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Co-Occurring Alteration of NOTCH and DDR Pathways Serves as Novel Predictor to Efficacious Immunotherapy in NSCLC

Although immune checkpoint inhibitors (ICIs) have shown remarkable benefit for treatment of advanced non-small lung cancer (NSCLC), only a minority of patients can achieve durable responses and the most patients produce an ultra-rapid progressive disease. Here, we collected the availably published d...

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Autores principales: Zhang, Zhimin, Gu, Yanyan, Su, Xiaona, Bai, Jing, Guan, Wei, Ma, Jungang, Luo, Jia, He, Juan, Zhang, Bicheng, Geng, Mingying, Xia, Xuefeng, Guan, Yanfang, Shen, Cheng, Chen, Chuan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100434/
https://www.ncbi.nlm.nih.gov/pubmed/33968765
http://dx.doi.org/10.3389/fonc.2021.659321
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author Zhang, Zhimin
Gu, Yanyan
Su, Xiaona
Bai, Jing
Guan, Wei
Ma, Jungang
Luo, Jia
He, Juan
Zhang, Bicheng
Geng, Mingying
Xia, Xuefeng
Guan, Yanfang
Shen, Cheng
Chen, Chuan
author_facet Zhang, Zhimin
Gu, Yanyan
Su, Xiaona
Bai, Jing
Guan, Wei
Ma, Jungang
Luo, Jia
He, Juan
Zhang, Bicheng
Geng, Mingying
Xia, Xuefeng
Guan, Yanfang
Shen, Cheng
Chen, Chuan
author_sort Zhang, Zhimin
collection PubMed
description Although immune checkpoint inhibitors (ICIs) have shown remarkable benefit for treatment of advanced non-small lung cancer (NSCLC), only a minority of patients can achieve durable responses and the most patients produce an ultra-rapid progressive disease. Here, we collected the availably published datasets and mined the determinants of response to immunotherapy on pathway levels. One hundred six NSCLC patients treated with immunotherapy were combined from Rizvi et al. and Hellman et al. studies (whole exon sequencing). Two independent validation datasets consisted of the MSKCC cohort (targeted sequencing) and data by Anagnostou and colleagues (whole exon sequencing). The Cancer Genome Atlas (TCGA) somatic mutation and gene expression data were applied to explore the immunobiology features. In the first combined cohort, we detected NOTCH pathway altered in 71% patients with durable clinical benefit (DCB) while only 36% among no durable benefit (NDB) (p = 0.005). Compared to NDB group, co-occurrence of NOTCH and at least two DDR (co-DDR) pathway was discovered in DCB group and contributed to a prolonged progression-free survival (PFS) [22.1 vs 3.6 months, p < 0.0001, HR, 0.34, 95% confidence interval (CI), 0.2–0.59]. In two independent datasets, co-occurrence of NOTCH+/co-DDR+ was also validated to be a better immunotherapy efficacy [Cohort 2: 13 vs 6 months, p = 0.034, HR, 0.55, 95% CI, 0.31–0.96; Cohort 3: 21 vs 11 months, p = 0.067, HR, 0.45, 95% CI, 0.18–1.1]. By analyzing TCGA cohort, we found patients with coexisting NOTCH+/co-DDR+ pathway had a higher TMB, more infiltration of CD4+T cells. Overall, co-occurrence of NOTCH and co-DDR pathway reflect a better immunotherapy efficacy in advanced NSCLC. This genomic predictor show promise in stratifying patients that suit for immunotherapy for future clinical practice.
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spelling pubmed-81004342021-05-07 Co-Occurring Alteration of NOTCH and DDR Pathways Serves as Novel Predictor to Efficacious Immunotherapy in NSCLC Zhang, Zhimin Gu, Yanyan Su, Xiaona Bai, Jing Guan, Wei Ma, Jungang Luo, Jia He, Juan Zhang, Bicheng Geng, Mingying Xia, Xuefeng Guan, Yanfang Shen, Cheng Chen, Chuan Front Oncol Oncology Although immune checkpoint inhibitors (ICIs) have shown remarkable benefit for treatment of advanced non-small lung cancer (NSCLC), only a minority of patients can achieve durable responses and the most patients produce an ultra-rapid progressive disease. Here, we collected the availably published datasets and mined the determinants of response to immunotherapy on pathway levels. One hundred six NSCLC patients treated with immunotherapy were combined from Rizvi et al. and Hellman et al. studies (whole exon sequencing). Two independent validation datasets consisted of the MSKCC cohort (targeted sequencing) and data by Anagnostou and colleagues (whole exon sequencing). The Cancer Genome Atlas (TCGA) somatic mutation and gene expression data were applied to explore the immunobiology features. In the first combined cohort, we detected NOTCH pathway altered in 71% patients with durable clinical benefit (DCB) while only 36% among no durable benefit (NDB) (p = 0.005). Compared to NDB group, co-occurrence of NOTCH and at least two DDR (co-DDR) pathway was discovered in DCB group and contributed to a prolonged progression-free survival (PFS) [22.1 vs 3.6 months, p < 0.0001, HR, 0.34, 95% confidence interval (CI), 0.2–0.59]. In two independent datasets, co-occurrence of NOTCH+/co-DDR+ was also validated to be a better immunotherapy efficacy [Cohort 2: 13 vs 6 months, p = 0.034, HR, 0.55, 95% CI, 0.31–0.96; Cohort 3: 21 vs 11 months, p = 0.067, HR, 0.45, 95% CI, 0.18–1.1]. By analyzing TCGA cohort, we found patients with coexisting NOTCH+/co-DDR+ pathway had a higher TMB, more infiltration of CD4+T cells. Overall, co-occurrence of NOTCH and co-DDR pathway reflect a better immunotherapy efficacy in advanced NSCLC. This genomic predictor show promise in stratifying patients that suit for immunotherapy for future clinical practice. Frontiers Media S.A. 2021-04-22 /pmc/articles/PMC8100434/ /pubmed/33968765 http://dx.doi.org/10.3389/fonc.2021.659321 Text en Copyright © 2021 Zhang, Gu, Su, Bai, Guan, Ma, Luo, He, Zhang, Geng, Xia, Guan, Shen and Chen 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 Oncology
Zhang, Zhimin
Gu, Yanyan
Su, Xiaona
Bai, Jing
Guan, Wei
Ma, Jungang
Luo, Jia
He, Juan
Zhang, Bicheng
Geng, Mingying
Xia, Xuefeng
Guan, Yanfang
Shen, Cheng
Chen, Chuan
Co-Occurring Alteration of NOTCH and DDR Pathways Serves as Novel Predictor to Efficacious Immunotherapy in NSCLC
title Co-Occurring Alteration of NOTCH and DDR Pathways Serves as Novel Predictor to Efficacious Immunotherapy in NSCLC
title_full Co-Occurring Alteration of NOTCH and DDR Pathways Serves as Novel Predictor to Efficacious Immunotherapy in NSCLC
title_fullStr Co-Occurring Alteration of NOTCH and DDR Pathways Serves as Novel Predictor to Efficacious Immunotherapy in NSCLC
title_full_unstemmed Co-Occurring Alteration of NOTCH and DDR Pathways Serves as Novel Predictor to Efficacious Immunotherapy in NSCLC
title_short Co-Occurring Alteration of NOTCH and DDR Pathways Serves as Novel Predictor to Efficacious Immunotherapy in NSCLC
title_sort co-occurring alteration of notch and ddr pathways serves as novel predictor to efficacious immunotherapy in nsclc
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100434/
https://www.ncbi.nlm.nih.gov/pubmed/33968765
http://dx.doi.org/10.3389/fonc.2021.659321
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