The predictive value of tumor mutation burden for immune checkpoint inhibitors therapy in non-small cell lung cancer is affected by patients' age.
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ABSTRACT:
SUBMITTER: Wu Y
PROVIDER: S-EPMC7146978 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
Publications
The predictive value of tumor mutation burden for immune checkpoint inhibitors therapy in non-small cell lung cancer is affected by patients' age.
Wu Yongfeng Y Xu Jinming J Xu Jiawei J Wang Yiqing Y Wang Luming L Lv Wang W Hu Jian J
Biomarker research 20200409
High tumor mutation burden (TMB), which is associated with increased tumor immunogenicity, has been identified to predict improved response to immune checkpoint inhibitors (ICIs) therapy in non-small cell lung cancer (NSCLC). As host immunity is also significant to eliminate cancer cells, however, its clinical impact on cancer immunotherapy is still largely unknown. Here we explored the influence of age, which is an important characteristic to evaluate immune response of patients, on TMB-based p ...[more]
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Project description:Background: Despite an increasing understanding about tumor mutation burden (TMB) in cancer immunity and cancer immunotherapy, the comprehensive cognition between TMB and efficiency of immune checkpoint inhibitors (ICIs) is still lacking. A systematic review and meta-analysis was conducted to evaluate the predictive value of TMB on efficacy of ICIs. Methods: Systematic literature search was conducted on PubMed, EMBASE, Web of Science and Cochrane Library up to June 16, 2019. Pooled odds ratio (OR) of objective response rate (ORR), hazard ratio (HR) of progression-free survival (PFS) and overall survival (OS) were estimated by inverse variance weighted fixed-effects model (I 2 ≤ 50%) or DerSimonian-Laird random-effects model (I 2 > 50%). In addition, heterogeneity analysis, sensitivity analysis, publication bias and subgroup analysis were conducted. Moreover, fractional polynomial regression was conducted to investigate the dose-response relationship between TMB cutoffs and efficacy of ICIs. Furthermore, we assessed ORR by TMB and programmed cell death ligand 1 (PD-L1) expression after layering each other in studies which the two could be both acquired. Results: Three thousand six hundred fifty-seven records were retrieved through database searching, and 29 studies with 4,431 patients were finally included in the meta-analysis. TMB high group had significantly improved ORR (pooled OR 3.31, 95% CI 2.61, 4.19, P < 0.001), PFS (pooled HR 0.59, 95% CI 0.49, 0.71, P < 0.001) and OS (pooled HR 0.68, 95% CI 0.53, 0.89, P = 0.004). Sensitivity analyses illustrated the results were stable, and publication bias was identified in ORR. Subgroup analyses showed the predictive value of TMB was significant in non-small-cell lung cancer (except for the OS) and melanoma. In addition, heterogeneity was substantial in targeted next generation sequencing group but tiny in whole exome sequencing group. Furthermore, TMB and PD-L1 expression were capable to predict improved ORR of ICIs after stratification of each other, with tiny heterogeneity. Conclusions: High tumor mutation burden predicted improved efficacy of immune checkpoint inhibitors in cancers, and targeted next generation sequencing for estimating tumor mutation burden in clinic should be standardized to eliminate heterogeneity in the future. Moreover, tumor mutation burden and programmed cell death ligand 1 expression were independent factors on predicting efficacy of immune checkpoint inhibitors.
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Project description:Background: To evaluate the clinical predictive value of tumor mutation burden (TMB) for immune checkpoint inhibitor (ICI) therapy in patients with non-small cell lung cancer (NSCLC). Method: As of 15 February 2020, PubMed, PMC and EMBASE databases as well as the American society of clinical oncology (ASCO) and European society of medical oncology (ESMO) databases were searched. The Mantel-Haenszel or inverse variance weighted fixed-effects model (I2 ≤ 50%) or random-effects model (I2 > 50%) were used to evaluate OR and its 95% CI of objective response rate (ORR) and disease control rate (DCR) , as well as HR and its 95% CI of progression-free survival (PFS) and overall survival (OS). In addition, we did publication bias, heterogeneity analysis, sensitivity analysis and subgroup analysis. And quality of the studies included and the level of evidence for outcome measures were evaluated. Results: 14 studies involving 2872 patients were included. The ORR (OR 3.52, 95%CI 2.32-5.35, p < 0.00001), DCR (OR 3.26, 95%CI 1.91-5.55, p < 0.0001), PFS (HR 0.81, 95%CI 0.74-0.89, p < 0.00001) and OS (HR 0.83, 95%CI 0.74-0.94, p = 0.002) of ICI therapy in the high TMB group were all superior to those in the low TMB group. Conclusions: TMB is a promising biomarker, which can predict the efficacy of ICI therapy in advanced NSCLC patients, included ORR, DCR, PFS and OS.
| S-EPMC7738995 | biostudies-literature
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Project description:Lysine (K)-specific demethylase 5C (KDM5C) plays a significant role in the tumor cell proliferation, invasion, drug resistance and the regulation of tumor-related gene expression. Here, we aimed to investigate its predictive value in patients with cancers received immune checkpoint inhibitors (ICIs). We explored the predictive value of KDM5C alterations and the association between KDM5C alteration and immune landscape by using published cohort with clinical outcome and sequenced data from online database. The frequency of KDM5C alterations was 2.1% across 48045 tumor samples with different cancers from 185 studies. KDM5C alterations were correlated with markedly inferior overall survival (OS, 53 vs. 102 months, P<0.0001) than those without. However, in ICI-treated group, patients with KDM5C alterations had a substantially prolonged OS than the wild-type group (not reached vs. 18 months, P=0.0041). The predictive value of KDM5C alterations for ICI treatment outcome was not observed in patients with microsatellite-stable tumors (P=0.2875). Intriguingly, patients with non-small-cell lung cancer and KDM5C alterations receiving ICI had the better progression-free survival than wild type group (13.2 vs. 3.2 months, P=0.0762). Mechanistically, KDM5C altered tumors had dramatically higher TMB level and was associated with significantly higher level of CD8+ T cell infiltration and T effector signature. In conclusion, KDM5C alterations was correlated with enhanced tumor immunogenicity and inflamed anti-tumor immunity, thus resulting in better treatment outcome in cancer patients receiving ICIs.
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