Tumor Mutational Burden as a Predictive Biomarker in Solid Tumors.
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ABSTRACT:
SUBMITTER: Sha D
PROVIDER: S-EPMC7710563 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The FDA approved pembrolizumab on June 16, 2020, for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high [TMB-H; ≥10 mutations/megabase (mut/Mb)] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. FDA granted the approval based on a clinically important overall response rate (29%; 95% confidence interval, 21-39) and duration of response (57% of responses lasting ≥ 12 months) in the subset of patients with TMB-H solid tumors (n = 102) spanning nine different tumor types enrolled in a multicenter single-arm trial (KEYNOTE-158). The efficacy of pembrolizumab was supported by the results of whole-exome sequencing (WES) analyses of TMB in additional patients enrolled across multiple pembrolizumab clinical trials, and a scientific understanding of the effects of PD-1 inhibition. Overall, the adverse event profile of pembrolizumab was similar to the adverse event profile observed in prior trials that supported the approval of pembrolizumab in other indications. This approval of pembrolizumab is the first time that the FDA has approved a cancer treatment for an indication based on TMB, and the fourth based on the presence of a biomarker rather than the primary site of origin.
| S-EPMC8416776 | biostudies-literature
Project description:BackgroundTumor mutational burden (TMB) has both prognostic value in resected non-small cell lung cancer (NSCLC) patients and predictive value for immunotherapy response. However, TMB evaluation by whole-exome sequencing (WES) is expensive and time-consuming, hampering its application in clinical practice. In our study, we aimed to construct a mutational burden estimation model, with a small set of genes, that could precisely estimate WES-TMB and, at the same time, has prognostic and predictive value for NSCLC patients.MethodsTMB estimation model was trained based on genomic data from 1056 NSCLC samples from The Cancer Genome Atlas (TCGA). Validation was performed using three independent cohorts, including Rizvi cohort and our own Asian cohorts, including 89 early-stage and n late-stage Asian NSCLC patients, respectively. TCGA data were obtained on September 3, 2018. The two Asian cohort studies were performed from September 1, 2018, to March 5, 2019. Pearson's correlation coefficient was used to assess the performance of estimated TMB with WES-TMB. The Kaplan-Meier survival analysis was applied to evaluate the association of estimated TMB with disease-free survival (DFS), overall survival (OS), and response to anti-programmed death-1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) therapy.ResultsThe estimation model, consisted of only 23 genes, correlated well with WES-TMB both in the training set of TCGA cohort and validation set of Rizvi cohort and our own Asian cohort. Estimated TMB by the 23-gene panel was significantly associated with DFS and OS in patients with early-stage NSCLC and could serve as a predictive biomarker for anti-PD-1 and anti-PD-L1 treatment response.ConclusionsThe 23-gene panel, instead of WES or the currently used panel-based methods, could be used to assess the WES-TMB with a high relevance. This customized targeted sequencing panel could be easily applied into clinical practice to predict the immunotherapy response and prognosis of NSCLC.
| S-EPMC7448445 | biostudies-literature
Project description:An association between mutational burden and response to immune checkpoint therapy has been documented in several cancer types. The potential for such a mutational burden threshold to predict response to immune checkpoint therapy was evaluated in several clinical datasets, where mutational burden was measured either by whole-exome sequencing (WXS) or using commercially available sequencing panels.WXS and RNA-seq data of 33 solid cancer types from TCGA were analyzed to determine whether a robust immune checkpoint activating mutation (iCAM) burden threshold associated with evidence of immune checkpoint activation exists in these cancers that may serve as a biomarker for response to immune checkpoint blockade therapy.We find that a robust iCAM threshold, associated with signatures of immune checkpoint activation, exists in 8 of 33 solid cancers: melanoma, lung adenocarcinoma, colon adenocarcinoma, endometrial cancer, stomach adenocarcinoma, cervical cancer, ER+HER2- breast cancer, and bladder-urothelial cancer. Tumors with mutational burden higher than the threshold (iCAM+) also had clear histologic evidence of lymphocytic infiltration. In published datasets of melanoma, lung adenocarcinoma and colon cancer, patients with iCAM+ tumors had significantly better response to immune checkpoint therapy compared to those with iCAM- tumors. ROC analysis using TCGA predictions as gold standard showed that iCAM+ tumors are accurately identifiable using clinical sequencing assays, such as FoundationOne or StrandAdvantage. Using the FoundationOne derived threshold, analysis of 113 melanoma tumors, showed that iCAM+ patients have significantly better response to immune checkpoint therapy. iCAM+ and iCAM- tumors have distinct mutation patterns and different immune microenvironments.In 8 solid cancers, a mutational burden threshold exists that may predict response to immune checkpoint blockade. This threshold is identifiable using available clinical sequencing assays.
| S-EPMC6016848 | biostudies-other
Project description:ImportanceTumor mutational burden (TMB) is a potential biomarker associated with response to immune checkpoint inhibitor therapies. The prognostic value associated with TMB in the absence of immunotherapy is uncertain.ObjectiveTo assess the prevalence of high TMB (TMB-H) and its association with overall survival (OS) among patients not treated with immunotherapy with the same 10 tumor types from the KEYNOTE-158 study.Design, setting, and participantsThis retrospective cohort study evaluated the prognostic value of TMB-H, assessed by Foundation Medicine (FMI) and defined as at least 10 mutations/megabase (mut/Mb) in the absence of immunotherapy. Data were sourced from the deidentified Flatiron Health-FMI clinicogenomic database collected up to July 31, 2018. Eligible patients were aged 18 years or older with any of the following solid cancer types: anal, biliary, endometrial, cervical, vulvar, small cell lung, thyroid, salivary gland, mesothelioma, or neuroendocrine tumor. Patients with microsatellite instability-high tumors were excluded from primary analysis. For OS analysis, patients were excluded if immunotherapy started on the FMI report date or earlier or if patients died before January 1, 2012, and patients were censored if immunotherapy was started later than the FMI report date. Data were analyzed from November 2018 to February 2019.Main outcomes and measuresOverall survival was analyzed using the Kaplan-Meier method and Cox proportional hazards model, adjusting for age, sex, cancer types, practice type, and albumin level.ResultsOf 2589 eligible patients, 1671 (64.5%) were women, and the mean (SD) age was 63.7 (11.7) years. Median (interquartile range) TMB was 2.6 (1.7-6.1) mut/Mb, and 332 patients (12.8%) had TMB-H (≥10 mut/Mb). Prevalence of TMB-H was highest among patients with small cell lung cancer (40.0%; 95% CI, 34.7%-45.6%) and neuroendocrine tumor (29.3%; 95% CI, 22.8%-36.6%) and lowest was among patients with mesothelioma (1.2%; 95% CI, 0.3%-4.4%) and thyroid cancer (2.7%; 95% CI, 1.2%-5.7%). Adjusted hazard ratio for OS of patients not treated with immunotherapy with TMB-H vs those without TMB-H was 0.94 (95% CI, 0.77-1.13). Comparable results were observed when including patients with high microsatellite instability tumors and calculating OS from first observed antineoplastic treatment date.Conclusions and relevanceThese findings suggest that prevalence of TMB-H varies widely depending on tumor type and TMB-H does not appear to be a factor associated with OS among patients across these cancer types treated in the absence of immunotherapy.
| S-EPMC7596577 | 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:This study was designed to investigate the impact of blood tumor mutational burden (bTMB) on advanced NSCLC in Southwest China. The relationship between the tTMB estimated by next-generation sequencing (NGS) and clinical outcome was retrospectively analyzed in tissue specimens from 21 patients with advanced NSCLC. Furthermore, the relationship between the bTMB estimated by NGS and clinical outcome was retrospectively assessed in blood specimens from 70 patients with advanced NSCLC. Finally, 13 advanced NSCLC patients were used to evaluate the utility of bTMB assessed by NGS in differentiating patients who would benefit from immunotherapy. In the tTMB group, tTMB ≥ 10 mutations/Mb was related to inferior progression-free survival (PFS) (hazard ratio [HR], 0.30; 95% CI, 0.08-1.17; log-rank P = 0.03) and overall survival (OS) (HR, 0.30; 95% CI, 0.08-1.16; log-rank P = 0.03). In the bTMB group, bTMB ≥ 6 mutations/Mb was associated with inferior PFS (HR, 0.32; 95% CI, 0.14-1.35; log-rank P < 0.01) and OS (HR, 0.31; 95% CI, 0.14-0.7; log-rank P < 0.01). In the immunotherapy section, bTMB ≥ 6 mutations/Mb was related to superior PFS (HR, 0.32; 95% CI, 0.14-1.35; log-rank P < 0.01) and objective response rates (ORRs) (bTMB < 6: 14.2%; 95% CI, 0.03-1.19; bTMB ≥ 6: 83.3%; 95% CI, 0.91-37.08; P = 0.02). These findings suggest that bTMB is a validated predictive biomarker for determining the clinical outcome of advanced NSCLC patients and may serve as a feasible predictor of the clinical benefit of immunotherapies (anti-PD-1 antibody) in the advanced NSCLC population in Yunnan Province.
| S-EPMC8160368 | biostudies-literature
Project description:Inactivating mutations in LKB1/STK11 are present in ~20% of non-small cell lung cancers (NSCLC) and portend poor response to anti-PD-1 immunotherapy in patients and genetically engineered mouse model (GEMMs). Here, we sought to uncover the basis for immunotherapy resistance of these tumors and to define strategies that overcome this barrier. Whereas high tumor mutational burden (TMB) often correlates with response to anti-PD1 treatment, we found that LKB1-deficient NSCLCs from non-smokers and GEMMs exhibited striking elevations in nonsynonymous mutations compared to LKB1 wildtype tumors. Correspondingly, LKB1 mutant NSCLC cell lines showed defects in both replication dependent and independent double-strand DNA break (DSB) repair, which were reversed upon LKB1 re-expression.
2021-03-17 | GSE137244 | GEO
Project description:Tumor mutational burden (TMB) reflects cancer mutation quantity. Mutations are processed to neo-antigens and presented by major histocompatibility complex (MHC) proteins to T cells. To evade immune eradication, cancers exploit checkpoints that dampen T cell reactivity. Immune checkpoint inhibitors (ICIs) have transformed cancer treatment by enabling T cell reactivation; however, response biomarkers are required, as most patients do not benefit. Higher TMB results in more neo-antigens, increasing chances for T cell recognition, and clinically correlates with better ICI outcomes. Nevertheless, TMB is an imperfect response biomarker. A composite predictor that also includes critical variables, such as MHC and T cell receptor repertoire, is needed.
| S-EPMC7878292 | biostudies-literature
Project description:High tumor mutational burden (TMB) is associated with response to checkpoint blockade in several cancers. We identify pathogenic germline variants associated with increased TMB (GVITMB). GVITMB were found in 7 genes using a pan-cancer approach (APC, FANCL, SLC25A13, ERCC3, MSH6, PMS2, and TP53) and 38 gene sets (e.g., those involved in DNA repair and programmed cell death). GVITMB were also associated with mutational signatures related to the dysfunction of the gene carrying the variant, somatic mutations that further affect the gene or pathway with the variant, or transcriptomic changes concordant with the expected effect of the variant. In a validation cohort of 140 patients with cutaneous melanoma, we found that patients with GVITMB had prolonged progression-free survival (p = 0.0349, hazard ratio = 0.688) and responded favorably (p = 0.0341, odds = 1.842) when treated with immune checkpoint inhibitors. Our results suggest that germline variants can influence the molecular phenotypes of tumors and predict the response to immune checkpoint inhibitors.
| S-EPMC7988326 | biostudies-literature
Project description:Despite therapeutic advances, lung cancer (LC) is one of the leading causes of cancer morbidity and mortality worldwide. Recently, the treatment of advanced LC has experienced important changes in survival benefit due to immune checkpoint inhibitors (ICIs). However, overall response rates (ORR) remain low in unselected patients and a large proportion of patients undergo disease progression in the first weeks of treatment. Therefore, there is a need of biomarkers to identify patients who will benefit from ICIs. The programmed cell death ligand 1 (PD-L1) expression has been the first biomarker developed. However, its use as a robust predictive biomarker has been limited due to the variability of techniques used, with different antibodies and thresholds. In this context, tumor mutational burden (TMB) has emerged as an additional powerful biomarker based on the observation of successful response to ICIs in solid tumors with high TMB. TMB can be defined as the total number of nonsynonymous mutations per DNA megabases being a mechanism generating neoantigens conditioning the tumor immunogenicity and response to ICIs. However, the latest data provide conflicting results regarding its role as a biomarker. Moreover, considering the results of the recent data, the use of peripheral blood T cell receptor (TCR) repertoire could be a new predictive biomarker. This review summarises recent findings describing the clinical utility of TMB and TCRβ (TCRB) and concludes that immune, neontigen, and checkpoint targeted variables are required in combination for accurately identifying patients who most likely will benefit of ICIs.
| S-EPMC7602200 | biostudies-literature