ArticleJournal for immunotherapy of cancer2022
Combination of AKT1 and CDH1 mutations predicts primary resistance to immunotherapy in dMMR/MSI-H gastrointestinal cancer.
Article in Journal for immunotherapy of cancer, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT06004713 (Multi-center, Non-interventional, Prospective Registry Study on the Treatment of Solid Tumors With Mismatch Repair Deficiency or Microsatellite Instability), which is not on this map. Cited by 28 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Multi-center, Non-interventional, Prospective Registry Study on the Treatment of Solid Tumors With Mismatch Repair Deficiency or Microsatellite Instability
Who cites it
28 citing papers in PubMed, 1 synthesis or guideline pooled it, 38 citations in OpenAlex.
- Pooled it
- Sintilimab plus Bevacizumab biosimilar IBI305 and chemotherapy as a first-line treatment in advanced gastric or gastroesophageal junction adenocarcinoma (SBAGA): a single-arm, phase Ib/II study.Nature communications · 2026Trial
- Toripalimab, bevacizumab, and irinotecan in dMMR/MSI locally advanced colorectal cancer: First-stage results from a phase 1b/2 trial.Cell reports. Medicine · 2025Trial
- Effects of Shenling Chengqi Decoction on Gastrointestinal Function and Immune Status of Patients with Gastrointestinal Injury in Severe Sepsis.Computational and mathematical methods in medicine · 2022Trial
- Site-Specific Genomic Markers Associated with Outcomes of PD-1 Blockade in Gastric and Esophagogastric Junction Cancer: Analysis of Japan's C-CAT Registry.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2026Article
- Early- and advanced-stage MSI-H non-colorectal cancers: best management and challenges in 2025.ESMO gastrointestinal oncology · 2026Review
- A comprehensive review of mechanisms underlying resistance to immune checkpoint inhibitors.Frontiers in immunology · 2026Review
- Mechanisms and therapeutic strategies for immunotherapy resistance in gastric cancer.Cancer cell international · 2025Review
- Cholesterol metabolism in LUAD progression: GJB3 as a key target for cell‑based therapeutic interventions.Molecular medicine reports · 2025Article
- Tumor-draining lymph nodes respond to immune checkpoint inhibition and orchestrate tumor immune remodeling.Cancer immunology, immunotherapy : CII · 2025Article
- Epidemiology, pathogenesis, biology and evolving management of MSI-H/dMMR cancers.Nature reviews. Clinical oncology · 2025Review
- Targeting amino acid metabolism to inhibit gastric cancer progression and promote anti-tumor immunity: a review.Frontiers in immunology · 2025Review
- The efficacy and safety of neoadjuvant and adjuvant chemo(radio)therapy combined with surgery in patients with locally advanced rectal cancer harboring defective mismatch repair system: a large-scale multicenter propensity score analysis.Frontiers in immunology · 2025Article
- Article
- Advances and challenges in neoantigen prediction for cancer immunotherapy.Frontiers in immunology · 2025Review
- Case Report: Failed response to anti-PD-1 immunotherapy in a colon cancer patient with high microsatellite instability.Frontiers in oncology · 2025Article
- Development of a streamlined NGS-based TCGA classification scheme for gastric cancer and its implications for personalized therapy.Journal of gastrointestinal oncology · 2024Article
- Programmed Cell Death-Related Gene Signature Associated with Prognosis and Immune Infiltration and the Roles of HMOX1 in the Proliferation and Apoptosis were Investigated in Uveal Melanoma.Genes & genomics · 2024Article
- KMT2C mutation as a predictor of immunotherapeutic efficacy in colorectal cancer.Scientific reports · 2024Article
- Research progress on the multi-omics and survival status of circulating tumor cells.Clinical and experimental medicine · 2024Review
Corrections and comments
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Authors and funding
17 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundGastrointestinal (GI) cancer is the second most common cancer type with mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) phenotype that is expected to respond to immune-checkpoint inhibitors (ICIs). However, approximately half of the patients with dMMR/MSI-H GI cancer derive no benefit from ICIs. We sought to identify the predictors of primary resistance to ICIs in dMMR/MSI-H GI cancer.
methodsThree independent cohorts were included: (1) the discovery cohort (65 patients with dMMR/MSI-H GI cancer) with ICI efficacy data and pre-ICIs tissue samples for genomic profile and tumor immune infiltration; (2) the validation cohort (22 patients with dMMR/MSI-H GI cancer) with ICI efficacy data and pre-ICIs plasma samples for genomic profile; and (3) the TCGA (The Cancer Genome Atlas) cohort not receiving ICIs (152 patients with MSI-H GI cancer) with genomic profile and survival data.
resultsAKT1 and CDH1 mutations were identified as independent predictors of poor progression-free survival (PFS) and primary resistance to ICIs in dMMR/MSI-H GI cancer. We combined these two genes as an immuno-oncology therapy predictor (IOpred), which could recognize 52.4% (11/21) of dMMR/MSI-H patients with primary resistance to ICIs with a positive predictive value (PPV) of 91.7% (11/12). Receiver operating characteristic analysis demonstrated IOpred with a good performance in predicting primary resistance (area under the curve 0.751). Patients with IOpred-Mut (mutant AKT1 or CDH1) GI cancer had significantly shorter PFS (HR=8.36, p<0.001) and overall survival (OS, HR=5.17, p<0.001) than IOpred-WT (wild-type for both AKT1 and CDH1) cases upon ICI treatment. The validation cohort also confirmed the correlation between IOpred-mutation and poorer prognosis (PFS, HR=4.68, p=0.004; OS, HR=15.98, p<0.001) in dMMR/MSI-H patients after ICIs. The PPV of IOpred in identifying primary resistance to ICIs was 80% (4/5) in the validation cohort. Additionally, IOpred-WT patients could be further stratified by tumor mutational burden (TMB), wherein TMB-low patients (TMB ≤26.19 mutations per megabase (Mb)) had a significantly higher primary resistance rate to ICIs (34.8% vs 6.7%, p=0.014) and poorer PFS (HR=3.46, p=0.008) and OS (HR=4.42, p=0.047) than TMB-high patients (TMB >26.19 mutations/Mb).
conclusionsIOpred was identified as a powerful predictor of primary resistance to ICIs in dMMR/MSI-H GI cancer, which might serve as a promising biomarker to help guide immunotherapy decision-making.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.