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 |
REPOSITORIES: biostudies-literature
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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.
| S-EPMC6848266 | biostudies-literature
Project description:Treatment with immune checkpoint inhibitors (ICIs) has considerably improved prognosis in multiple cancers. However, regardless of PD-L1 expression and TMB, better predictive biomarkers are required to identify ICI-responsive patients. We analyzed a pan-cancer cohort as the discovery cohort to identify the role of Max's giant associated protein (MGA) mutation in the outcome of ICI treatment in different types of cancers. A pooled lung adenocarcinoma (LUAD) cohort was considered as the validation cohort. Another two LUAD cohorts who received conventional treatment were included for prognostic analysis and mechanism exploration. In the discovery cohort, MGA mutation was a favorable survival biomarker for patients with LUAD than in those with other types of cancers. MGA mutation was positively correlated with the TMB score. The results of the validation cohort were consistent with those of the discovery cohort. Patients with MGA mutation in the TMB-low subgroup had longer survival. Two LUAD cohorts who received standard treatment showed that the MGA mutation was not a prognostic biomarker for standard treatment. Mechanically, we found that the co-mutant genes did not affect the prognostic role of MGA mutation. Gene-set enrichment analysis revealed that genes belonging to the immunodeficiency pathway were enriched in the MGA wild-type group in LUAD. Moreover, activated NK cells were more enriched in the MGA mutant LUAD group. In conclusion, our results demonstrated that MGA mutation was an independent predictive biomarker for ICI therapy. These results may provide a novel insight into identifying potential patients with LUAD for ICI therapy.
| S-EPMC8558674 | biostudies-literature
Project description:BackgroundA critical and challenging process in immunotherapy is to identify cancer patients who could benefit from immune checkpoint inhibitors (ICIs). Exploration of predictive biomarkers could help to maximize the clinical benefits. Eph receptors have been shown to play essential roles in tumor immunity. However, the association between EPH gene mutation and ICI response is lacking.MethodsClinical data and whole-exome sequencing (WES) data from published studies were collected and consolidated as a discovery cohort to analyze the association between EPH gene mutation and efficacy of ICI therapy. Another independent cohort from Memorial Sloan Kettering Cancer Center (MSKCC) was adopted to validate our findings. The Cancer Genome Atlas (TCGA) cohort was used to perform anti-tumor immunity and pathway enrichment analysis.ResultsAmong fourteen EPH genes, EPHA7-mutant (EPHA7-MUT) was enriched in patients responding to ICI therapy (FDR adjusted P < 0.05). In the discovery cohort (n = 386), significant differences were detected between EPHA7-MUT and EPHA7-wildtype (EPHA7-WT) patients regarding objective response rate (ORR, 52.6% vs 29.1%, FDR adjusted P = 0.0357) and durable clinical benefit (DCB, 70.3% vs 42.7%, FDR adjusted P = 0.0200). In the validation cohort (n = 1144), significant overall survival advantage was observed in EPHA7-MUT patients (HR = 0.62 [95% confidence interval, 0.39 to 0.97], multivariable adjusted P = 0.0367), which was independent of tumor mutational burden (TMB) and copy number alteration (CNA). Notably, EPHA7-MUT patients without ICI therapy had significantly worse overall survival in TCGA cohort (HR = 1.33 [95% confidence interval, 1.06 to 1.67], multivariable adjusted P = 0.0139). Further gene set enrichment analysis revealed enhanced anti-tumor immunity in EPHA7-MUT tumor.ConclusionsEPHA7-MUT successfully predicted better clinical outcomes in ICI-treated patients across multiple cancer types, indicating that EPHA7-MUT could serve as a potential predictive biomarker for immune checkpoint inhibitors.
| S-EPMC7852135 | biostudies-literature
Project description:BackgroundCD73 induces the dephosphorylation of adenosine monophosphate converting it to adenosine, enabling malignancies to escape from immune surveillance. Although CD73 overexpression has been reported to be a poor prognostic factor in several malignancies including non-small cell lung cancer (NSCLC), its predictive relevance in NSCLC patients receiving immune checkpoint inhibitors is unknown. The present research was conducted to investigate the prognostic significance of CD73 expression in NSCLC patients receiving immune checkpoint inhibitors (ICIs).MethodsWe screened 91 patients with advanced or recurrent NSCLC who received immune checkpoint inhibitors. CD73 expression was evaluated immunohistochemically using tissue specimens obtained just before treatment with ICIs.ResultsAnalysis of progression-free survival (PFS) and overall survival (OS) in relation to several levels of CD73 expression (1%, 10%, 30%, and 50%) showed that both tended to be more favorable as expression of CD73 increased. PFS and OS were longer for patients in whom at least 50% of the tumor cells expressed CD73 than for those in whom <50% of the tumor cells did so. In patients who were positive for EGFR mutation, immune checkpoint inhibitors were significantly more effective in those with high CD73 expression, whereas CD73 expression did not significantly affect the efficacy in patients with EGFR mutation-negative NSCLC. Furthermore, CD73 expression was predictive factor for the PFS independent of PD-L1 expression in patients with EGFR mutation.ConclusionsHigh CD73 expression may predict a favorable response to ICIs in NSCLC patients, especially those harboring EGFR mutations.Key pointsSignificant findings of the study: In patients who were positive for EGFR mutation, immune checkpoint inhibitors (ICIs) were significantly more effective in those with high CD73 expression, whereas CD73 expression did not significantly affect the efficacy in patients with EGFR mutation-negative NSCLC.What this study addsHigh CD73 expression may predict a favorable response to immune checkpoint inhibitors in NSCLC patients, especially those harboring EGFR mutations.
| S-EPMC7113063 | biostudies-literature
Project description:Immune checkpoint inhibitors (ICIs) have emerged as a promising treatment option in the fight against advanced non-small-cell lung cancer (NSCLC). KRAS is the most frequently mutated oncogene in NSCLC. We performed this meta-analysis to investigate if KRAS mutation status affects survival benefits of ICIs in patients with advanced NSCLC. Electronic databases were searched for eligible studies. We included randomized trials with the data of overall survival stratified by KRAS mutation status. From 3 eligible studies, 138 patients with KRAS mutant NSCLC and 371 with KRAS wild-type tumor were included in the meta-analysis. Compared to chemotherapy with docetaxel, ICIs improved overall survival in patients with previously treated KRAS mutant NSCLC (hazard ratio = 0.64 [95% confidence interval, 0.43-0.96], P = 0.03). For patients with KRAS wild-type NSCLC, however, ICIs did not prolong overall survival over that with chemotherapy (hazard ratio = 0.88 [95% confidence interval, 0.68-1.13], P = 0.30). In conclusion, ICIs as a salvage therapy improved overall survival over that with docetaxel in advanced NSCLC patients with KRAS mutation, but not in those with KRAS wild-type tumor. These results suggest that KRAS mutation status may be a potential biomarker for survival benefits to ICIs.
| S-EPMC5564642 | biostudies-other
Project description:Immune checkpoint inhibitors (ICIs) therapy elicits admirable anti-tumor responses across many types of cancer. Growing evidence point to a link to Mediator complex subunit 12 (MED12) and DNA damage repair (DDR) and TGF-β signing, while the clinical data on the association of MED12 and ICIs response are lacking. In this study, clinical and whole-exome sequencing (WES) data from published studies were merged as a WES cohort to explore the association between MED12 mutation (MED12-Mut) and ICIs efficiency across cancers. Then, Memorial Sloan Kettering Cancer Center (MSKCC) cohort was used for validating our findings. The Cancer Genome Atlas (TCGA) cohort was used to perform anti-tumor immunity and prognosis analysis. In the WES cohort (n = 474), significant differences were detected between MED12-Mut and MED12-wildtype (MED12-Wt) patients regarding durable clinical benefit (DCB, 80.00% vs. 53.67%, P = 0.022). In addition, significantly prolonged PFS was observed in MED12-Mut patients (mPFS: not reached, NR vs. 5.87 months, HR: 0.38, 95% CI 0.17-0.85, log-rank P = 0.015), After taking into account age, gender, metastasis, treatment and TMB status, the result of multivariable Cox proportional hazards regression showed significantly better PFS (HR:0.40, 95% CI 0.18-0.92; P = 0.031). In the MSKCC cohort (n = 1513), overall survival advantage was achieved in MED12-Mut patients (mOS: 41 vs. 19 months, HR:0.54, 95%CI 0.34-0.85; log-rank P = 0.007), after taking into account same factors in WES cohort, this link still existed (HR: 0.60, 95% CI: 0.38-0.96, P = 0.033), Notably, TMB was also found significantly higher in MED12-Mut patients in both WES and MSKCC cohort. Further tumor-infiltrating lymphocytes and DDR-related gene analysis revealed anti-tumor immunity in MED12-Mut patients. Totally, MED12-Mut successfully predicted better clinical outcomes in ICIs-treated pan-cancer cohort, indicating that MED12-Mut could serve as a potential predictive biomarker for immune checkpoint inhibitors in pan-cancer.
| S-EPMC9618186 | biostudies-literature
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
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.
| S-EPMC8089485 | biostudies-literature
Project description:Treatment with immune checkpoint inhibitors (ICPIs) extends survival in a proportion of patients across multiple cancers. Tumor mutational burden (TMB)-the number of somatic mutations per DNA megabase (Mb)-has emerged as a proxy for neoantigen burden that is an independent biomarker associated with ICPI outcomes. Based on findings from recent studies, TMB can be reliably estimated using validated algorithms from next-generation sequencing assays that interrogate a sufficiently large subset of the exome as an alternative to whole-exome sequencing. Biological processes contributing to elevated TMB can result from exposure to cigarette smoke and ultraviolet radiation, from deleterious mutations in mismatch repair leading to microsatellite instability, or from mutations in the DNA repair machinery. A variety of clinical studies have shown that patients with higher TMB experience longer survival and greater response rates following treatment with ICPIs compared with those who have lower TMB levels; this includes a prospective randomized clinical trial that found a TMB threshold of ?10 mutations per Mb to be predictive of longer progression-free survival in patients with non-small cell lung cancer. Multiple trials are underway to validate the predictive values of TMB across cancer types and in patients treated with other immunotherapies. Here we review the rationale, algorithm development methodology, and existing clinical data supporting the use of TMB as a predictive biomarker for treatment with ICPIs. We discuss emerging roles for TMB and its potential future value for stratifying patients according to their likelihood of ICPI treatment response. IMPLICATIONS FOR PRACTICE: Tumor mutational burden (TMB) is a newly established independent predictor of immune checkpoint inhibitor (ICPI) treatment outcome across multiple tumor types. Certain next-generation sequencing-based techniques allow TMB to be reliably estimated from a subset of the exome without the use of whole-exome sequencing, thus facilitating the adoption of TMB assessment in community oncology settings. Analyses of multiple clinical trials across several cancer types have demonstrated that TMB stratifies patients who are receiving ICPIs by response rate and survival. TMB, alongside other genomic biomarkers, may provide complementary information in selecting patients for ICPI-based therapies.
| S-EPMC6964127 | biostudies-literature
Project description:BackgroundImmune checkpoint inhibitors (ICIs) have achieved substantial advancements in clinical care. However, there is no strong evidence for identified biomarkers of ICIs in NPC.MethodsIn this retrospective study, 284 patients were enrolled into a training or validation cohort. Inflammatory indexes based on peripheral blood parameters were evaluated, including the systemic immune-inflammation index (SII), the neutrophil-lymphocyte ratio (NLR), the platelet-lymphocyte ratio (PLR), the lymphocyte-to-C-reactive protein ratio (LCR), and the lymphocyte-monocyte ratio (LMR). The optimum cut-off value for patient stratification was identified using X-tile. The Kaplan-Meier method and Cox's proportional regression analyses were used to identify prognostic factors.ResultsImmunotherapy significantly changed the levels of SII, NLR, PLR, LCR and LMR in NPC patients. Patients with lower SII, NLR, and PLR, as well as those with higher LCR and LMR, before immunotherapy had superior PFS (all p < 0.05). Moreover, PFS in the decreased SII, reduced NLR and increased LMR group was significantly longer than in the opposite group (all p < 0.05). Both univariate and multivariate analyses validated that baseline SII and LMR, and the immunotherapy-related SII reduction and LMR elevation were independent prognostic factors for PFS in advanced NPC patients receiving ICIs.ConclusionsImmune checkpoint inhibitor treatments significantly changed the levels of SII, NLR, PLR, LCR and LMR in NPC patients treated with immunotherapy. A lower baseline SII and a higher baseline LMR, and a reduction in SII and an elevation in LMR after immunotherapy are favorable factors for predicting survival among advanced NPC patients.
| S-EPMC10836292 | biostudies-literature