The association between tumor mutational burden and prognosis is dependent on treatment context.
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ABSTRACT:
SUBMITTER: Valero C
PROVIDER: S-EPMC7796993 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Characterization of tumors utilizing next-generation sequencing methods, including assessment of the number of somatic mutations (tumor mutational burden [TMB]), is currently at the forefront of the field of personalized medicine. Recent clinical studies have associated high TMB with improved patient response rates and survival benefit from immune checkpoint inhibitors; hence, TMB is emerging as a biomarker of response for these immunotherapy agents. However, variability in current methods for TMB estimation and reporting is evident, demonstrating a need for standardization and harmonization of TMB assessment methodology across assays and centers. Two uniquely placed organizations, Friends of Cancer Research (Friends) and the Quality Assurance Initiative Pathology (QuIP), have collaborated to coordinate efforts for international multistakeholder initiatives to address this need. Friends and QuIP, who have partnered with several academic centers, pharmaceutical organizations, and diagnostic companies, have adopted complementary, multidisciplinary approaches toward the goal of proposing evidence-based recommendations for achieving consistent TMB estimation and reporting in clinical samples across assays and centers. Many factors influence TMB assessment, including preanalytical factors, choice of assay, and methods of reporting. Preliminary analyses highlight the importance of targeted gene panel size and composition, and bioinformatic parameters for reliable TMB estimation. Herein, Friends and QuIP propose recommendations toward consistent TMB estimation and reporting methods in clinical samples across assays and centers. These recommendations should be followed to minimize variability in TMB estimation and reporting, which will ensure reliable and reproducible identification of patients who are likely to benefit from immune checkpoint inhibitors.
| S-EPMC6618007 | biostudies-literature
Project description:More than 2000 immuno-oncology agents are being tested or are in use as a result of the cancer immunotherapy revolution. Manipulation of co-inhibitory receptors has achieved tumor eradication in a minority of patients, but widespread immune-related adverse events (irAEs) compromised tolerance to healthy self-tissues in the majority. We have proposed that a major mechanism of irAEs is similar to a graft-versus-malignancy effect of graft-versus-host disease. To verify our hypothesis, we retrieved post-marketing data of adverse events from the U.S. Food and Drug Administration Adverse Event Reporting System. A significant positive correlation was revealed in 7677 patients between the reporting odds ratio of irAEs during immune checkpoint inhibitor therapy and the corresponding tumor mutational burden across 19 cancer types. These results can be interpreted to mean that the ICI drugs unleashed T cells against "altered-self," self, and tumors resulting in better overall survival.
| S-EPMC7183506 | biostudies-literature
Project description:Acute myeloid leukemia (AML) is a heterogeneous disease related to a broad spectrum of molecular alterations. The successes of immunotherapies treating solid tumors and a deeper understanding of the immune systems of patients with hematologic malignancies have promoted the development of immunotherapies for the treatment of AML. And high tumor mutational burden (TMB) is an emerging predictive biomarker for response to immunotherapy. However, the association of gene mutation in AML with TMB and immunological features still has not been clearly elucidated. In our study, based on The Cancer Genome Atlas (TCGA) and BeatAML cohorts, 20 frequently mutated genes were found to be covered by both datasets in AML. And TP53 mutation was associated with a poor prognosis, and its mutation displayed exclusiveness with other common mutated genes in both datasets. Moreover, TP53 mutation correlated with TMB and the immune microenvironment. Gene Set Enrichment Analysis (GSEA) showed that TP53 mutation upregulated signaling pathways involved in the immune system. In summary, TP53 mutation is frequently mutated in AML, and its mutation is associated with dismal outcome, TMB, and immunological features, which may serve as a biomarker to predict immune response in AML.
| S-EPMC8566372 | biostudies-literature
Project description:BackgroundTumor mutational burden (TMB) and stromal CD8-positive tumor-infiltrating lymphocytes (CD8+TILs) serve important roles in antitumor immune responses to radiotherapy. This study aimed to elucidate the association between TMB, CD8+TILs, and clinical factors in patients with cervical cancer treated with radiotherapy.MethodsPatients with squamous cell carcinoma of the uterine cervix treated with definitive radiotherapy, and with available somatic mutation data and immunohistochemical staining data from identical tumor tissues, were enrolled retrospectively. The association between TMB and/or CD8+TIL density and patient characteristics, mutation profiles, and treatment outcome was analyzed.ResultsThe study analyzed 44 patients (median follow-up period, 61 months). There was no significant correlation between TMB and CD8+TIL density, or between TMB or CD8+TIL density and patient characteristics. TMB-high or CD8+TIL density-low status was associated with worse overall survival and distant metastasis-free survival; the predictive value of these factors became greater when used in combination. TMB-high or CD8+TIL density-high status was associated with ARID1A mutations.ConclusionsThese data indicate independence of TMB and CD8+TIL density and the involvement of ARID1A alterations in antitumor immune responses in patients with cervical cancers treated with radiotherapy, warranting further mechanistic research and prospective validation.
| S-EPMC9954714 | biostudies-literature
Project description:A significant association between high blood-based tumor mutational burden (bTMB) and improved progression-free survival (PFS) was observed in advanced non-small cell lung cancer (NSCLC) receiving atezolizumab. However, this result was unrepeatable in a recent prospective study. We hypothesized that there might be a non-linear association between bTMB and survival. This study used the clinical and genetic data from POPLAR (n = 105, training set) and OAK (n = 324, validation set) trials. The non-linear association between bTMB and survival was assessed using restricted cubic spline (RCS). The cutoff values for bTMB were calculated via X-tile software. Non-linear relationships were observed between bTMB and PFS and overall survival (OS) in RCS plots (both P non-linearity < 0.001). The optimal cutoff values of bTMB for predicting PFS and OS were 7 and 14 mutations/Mb, respectively. The median PFS and OS of patients with low and high bTMB were significantly longer than those of patients with medium bTMB in the training, validation, and combined sets. Low and high bTMB were also associated with longer PFS and OS in high-programmed death-ligand 1 (PD-L1) expression population. In conclusion, there was a positive non-linear association between bTMB and survival in NSCLC patients receiving atezolizumab. Patients with low bTMB could also derive benefit from immunotherapy.
| S-EPMC7051187 | biostudies-literature
Project description:Potential clinical biomarkers are often assessed with Cox regressions or their ability to differentiate two groups of patients based on a single cutoff. However, both of these approaches assume a monotonic relationship between the potential biomarker and survival. Tumor mutational burden (TMB) is currently being studied as a predictive biomarker for immunotherapy, and a single cutoff is often used to divide patients. In this study, we introduce a two-cutoff approach that allows splitting of patients when a non-monotonic relationship is present and explore the use of neural networks to model more complex relationships of TMB to outcome data. Using real-world data, we find that while in most cases the true relationship between TMB and survival appears monotonic, that is not always the case and researchers should be made aware of this possibility.SignificanceWhen a non-monotonic relationship to survival is present it is not possible to divide patients by a single value of a predictor. Neural networks allow for complex transformations and can be used to correctly split patients when a non-monotonic relationship is present.
| S-EPMC11229404 | biostudies-literature
Project description:Gynecologic carcinosarcomas, previously known as malignant mixed Müllerian tumors, are uncommon malignancies that demonstrate an aggressive biology and lack a standard therapeutic approach. Molecular analyses have revealed recurrent alterations in chromatin remodeling genes, but clinical support for therapeutic significance is lacking. We prospectively identified a patient with refractory uterine carcinosarcoma whose tumor was subject to molecular profiling at diagnosis and again at radiographic progression. Initial molecular testing did not assess tumor mutational burden, DNA polymerase ɛ (POLE), or microsatellite status. After the failure of several lines of chemotherapy, comprehensive genomic profiling of a repeat biopsy identified two missense mutations of the exonuclease domain of POLE (P286R and T323A). Tumor mutational burden was elevated (169 mutations per DNA megabase), consistent with an ultramutator phenotype. As seen in previously reported POLE-endometrioid cases, our patient harbored alterations in PIK3CA, ARID1A, and PTEN and was microsatellite stable, with appreciable tumor-infiltrating lymphocytes. She achieved an ongoing durable response with pembrolizumab. This is the first report of programmed cell death protein 1 response in uterine carcinosarcoma. KEY POINTS:Uterine carcinosarcoma is an uncommon and aggressive histologic variant of endometrial carcinoma with a poor prognosis.Inactivating DNA polymerase ɛ (POLE) mutations have been associated with high tumor mutational burden (TMB) and response to immune checkpoint inhibition.To the authors' knowledge, this is the first report of response to immune checkpoint inhibitor therapy in a patient with uterine carcinosarcoma.This case further supports expanding genomic profiling to include assessment of tumor mutational burden across tumor types, given the potential for immune checkpoint inhibitor therapy in TMB-high tumors.
| S-EPMC5947455 | biostudies-literature
Project description:Tumor mutational burden (TMB) is considered a potential biomarker for predicting the response and effect of immune checkpoint inhibitors (ICIs). To find specific gene mutations related to TMB and the prognosis of patients, the frequently mutated genes in gastric cancer patients from TCGA and ICGC were obtained and the correlation between gene mutation, TMB, and prognosis was analyzed. Furthermore, to clarify whether specific gene mutations can be used as predictive biomarkers of ICIs, a gene set enrichment analysis (GSEA) for immune pathways and an immune infiltration analysis were conducted. The results showed that CUB and Sushi multiple domains 1 (CSMD1) mutation (CSMD1-mut) were associated with higher TMB and better prognosis in patients. The genetic map showed that, compared with wild-type samples, the loss of chromosomes 4q, 5q, 8p, and 9p decreased and the status of microsatellite instability increased in the CSMD1-mut samples. The GSEA analysis showed that immune-related pathways were enriched in the CSMD1-mut samples. The immune infiltration analysis showed that the anti-tumor immune cells were upregulated and that the tumor-promoting immune cells were downregulated in the CSMD1-mut samples. The gene co-expression analysis showed that PD-L1 expression was higher in the CSMD1-mut samples. In summary, CSMD1-mut in gastric cancer was associated with increased TMB and favorable survival and may have potential significance in predicting the efficacy of anti-PD-L1.
| S-EPMC8623648 | biostudies-literature
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:Immunotherapies based on immune checkpoint inhibitors are emerging as an innovative treatment for different types of advanced cancers. While the utility of immune checkpoint inhibitors has been clearly demonstrated, the response rate is highly variable across individuals. Due to the cost and toxicity of these immunotherapies, a critical challenge in this field is the identification of predictive biomarkers to discriminate which patients may respond to immunotherapy. Recently, a high tumor mutational burden (TMB) has been identified as a genetic signature that is associated with a favorable outcome for immune checkpoint inhibitor therapy. The TMB is defined as the total number of nonsynonymous mutations per coding area of a tumor genome. Initially, it was determined using whole exome sequencing, but due to the high costs and long turnaround time of this method, targeted panel sequencing is currently being explored to measure TMB. In the near future, TMB evaluation may play an important role in immuno-oncology, but its implementation in a routine setting involves robust analytical and clinical validation. Standardization is also needed in order to make informed decisions about patients. This review presents the methodologies employed for determining TMB and discusses the factors that may have an impact on its measurement.
| S-EPMC6249625 | biostudies-literature