Dataset Information

Association Between Tumor Mutation Burden (TMB) and Outcomes of Cancer Patients Treated With PD-1/PD-L1 Inhibitions: A Meta-Analysis.

ABSTRACT: Background: Programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitions are being strongly recommended for the treatment of various cancers, while the efficacy of PD-1/PD-L1 inhibitions varies from individuals. It is urgent to explore some biomarkers to screen the most appropriate cancer patients. Tumor mutation burden (TMB) as a potential alternative has been drawing more and more attention. Therefore, we conducted a meta-analysis to quantitatively explore the association between TMB and outcomes of PD-1/PD-L1 inhibitions. Methods: We searched eligible studies that evaluated the association between TMB and the outcomes of PD-1/PD-L1 inhibitions from PubMed, Embase, and Cochrane database up to October 2018. The primary endpoints were the progression-free survival (PFS) and the overall survival (OS) in patients with high TMB or low TMB. The pooled hazard ratios (HR) for PFS and OS were performed by Stata. Results: In this analysis, a total of 2,661 patients from eight studies were included. Comparing PD-1/PD-L1 inhibitions to chemotherapy, the pooled HR for PFS and OS in patients with high TMB was 0.66 [95% confidence interval (CI) 0.50 to 0.88; P = 0.004] and 0.73 (95% CI 0.50 to 1.08; P = 0.114), respectively, while the pooled HR for PFS and OS in patients with low TMB was 1.38 (95% CI 0.82 to 2.31; P = 0.229) and 1.00 (95% CI 0.80 to 1.24; P = 0.970), respectively. Meanwhile, comparing patients with high TMB to patients with low TMB, the pooled HR for PFS in patients treated with PD-1/PD-L1 inhibitions was 0.47 (95% CI 0.35 to 0.63; P = 0.000). Patients with high TMB showed significant benefits from PD-1/PD-L1 inhibitions compared to patients with low TMB. Conclusion: Despite the present technical and practical barriers, TMB may be a preferable biomarker to optimize the efficacy of PD-1/PD-L1 inhibitions.

SUBMITTER: Zhu J

PROVIDER: S-EPMC6587434 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Association Between Tumor Mutation Burden (TMB) and Outcomes of Cancer Patients Treated With PD-1/PD-L1 Inhibitions: A Meta-Analysis.

Zhu Jiaxin J Zhang Tiantian T Li Jiahao J Lin Junming J Liang Wenhua W Huang Wenjie W Wan Ning N Jiang Jie J

Frontiers in pharmacology 20190614

<b>Background:</b> Programmed cell death 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitions are being strongly recommended for the treatment of various cancers, while the efficacy of PD-1/PD-L1 inhibitions varies from individuals. It is urgent to explore some biomarkers to screen the most appropriate cancer patients. Tumor mutation burden (TMB) as a potential alternative has been drawing more and more attention. Therefore, we conducted a meta-analysis to quantitatively explore the as ...[more]

PMID: 31258479

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Project description:ImportanceAlthough tumor mutation burden (TMB) has been explored as a potential biomarker of immunotherapy efficacy in solid tumors, there still is a lack of consensus about the optimal TMB threshold that best discriminates improved outcomes of immune checkpoint inhibitor therapy among patients with non-small cell lung cancer (NSCLC).ObjectivesTo determine the association between increasing TMB levels and immunotherapy efficacy across clinically relevant programmed death ligand-1 (PD-L1) levels in patients with NSCLC.Design, setting, and participantsThis multicenter cohort study included patients with advanced NSCLC treated with immunotherapy who received programmed cell death-1 (PD-1) or PD-L1 inhibition in the Dana-Farber Cancer Institute (DFCI), Memorial Sloan Kettering Cancer Center (MSKCC), and in the Stand Up To Cancer (SU2C)/Mark Foundation data sets. Clinicopathological and genomic data were collected from patients between September 2013 and September 2020. Data analysis was performed from November 2021 to February 2022.ExposuresTreatment with PD-1/PD-L1 inhibition without chemotherapy.Main outcomes and measuresAssociation of TMB levels with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).ResultsIn the entire cohort of 1552 patients with advanced NSCLC who received PD-1/PD-L1 blockade, the median (range) age was 66 (22-92) years, 830 (53.5%) were women, and 1347 (86.8%) had cancer with nonsquamous histologic profile. A regression tree modeling ORR as a function of TMB identified 2 TMB groupings in the discovery cohort (MSKCC), defined as low TMB (≤19.0 mutations per megabase) and high TMB (>19.0 mutations per megabase), which were associated with increasing improvements in ORR, PFS, and OS in the discovery cohort and in 2 independent cohorts (DFCI and SU2C/Mark Foundation). These TMB levels also were associated with significant improvements in outcomes of immunotherapy in each PD-L1 tumor proportion score subgroup of less than 1%, 1% to 49%, and 50% or higher. The ORR to PD-1/PD-L1 inhibition was as high as 57% in patients with high TMB and PD-L1 expression 50% or higher and as low as 8.7% in patients with low TMB and PD-L1 expression less than 1%. Multiplexed immunofluorescence and transcriptomic profiling revealed that high TMB levels were associated with increased CD8-positive, PD-L1-positive T-cell infiltration, increased PD-L1 expression on tumor and immune cells, and upregulation of innate and adaptive immune response signatures.Conclusions and relevanceThese findings suggest that increasing TMB levels are associated with immune cell infiltration and an inflammatory T-cell-mediated response, resulting in increased sensitivity to PD-1/PD-L1 blockade in NSCLC across PD-L1 expression subgroups.

Project description:Lung squamous cell carcinoma (LUSC) is a common type of lung cancer with high incidence and mortality rate. Tumor mutational burden (TMB) is an emerging biomarker for selecting patients with non-small cell lung cancer (NSCLC) for immunotherapy. This study aimed to reveal TMB involved in the mechanisms of LUSC and develop a model to predict the overall survival of LUSC patients. The information of patients with LUSC were obtained from the cancer genome atlas database (TCGA). Differentially expressed genes (DEGs) between low- and the high-TMB groups were identified and taken as nodes for the protein-protein interaction (PPI) network construction. Gene oncology (GO) enrichment analysis and gene set enrichment analysis (GSEA) were used to investigate the potential molecular mechanism. Then, we identified the factors affecting the prognosis of LUSC through cox analysis, and developed a risk score signature. Kaplan-Meier method was conducted to analyze the difference in survival between the high- and low-risk groups. We constructed a nomogram based on the risk score model and clinical characteristics to predict the overall survival of patients with LUSC. Finally, the signature and nomogram were further validated by using the gene expression data downloaded from the Gene Expression Omnibus (GEO) database. 30 DEGs between high- and low-TMB groups were identified. PPI analysis identified CD22, TLR10, PIGR and SELE as the hub genes. Cox analysis indicated that FAM107A, IGLL1, SELE and T stage were independent prognostic factors of LUSC. Low-risk scores group lived longer than that of patients with high-risk scores in LUSC. Finally, we built a nomogram that integrated the clinical characteristics (TMN stage, age, gender) with the three-gene signature to predict the survival probability of LUSC patients. Further verification in the GEO dataset. TMB might contribute to the pathogenesis of LUSC. TMB-associated genes can be used to develope a model to predict the OS of lung squamous cell carcinoma patients.

Project description:BackgroundThe predictive role of blood-based tumor mutation burden (bTMB) for selecting advanced nonsmall cell lung cancer (NSCLC) patients who might benefit from immune checkpoint inhibitors (ICIs) is still under debate. Therefore, the purpose of this meta-analysis was to evaluate the efficacy of programmed cell death 1 (PD-1) /programmed cell death ligand 1 (PD-L1) inhibitors versus that of standard-of-care therapy in patients with NSCLC who were bTMB high and bTMB low.MethodsPubMed, Embase, Cochrane, the Web of Science, and ClinicalTrials.gov were searched systematically from inception to February 2021 for studies of PD-1/PD-L1 inhibitors (durvalumab OR atezolizumab OR avelumab OR pembrolizumab OR Nivolumab) that provided hazard ratios (HRs) for overall survival (OS) or progression-free survival (PFS), or odds ratios (ORs) for objective response rate (ORR) in both bTMB high and bTMB low groups.ResultsA total of 2338 patients with advanced or metastatic NSCLC from six randomized controlled trials, which all used chemotherapy (CT) as a control, were included in this study. Compared with CT, PD-1/PD-L1 inhibitor therapy improved OS (HR 0.62, 95% CI 0.52-0.75, P < 0.01), PFS (HR 0.57, 95% CI 0.48-0.67, P < 0.01), and ORR (OR 2.69, 95% CI 1.84-3.93, P < 0.01) in bTMB-high NSCLC patients but not in bTMB-low patients (OS HR 0.86, 95% CI 0.69-1.07, P = 0.17; PFS HR 1.00, 95% CI 0.78-1.27, P = 0.98; ORR OR 0.63, 95% CI 0.49-0.80, P = 0.03). Subgroup analyses showed that these results were consistent across all subgroups (line of therapy, therapy regimen, type of NGS panel, PD-L1 expression, and cutoff value). Meta-regression analysis showed that the proportion of patients with squamous cell histology had no statistical effect on clinical outcomes. Sensitivity analyses illustrated that all results were stable.ConclusionsThe efficacy of PD-1/PD-L1 inhibitor therapy in advanced NSCLC patients may be dependent on bTMB level. Patients with high bTMB tend to obtain significantly better OS, PFS, and ORR from PD-1/PD-L1 inhibitor therapy than from CT. However, because of multiple limitations, including those related to reproducibility, the results are exploratory and should be interpreted with caution.

Dataset Information

Association Between Tumor Mutation Burden (TMB) and Outcomes of Cancer Patients Treated With PD-1/PD-L1 Inhibitions: A Meta-Analysis.

Publications

Association Between Tumor Mutation Burden (TMB) and Outcomes of Cancer Patients Treated With PD-1/PD-L1 Inhibitions: A Meta-Analysis.

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