{
  "abstract": "Background Microsatellite instability-high (MSI-H), high tumor mutational burden (TMB), and POLE exonuclease-domain mutations define hypermutated gastrointestinal (GI) tumors with potential prognostic and therapeutic relevance. While MSI is established, the role of TMB and POLE status—particularly in MSI-negative tumors—requires clarification to inform precision immunotherapyMethods A total of 1,025 colorectal and gastric cancer cases from The Cancer Genome Atlas were analyzed for microsatellite instability, tumor mutational burden, and POLE mutation status. Overall survival was assessed using multivariable regression. Microsatellite instability-high status was defined using MANTIS or MSIsensor scoring; tumor mutational burden-high was defined as ten or more nonsynonymous mutations per megabase; POLE-mutant status was defined by exonuclease domain mutations. Survival and treatment outcomes were benchmarked using published results from phase II and III clinical trials, including KEYNOTE-177, KEYNOTE-061, KEYNOTE-062, and Ambrosini et al. 1 Results Tumors with microsatellite instability-high status demonstrated improved overall survival compared to microsatellite-stable tumors (hazard ratio range 0.65 to 0.74). POLE-mutated colorectal cancers exhibited a five-year disease-free survival rate of 100% in stage II. In The Cancer Genome Atlas gastric cohort, tumors with high tumor mutational burden showed enhanced immune cell infiltration and significantly better overall survival (p < 0.05). In metastatic colorectal cancer, first-line pembrolizumab yielded superior overall survival in microsatellite instability-high tumors compared to chemotherapy (77.5 vs 36.7 months). POLE-mutated, microsatellite-stable colorectal tumors demonstrated an objective response rate of 89% to immune checkpoint inhibitors—exceeding that of microsatellite instability-high tumors—and progression-free survival was not reached. Tumor mutational burden of ten or more mutations per megabase independently predicted favorable outcomes with immune therapy, even after adjusting for microsatellite instability (hazard ratio 0.67; p = 0.02).Conclusions Microsatellite instability-high status, high tumor mutational burden, and POLE exonuclease domain mutations are favorable biomarkers associated with improved survival and heightened response to immune checkpoint therapy in gastrointestinal cancers. POLE-mutated and tumor mutational burden-high tumors that are microsatellite-stable represent under-recognized, immunotherapy-responsive subgroups. Routine testing for all three biomarkers may enable more accurate risk stratification and personalized treatment selection in gastrointestinal oncology.Reference Ambrosini M, Rousseau B, Manca P, Artz O, Marabelle A, André T, Maddalena G, Mazzoli G, Intini R, Cohen R, Cercek A, Segal NH, Saltz L, Varghese AM, Yaeger R, Nusrat M, Goldberg Z, Ku GY, El Dika I, Margalit O, Grinshpun A, Murtaza Kasi P, Schilsky R, Lutfi A, Shacham-Shmueli E, Khan Afghan M, Weiss L, Westphalen CB, Conca V, Decker B, Randon G, Elez E, Fakih M, Schrock AB, Cremolini C, Jayachandran P, Overman MJ, Lonardi S, Pietrantonio F. Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer. Ann Oncol. 2024 Jul;35(7):643-655. doi: 10.1016/j.annonc.2024.03.009. Epub 2024 May 22. PMID: 38777726.",
  "authors": [
    {
      "affiliations": [
        "Fatima Jinnah Medical College, Lahore, Punjab, Pakistan"
      ],
      "name": "Rubab Fatimaa"
    },
    {
      "affiliations": [
        "Fatima Jinnah Medical College, Lahore, Punjab, Pakistan"
      ],
      "name": "Rida Fatima"
    },
    {
      "affiliations": [
        "UT Health Houston, Houston, TX, USA"
      ],
      "name": "Muhammad Arbaz Arshad Khan"
    }
  ],
  "title": "190 Microsatellite instability, tumor mutational burden, and POLE mutations in gastrointestinal cancers: prognostic and predictive significance from TCGA and clinical trials",
  "uid": "fe793a4c-aa60-5ca3-923a-6fa097abe307"
}