Impact of panel design and cut-off on tumour mutational burden assessment in metastatic solid tumour samples.
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ABSTRACT:
SUBMITTER: Mankor JM
PROVIDER: S-EPMC7109082 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tumour mutational burden (TMB) has emerged as a reproducible biomarker to predict immunotherapy response across multiple cancer types. However, a key aspect of TMB measurement that is often overlooked is the source of tissue sample used, which creates a potential for systematic bias. The predominant source is either primary or metastatic tumour tissue. Primary tumours are more heterogeneous and reflect a longer period of tumour evolution, whereas metastases tend to have a more monoclonal structure and potentially different TMB scores. Studies to date measuring TMB have used a heterogeneous set of primary and metastatic tissues, which may explain some of the variability in predictive TMB values across studies. This paper presents data to show that there is a systematic difference whereby metastatic TMB is biased towards higher values than primary TMB (36% higher, paired Wilcoxon, P = 0.0008). However, effectiveness in predicting overall survival during immune checkpoint inhibitor therapy was found to be equivalent between primary and metastatic TMB. We highlight that lower TMB in primary tissue may be important in cases with borderline primary TMB, where assaying metastatic TMB may lead to a different treatment stratification result. As TMB progresses towards clinical implementation, particularly in classically non-immunogenic tumour types, it is important to have better curated trials with either the source of tissue annotated or a prospective study assessing concordance between paired primary and metastatic tissue.
| S-EPMC9216665 | biostudies-literature
Project description:IntroductionTumour mutational burden (TMB) is an important emerging biomarker for immune checkpoint inhibitors (ICI). The stability of TMB values across distinct EBUS tumour regions is not well defined in advanced lung cancer patients.MethodsThis study included a whole-genome sequencing cohort (n=11, LxG cohort) and a targeted Oncomine TML panel cohort (n=10, SxD cohort), where paired primary and metastatic samples were obtained by endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA).ResultsThe LxG cohort displayed a strong correlation between the paired primary and metastatic sites, with a median TMB score of 7.70 ± 5.39 and 8.31 ± 5.88 respectively. Evaluation of the SxD cohort demonstrated greater inter-tumoural TMB heterogeneity, where Spearman correlation between the primary and metastatic sites fell short of significance. Whilst median TMB scores were not significantly different between the two sites, 3 out of 10 paired samples were discordant when using a TMB cut-off of 10 mutations per Mb. In addition, PD-L1 copy number and KRAS mutations were assessed, demonstrating the feasibility of performing multiple molecular tests relevant to ICI treatment using a single EBUS sample. We also observed good consistency in PD-L1 copy number and KRAS mutation, where cut-off estimates were consistent across the primary and metastatic sites.ConclusionsAssessment of TMB acquired by EBUS from multiple sites is highly feasible and has the potential to improve accuracy of TMB panels as a companion diagnostic test. We demonstrate similar TMB values across primary and metastatic sites, however 3 out of 10 samples displayed inter-tumoural heterogeneity that would alter clinical management.
| S-EPMC10042177 | biostudies-literature
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:Tumor mutational burden (TMB), defined as the number of somatic mutations per megabase of interrogated genomic sequence, varies across malignancies. Panel sequencing-based estimates of TMB have largely replaced whole-exome sequencing-derived TMB in the clinic. Retrospective evidence suggests that TMB can predict the efficacy of immune checkpoint inhibitors, and data from KEYNOTE-158 led to the recent FDA approval of pembrolizumab for the TMB-high tumor subgroup. Unmet needs include prospective validation of TMB cutoffs in relationship to tumor type and patient outcomes. Furthermore, standardization and harmonization of TMB measurement across test platforms are important to the successful implementation of TMB in clinical practice. SIGNIFICANCE: Evaluation of TMB as a predictive biomarker creates the need to harmonize panel-based TMB estimation and standardize its reporting. TMB can improve the predictive accuracy for immunotherapy outcomes, and has the potential to expand the candidate pool of patients for treatment with immune checkpoint inhibitors.
| S-EPMC7710563 | biostudies-literature
Project description:BackgroundCirculating tumour DNA (ctDNA) may serve as a measure of tumour burden and a useful tool for non-invasive monitoring of cancer. However, ctDNA is not always detectable in patients at time of diagnosis of metastatic disease. Therefore, there is a need to understand the correlation between ctDNA levels and the patients' overall metabolic tumour burden (MTB).MethodsThirty-two treatment naïve metastatic melanoma patients were included in the study. MTB and metabolic tumour volume (MTV) was measured by 18F-fluoro-D-glucose positron emission tomography/computed tomography (FDG PET/CT). Plasma ctDNA was quantified using droplet digital PCR (ddPCR).ResultsCtDNA was detected in 23 of 32 patients. Overall, a significant correlation was observed between ctDNA levels and MTB (p < 0.001). CtDNA was not detectable in patients with an MTB of ≤10, defining this value as the lower limit of tumour burden that can be detected through ctDNA analysis by ddPCR.ConclusionsWe showed that ctDNA levels measured by ddPCR correlate with MTB in treatment naïve metastatic melanoma patients and observed a limit in tumour size for which ctDNA cannot be detected in blood. Nevertheless, our findings support the use of ctDNA as a non-invasive complementary modality to functional imaging for monitoring tumour burden.
| S-EPMC6038195 | biostudies-literature
Project description:BackgroundPD-L1 expression and tumour mutational burden (TMB) are both associated with the responses of multiple tumours to immune checkpoint inhibitor (ICI) therapy. However, their prevalence and correlations may differ in different types of advanced solid tumours.MethodsPD-L1 expression, TMB, and PD-1+ Tils (tumour-infiltrating lymphocytes) infiltration and their relationships were assessed in 6668 advanced solid tumour specimens across 25 tumour types. CD8+ T cell infiltration was analysed in 347 NSCLC samples. The associations of these biomarkers with the therapeutic effect of PD-1 inhibitor were analysed in a cohort of NSCLC samples.ResultsPD-L1 expression levels and TMB in different tumour types varied widely and their relationship was not significantly correlated in most cancer types, with only a small association across all specimens (Spearman R = 0.059). PD-1+ Tils infiltration was positively correlated with PD-L1 expression across all samples (Spearman R = 0.3056). However, there is no such correlation between PD-1+ Tils infiltration and TMB. In NSCLC samples, CD8+ T cell infiltration was correlated with PD-1+ Tils infiltration and PD-L1 expression but not with TMB (Spearman R = 0.4117, 0.2045, and 0.0007, respectively). Patients in the CR/PR group (anti-PD-1 therapy) had higher levels of PD-L1 expression, TMB, PD-1+ Tils, and CD8+ T cell infiltration, and many patients in this group exhibited concomitantly elevated levels of multiple biomarkers.ConclusionsOur results showed the PD-L1 expression status and TMB in various types of advanced solid tumours in Chinese patients and their relationships with PD-1+ Tils and CD8+ T cell infiltration, which may inform ICI treatment.
| S-EPMC7397649 | biostudies-literature
Project description:Extraskeletal myxoid chondrosarcoma (EMC) is an ultra-rare cancer that makes up less than 3% of all soft tissue sarcomas. It most often arises in the soft tissues of the proximal limbs and has a higher incidence in males. Though EMC has a good prognosis, it has an indolent course with high rates of local recurrence as well as metastasis to the lungs. EMC is characterized in 70% of cases by an EWS1-NR4A3 translocation, leading to constitutive expression of NR4A3. Structural variants (SVs) in EMC, especially large-scale genomic alterations, have not been well studied and studies are severely limited by sample size. In this study, we describe Whole Genome Sequencing (WGS) of a rare case of matched EMC primary tumor, lung metastasis, and pelvic metastasis to identify genomic alterations. We examined somatic variants, copy number variants (CNVs), and larger scale SVs such as translocations and breakend points. While the primary tumor and lung metastasis had similar somatic variations and CNVs, the pelvic metastasis had more unique SVs with especially increased mutational burden of SVs in chromosome 2. This suggests that different molecular drivers appear in more advanced, relapsing EMC compared with the primary tumor and early lung metastasis. Genomic studies such as ours may identify novel molecular complexities in rare cancers that may be leveraged for therapeutic strategies and precision medicine.
| S-EPMC11285543 | biostudies-literature
Project description:BackgroundTraditionally, mutational burden and mutational signatures have been assessed by tumor-normal pair DNA sequencing. The requirement of having both normal and tumor samples is not always feasible from a clinical perspective, and led us to investigate the efficacy of using RNA sequencing of only the tumor sample to determine the mutational burden and signatures, and subsequently molecular cause of the cancer. The potential advantages include reducing the cost of testing, and simultaneously providing information on the gene expression profile and gene fusions present in the tumor.ResultsIn this study, we devised supervised and unsupervised learning methods to determine mutational signatures from tumor RNA-seq data. As applications, we applied the methods to a training set of 587 TCGA uterine cancer RNA-seq samples, and examined in an independent testing set of 521 TCGA colorectal cancer RNA-seq samples. Both diseases are known associated with microsatellite instable high (MSI-H) and driver defects in DNA polymerase ɛ (POLɛ). From RNA-seq called variants, we found majority (> 95%) are likely germline variants, leading to C > T enriched germline variants (dbSNP) widely applicable in tumor and normal RNA-seq samples. We found significant associations between RNA-derived mutational burdens and MSI/POLɛ status, and insignificant relationship between RNA-seq total coverage and derived mutational burdens. Additionally we found that over 80% of variants could be explained by using the COSMIC mutational signature-5, -6 and -10, which are implicated in natural aging, MSI-H, and POLɛ, respectively. For classifying tumor type, within UCEC we achieved a recall of 0.56 and 0.78, and specificity of 0.66 and 0.99 for MSI and POLɛ respectively. By applying learnt RNA signatures from UCEC to COAD, we were able to improve our classification of both MSI and POLɛ.ConclusionsTaken together, our work provides a novel method to detect RNA-seq derived mutational signatures with effective procedures to remove likely germline variants. It can leads to accurate classification of underlying driving mechanisms of DNA damage deficiency.
| S-EPMC7923324 | biostudies-literature
Project description:BackgroundThe tumorigenesis of prostate cancer involves genetic mutations. Tumour mutational burden (TMB) is an emerging biomarker for predicting the efficacy of immunotherapy.ResultsSingle-nucleotide polymorphisms were the most common variant type, and C>T transversion was the most commonly presented type of single-nucleotide variant. The high-TMB group had lower overall survival (OS) than the low-TMB group. TMB was associated with age, T stage and N stage. Functional enrichment analysis of differentially expressed genes (DEGs) showed that they are involved in pathways related to the terms spindle, chromosomal region, nuclear division, chromosome segregation, cell cycle, oocyte meiosis and other terms associated with DNA mutation and cell proliferation. Six hub genes, PLK1, KIF2C, MELK, EXO1, CEP55 and CDK1, were identified. All the genes were associated with disease-free survival, and CEP55 and CDK1 were associated with OS.ConclusionsThe present study provides a comprehensive analysis of the significance of TMB and DEGs and infiltrating immune cells related to TMB, which provides helpful information for exploring the significance of TMB in prostate cancer.
| S-EPMC7905899 | biostudies-literature
Project description:IntroductionA major development in solid malignancy treatment is the application of immune checkpoint inhibitors (ICIs), which have produced durable responses and increased survival rates. However, the therapeutic effect of ICIs has great heterogeneity in patients with cancer. We propose a systematic review to evaluate the predictive value of tumour mutation burden (TMB) on efficacy of ICIs.Methods and analysisA systematic literature search will be conducted in the PubMed, OVID, Web of Science, Embase and Cochrane Central Register of Controlled Trials Library databases up to 31 May 2022. We will compare the efficacy of ICIs between TMB high group and TMB low group in terms of the HRs of overall survival (OS) and progression-free survival (PFS), and the OR of the objective response rate/overall response rate (ORR). The HRs of PFS and OS, and the OR of ORR, will be measured by an inverse variance weighted fixed effects model (I2≤50%) or a DerSimonian-Laird random effects model (I2>50%). In addition, subgroup analysis, sensitivity analysis, heterogeneity analysis and publication bias will be conducted. We plan to conduct a subgroup analysis on age, sex, area, number of patients (high/low TMB), cancer type, tumour size, stage, line of therapy, TMB sequencing method, type of immunotherapy and follow-up period.Ethics and disseminationEthical approval and informed consent are not needed, as the study will be a literature review and will not involve direct contact with patients or alterations to patient care. This systematic review is anticipated to be finished in December 2023, and the results will be published in a peer-reviewed journal.Prospero registration numberCRD42021262480.
| S-EPMC9358952 | biostudies-literature