Combination of AKT1 and CDH1 mutations predicts primary resistance to immunotherapy in dMMR/MSI-H gastrointestinal cancer.
J Immunother Cancer
; 10(6)2022 06.
Article
em En
| MEDLINE
| ID: mdl-35705314
ABSTRACT
BACKGROUND:
Gastrointestinal (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.METHODS:
Three 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.RESULTS:
AKT1 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).CONCLUSIONS:
IOpred 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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Caderinas
/
Resistencia a Medicamentos Antineoplásicos
/
Proteínas Proto-Oncogênicas c-akt
/
Instabilidade de Microssatélites
/
Neoplasias Gastrointestinais
/
Imunoterapia
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
J Immunother Cancer
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
China