pages 2168-2185Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-21-0219
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Funding
- AGA Research Foundation's AGAGastric Cancer Foundation Ben Feinstein Memorial Research Scholar Award in Gastric Cancer [AGA2020-13-02]
- Stand Up To Cancer Gastric Cancer Interception Award
- Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI) - Ministry of Health & Welfare, Republic of Korea [HR20C0025]
- SKKU Excellence in Research Award Research Fund, Sungkyungkwan University
- Korea Health Promotion Institute [HR20C0025010021] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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The study shows that patients with microsatellite instability and elevated mutational burden in gastric cancer are associated with clinical response to anti-PD-1 antibodies. By combining whole-exome sequencing with single-cell RNA sequencing, dynamic tumor evolution with collapse of mutational architecture in responders is identified. Diversity in T-cell receptor repertoire is linked to better response to pembrolizumab.
Sequence alterations in microsatellites and an elevated mutational burden are observed in 20% of gastric cancers and associated with clinical response to anti-PD-1 antibodies. However, 50% of microsatellite instability-high (MSI-H) cancers are intrinsically resistant to PD-1 therapies. We conducted a phase II trial of pembrolizumab in patients with advanced MSI-H gastric cancer and included serial and multi-region tissue samples in addition to serial peripheral blood analyses. The number of whole-exome sequencing (WES)-derived nonsynonymous mutations correlated with antitumor activity and prolonged progression-free survival (PFS). Coupling WES to single-cell RNA sequencing, we identified dynamic tumor evolution with greater on-treatment collapse of mutational architecture in responders. Diverse T-cell receptor repertoire was associated with longer PFS to pembrolizumab. In addition, an increase in PD-1(+) CD8(+) T cells correlated with durable clinical benefit. Our findings highlight the genomic, immunologic, and clinical outcome heterogeneity within MSI-H gastric cancer and may inform development of strategies to enhance responsiveness. SIGNIFICANCE: This study highlights response heterogeneity within MSI-H gastric cancer treated with pembrolizumab monotherapy and underscores the potential for extended baseline and early on-treatment biomarker analyses to identify responders. The observed markers of intrinsic resistance have implications for patient stratification to inform novel combinations among patients with intrinsically resistant features.
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