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Predictive Value of the TP53/PIK3CA/ATM Mutation Classifier for Patients With Bladder Cancer Responding to Immune Checkpoint Inhibitor Therapy
BACKGROUND: Only a proportion of patients with bladder cancer may benefit from durable response to immune checkpoint inhibitor (ICI) therapy. More precise indicators of response to immunotherapy are warranted. Our study aimed to construct a more precise classifier for predicting the benefit of immun...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371040/ https://www.ncbi.nlm.nih.gov/pubmed/34421886 http://dx.doi.org/10.3389/fimmu.2021.643282 |
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author | Pan, Yi-Hui Zhang, Jia-Xing Chen, Xu Liu, Fei Cao, Jia-Zheng Chen, Yu Chen, Wei Luo, Jun-Hang |
author_facet | Pan, Yi-Hui Zhang, Jia-Xing Chen, Xu Liu, Fei Cao, Jia-Zheng Chen, Yu Chen, Wei Luo, Jun-Hang |
author_sort | Pan, Yi-Hui |
collection | PubMed |
description | BACKGROUND: Only a proportion of patients with bladder cancer may benefit from durable response to immune checkpoint inhibitor (ICI) therapy. More precise indicators of response to immunotherapy are warranted. Our study aimed to construct a more precise classifier for predicting the benefit of immune checkpoint inhibitor therapy. METHODS: This multi-cohort study examined the top 20 frequently mutated genes in five cohorts of patients with bladder cancer and developed the TP53/PIK3CA/ATM mutation classifier based on the MSKCC ICI cohort. The classifier was then validated in a validation set consisting of IMvigor210 cohort and Broad/Dana-Farber cohort. The molecular profile and immune infiltration characteristics in each subgroup as defined by this classifier were explored. RESULTS: Among all 881 patients with bladder cancer, the mutation frequency of TP53, PIK3CA, and ATM ranked in the top 20 mutated genes. The TP53/PIK3CA/ATM mutation classifier was constructed based on the Memorial Sloan Kettering Cancer Center (MSKCC) ICI cohort and only showed predictive value for patients with bladder cancer who received ICI therapy (median overall survival: low-risk group, not reached; moderate-risk group, 13.0 months; high-risk group, 8.0 months; P<0.0001). Similar results were found in subgroups of MSKCC ICI cohort defined by tumor mutation burden. Multivariate Cox analysis revealed that the risk group defined by the classifier served as an independent prognostic factor for overall survival in patients with bladder cancer. Efficacy of the classifier was verified in a validation set consisting of IMvigor210 cohort and Broad/Dana-Farber cohort. Lower expression of PD-1/PD-L1 and less tumor immune infiltration were observed in the high-risk group than the other two groups of the TCGA cohort and the IMvigor210 cohort. CONCLUSION: Our study constructed a TP53/PIK3CA/ATM mutation classifier to predict the benefit of immune checkpoint inhibitor therapy for patients with bladder cancer. This classifier can potentially complement the tumor mutation burden and guide clinical ICI treatment decisions according to distinct risk levels. |
format | Online Article Text |
id | pubmed-8371040 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-83710402021-08-19 Predictive Value of the TP53/PIK3CA/ATM Mutation Classifier for Patients With Bladder Cancer Responding to Immune Checkpoint Inhibitor Therapy Pan, Yi-Hui Zhang, Jia-Xing Chen, Xu Liu, Fei Cao, Jia-Zheng Chen, Yu Chen, Wei Luo, Jun-Hang Front Immunol Immunology BACKGROUND: Only a proportion of patients with bladder cancer may benefit from durable response to immune checkpoint inhibitor (ICI) therapy. More precise indicators of response to immunotherapy are warranted. Our study aimed to construct a more precise classifier for predicting the benefit of immune checkpoint inhibitor therapy. METHODS: This multi-cohort study examined the top 20 frequently mutated genes in five cohorts of patients with bladder cancer and developed the TP53/PIK3CA/ATM mutation classifier based on the MSKCC ICI cohort. The classifier was then validated in a validation set consisting of IMvigor210 cohort and Broad/Dana-Farber cohort. The molecular profile and immune infiltration characteristics in each subgroup as defined by this classifier were explored. RESULTS: Among all 881 patients with bladder cancer, the mutation frequency of TP53, PIK3CA, and ATM ranked in the top 20 mutated genes. The TP53/PIK3CA/ATM mutation classifier was constructed based on the Memorial Sloan Kettering Cancer Center (MSKCC) ICI cohort and only showed predictive value for patients with bladder cancer who received ICI therapy (median overall survival: low-risk group, not reached; moderate-risk group, 13.0 months; high-risk group, 8.0 months; P<0.0001). Similar results were found in subgroups of MSKCC ICI cohort defined by tumor mutation burden. Multivariate Cox analysis revealed that the risk group defined by the classifier served as an independent prognostic factor for overall survival in patients with bladder cancer. Efficacy of the classifier was verified in a validation set consisting of IMvigor210 cohort and Broad/Dana-Farber cohort. Lower expression of PD-1/PD-L1 and less tumor immune infiltration were observed in the high-risk group than the other two groups of the TCGA cohort and the IMvigor210 cohort. CONCLUSION: Our study constructed a TP53/PIK3CA/ATM mutation classifier to predict the benefit of immune checkpoint inhibitor therapy for patients with bladder cancer. This classifier can potentially complement the tumor mutation burden and guide clinical ICI treatment decisions according to distinct risk levels. Frontiers Media S.A. 2021-08-04 /pmc/articles/PMC8371040/ /pubmed/34421886 http://dx.doi.org/10.3389/fimmu.2021.643282 Text en Copyright © 2021 Pan, Zhang, Chen, Liu, Cao, Chen, Chen and Luo https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Pan, Yi-Hui Zhang, Jia-Xing Chen, Xu Liu, Fei Cao, Jia-Zheng Chen, Yu Chen, Wei Luo, Jun-Hang Predictive Value of the TP53/PIK3CA/ATM Mutation Classifier for Patients With Bladder Cancer Responding to Immune Checkpoint Inhibitor Therapy |
title | Predictive Value of the TP53/PIK3CA/ATM Mutation Classifier for Patients With Bladder Cancer Responding to Immune Checkpoint Inhibitor Therapy |
title_full | Predictive Value of the TP53/PIK3CA/ATM Mutation Classifier for Patients With Bladder Cancer Responding to Immune Checkpoint Inhibitor Therapy |
title_fullStr | Predictive Value of the TP53/PIK3CA/ATM Mutation Classifier for Patients With Bladder Cancer Responding to Immune Checkpoint Inhibitor Therapy |
title_full_unstemmed | Predictive Value of the TP53/PIK3CA/ATM Mutation Classifier for Patients With Bladder Cancer Responding to Immune Checkpoint Inhibitor Therapy |
title_short | Predictive Value of the TP53/PIK3CA/ATM Mutation Classifier for Patients With Bladder Cancer Responding to Immune Checkpoint Inhibitor Therapy |
title_sort | predictive value of the tp53/pik3ca/atm mutation classifier for patients with bladder cancer responding to immune checkpoint inhibitor therapy |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371040/ https://www.ncbi.nlm.nih.gov/pubmed/34421886 http://dx.doi.org/10.3389/fimmu.2021.643282 |
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