[Update] Prevalence of High Tumor Mutational Burden and Association With Survival in Patients With Less Common Solid Tumors | tmb life care – Sonduongpaper

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Key Points

What is the prevalence of high tumor mutational burden (TMB-H), defined as 10 or more mutations per megabase, and what is its association with overall survival among patients with 10 rare solid tumor types not treated with immunotherapy?

In this cohort study among 2589 patients, nearly 13% had TMB-H tumors. Overall survival among patients with TMB-H tumors did not differ from that observed among patients with non–TMB-H tumors when receiving nonimmunotherapy treatments.

These findings suggest that TMB-H was not associated with overall survival in patients with these cancer types in the absence of immunotherapy.


Tumor 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.

To 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 Participants 
This 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 Measures 
Overall survival was analyzed using the Kaplan-Meier method and Cox proportional hazards model, adjusting for age, sex, cancer types, practice type, and albumin level.

Of 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 Relevance 
These 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.


Tumor mutational burden (TMB), defined as the total number of somatic mutations per coding area of a tumor genome, is an emerging clinical biomarker associated with response to immune checkpoint inhibitor (ICI) therapy.1,2 TMB has been shown to vary markedly among tumor types as well as among patients within tumor types.3,4 Higher TMB is commonly observed in cancers associated with mutagens, such as ultraviolet light exposure in melanoma and smoking in non–small-cell lung cancer (NSCLC),4 with prevalence of high TMB (TMB-H; defined here as ≥10 mutations/megabase [mut/Mb]) in approximately 52% of patients with melanoma and 38% to 42% of patients with NSCLC.3 By comparison, less than 5% prevalence of TMB-H has been reported in other tumor types, including mesothelioma, sarcomas, and prostate cancers.3

High TMB has been associated with increased expression of tumor-specific neoantigens,5 a subset of which can be recognized by the immune system. Higher numbers of somatic mutations in tumor DNA have been hypothesized to increase the likelihood of the immune system recognizing and eliminating tumor cells during treatment with ICI therapy.3 Evidence supporting this hypothesis from randomized clinical trials has yet to emerge, to our knowledge. However, in a 2018 meta-analysis,6 significant associations between TMB and objective response rate (ORR) were reported across multiple tumor types for patients receiving anti–programmed cell death 1 or anti–programmed cell death ligand 1 therapy. Additionally, higher TMB (albeit assessed with differing analytic methods and defined with differing thresholds) has been associated with response to ICI therapy in several tumor types, including NSCLC,711 small cell lung cancer (SCLC),12 melanoma,13 and colorectal cancer.14 Evidence has been equivocal as to whether higher TMB is associated with outcomes independent of therapy. In the Lung Adjuvant Cisplatin Evaluation-Bio-II study, nonsynonymous TMB of more than 8 mut/Mb was associated with favorable outcomes, such as overall survival (OS), progression-free survival, and lung cancer–specific survival, in patients with NSCLC,15 whereas other studies have indicated significantly longer disease-free survival in patients with lung adenocarcinomas with low TMB16 or no association between TMB and OS in patients with SCLC.17 Little is known about the association of TMB-H with outcomes among patients with less common types of cancer not treated with immunotherapy.

The KEYNOTE-158 study18 is an ongoing phase 2 multicohort study prospectively evaluating multiple biomarkers, including TMB, for associations with response to monotherapy with the anti–programmed cell death 1 monoclonal antibody pembrolizumab in 10 less common types of advanced cancer. Preliminary findings from the KEYNOTE-158 study indicated that patients with TMB-H, defined as 10 or more mut/Mb (assessed in formalin-fixed and paraffin-embedded [FFPE] tissue using the FoundationOne [F1] clinical trial assay based on the F1 Companion Diagnostic [CDx] assay platform; Foundation Medicine), had an ORR of 29% (95% CI, 21%-39%) compared with 6% (95% CI, 5%-8%) for patients with non–TMB-H tumors.19 Because KEYNOTE-158 is a single-group nonrandomized study, it is uncertain whether associations between TMB-H and outcomes represent evidence for TMB-H as a biomarker associated with response to pembrolizumab monotherapy or evidence of an association between TMB-H and prognosis. Currently, to our knowledge, there are no real-world data to describe the prevalence of TMB-H or its association with outcomes in the 10 tumor types evaluated in KEYNOTE-158 when such patients received standard-of-care nonimmunotherapy treatment. Using the deidentified Flatiron Health (FH)–Foundation Medicine (FMI) clinicogenomic database (CGDB), we therefore investigated prevalence of TMB-H and its potential association with OS in a real-world data set of patients not receiving immunotherapy for the 10 tumor types evaluated in KEYNOTE-158.


Institutional review board approval of the study protocol was obtained prior to study conduct and included a waiver of informed consent because there was no more than minimal risk, the study could not be practicably conducted without waiver or alteration, and the study could not be practicably conducted without use of protected health information. This study is reported following Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Study Design and Patients

This was a retrospective, observational study across 10 tumor types evaluated in the KEYNOTE-158 study18 using data from the CGDB collected up to July 31, 2018, the data cutoff date for this analysis. The CGDB links deidentified electronic health record (EHR)–derived patient-level data from the nationwide FH network (comprised of >265 oncology practices across the US, representing more than 2 million patients with cancer) with targeted comprehensive genomic profiling data from FMI, when such testing was performed as part of routine clinical care. Clinical data from FH included structured clinical and demographic data, such as laboratory values and drug orders and administrations; stage at diagnosis and date of diagnosis were not available. Genomic data from FMI included specimen features (eg, pathologic tumor purity) and alteration-level details (eg, TMB, genomic position, reference and alternate alleles, mutant allele count, and minor allele frequency). Tumor types were as reported by the ordering physician when submitting a patient’s tumor sample to FMI, with confirmation by a pathologist at FMI.

For this analysis, eligible patients were aged 18 years or older as of FMI report date (representing the earliest date on which FMI communicated test results to the ordering physician with respect to a single test requisition); had a valid measurement of TMB (per comprehensive genomic profiling by FMI); had at least 1 documented clinic visit observed in the CGDB after January 1, 2011; had a pathologist-confirmed solid tumor of 1 of the following types: anal carcinoma, biliary adenocarcinoma, cervical carcinoma, endometrial carcinoma, mesothelioma, neuroendocrine tumor (NET), salivary gland carcinoma, SCLC, thyroid carcinoma, or vulvar carcinoma. Patients were excluded if they had confirmed cancer other than the prespecified tumor types or if their cancer type was not otherwise specified. Patients were excluded from OS analysis if they had received immunotherapy on or before their FMI report date or were censored at the time of immunotherapy receipt if they began immunotherapy after their FMI report date.

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Assessment of TMB

For assessment of TMB in the primary analysis, FFPE tumor tissue specimens were analyzed using either the most recent bait sets of FMI’s solid tissue assay, corresponding to the F1 assay or its successor, F1CDx; comparability of TMB values between F1 and F1CDx have been described previously.20 TMB was defined as the number of somatic base substitutions and short insertions and deletions identified from coding regions within the FMI test, filtering out known or likely oncogenic driver mutations to reduce bias. The resultant count was divided by the size of the genomic region interrogated to yield a resultant number of mutations per megabase.21 This method for TMB assessment has been analytically validated20 and demonstrates strong agreement with whole exome sequencing. For the primary analysis, TMB-H had the same cutoff used for the KEYNOTE-158 analysis18 (ie, ≥10 mut/Mb), but for an additional exploratory analysis, the cutoff was 13 or more mut/Mb, a threshold that has been evaluated in other clinical trials.11

Statistical Analysis

The primary objectives were to evaluate the association between TMB and OS from time of FMI report date among patients receiving routine clinical care for any of the 10 tumor types included in KEYNOTE-15818 and to evaluate prevalence of TMB-H in these tumor types. All statistical analyses were prespecified. The primary analysis was descriptive and combined all tumor types included in the analysis. Patients were included in the primary analysis if they were tested using either of the most recent bait sets of FMI’s solid tissue assay. Patients with confirmed microsatellite instability–high (MSI-H) cancers were excluded from the primary analysis of this study. Prevalence of TMB-H (ie, TMB ≥10 mut/Mb) was reported with corresponding 95% CIs calculated using Wilson score interval. OS from FMI report date (the primary index date) to the date of death of any cause or censor date (the date of a patient’s first use of immunotherapy, if any, otherwise the date of a patient’s last visit in the FH network) was analyzed with the Kaplan-Meier method, stratified by TMB status (TMB-H vs non–TMB-H) with corresponding 95% CIs. Cox proportional hazards modeling was performed to compare OS by TMB status (TMB-H vs non–TMB-H) and was adjusted for age at the FMI report date, sex, type of cancer, type of practice (ie, community vs academic), and last serum albumin concentration (≥3 g/dL vs <3 g/dL [to convert to grams per liter, multiply by 10]) within 90 days before FMI report date.

Sensitivity analyses were performed for patients with the following different scenarios: histological characteristics (all vs tumor-specific), MSI-H cancers (included vs excluded), bait sets (all vs F1/F1CDx only), index date (first antineoplastic treatment date vs FMI report date), and differing TMB cutoffs (≥10 mut/Mb vs ≥13 mut/Mb).

Data were analyzed using R statistical software version 3.6.1 (R Project for Statistical Computing). A 2-sided 95% CI (97.5%, 2.5% quantiles) was used. Data were analyzed from November 2018 to February 2019.


Baseline Characteristics

A total of 2992 patients with any of the 10 tumor types and who were not treated with immunotherapy prior to FMI report were included. For primary analysis, 109 patients (3.6%) with confirmed MSI-H cancer were excluded per the prespecified analysis plan; of these, 101 patients (92.7%) had endometrial cancer. An additional 294 patients (9.8%) were excluded because they were tested using an older version of the F1 assay. Overall, 2589 patients were included in the primary analysis (eFigure in the Supplement); the mean (SD) age of these patients was 63.7 (11.7) years, and most patients were women (1671 patients [64.5%]), and White individuals (1803 patients [69.6%]). The 3 most common tumor types in the overall cohort were biliary (706 patients [27.3%]), endometrial (590 patients [22.8%]), and SCLC (305 patients [11.8%]) (Figure 1A and Table 1). The median (interquartile range) duration of follow-up was 5.4 (1.5-11.3) months from the date of FMI report and 13.0 (6.0-24.6) months from the date of the first antineoplastic treatment, with 1877 patients (72.5%) recorded as having at least 1 order or administration for antineoplastic therapy as of the FMI report date (Table 1). Neither median follow-up from FMI report date nor median follow-up from first antineoplastic date differed significantly between patients with TMB-H and those without TMB-H.

Prevalence of TMB-H

Of 2589 patients included for primary analysis, 332 (12.8%) had TMB-H (≥10 mut/Mb). TMB status varied by tumor type, with the median (interquartile range) TMB of 2.6 (1.7-6.1) mut/Mb in the entire cohort and with a range from 1.7 mut/Mb among patients with mesothelioma, salivary, or thyroid cancer to 8.7 mut/Mb among patients with SCLC. Prevalence of TMB-H was highest in patients with SCLC (40.0%; 95% CI, 34.7%-45.6%), NET (29.3%; 95% CI, 22.8%-36.6%), and cervical cancer (14.9%; 95% CI, 9.5%-22.6%) whereas prevalence of TMB-H was lowest in patients with mesothelioma (1.2%; 95% CI, 0.3%-4.4%), thyroid cancer (2.7%; 95% CI, 1.2%-5.7%), and biliary cancer (4.0%; 95% CI, 2.8%-5.7%) (Figure 1B). Among 164 patients with NETs, there were 90 patients with lung large cell NET (41 patients [45.6%] with TMB-H), 51 patients with colon NET (6 patients [11.8%] with TMB-H), 17 patients with small intestine NET (1 patient [5.9%] with TMB-H), and 6 patients with rectum NET (0 patients with TMB-H). Prevalence of TMB-H in the cohort was 9.2% (95% CI, 8.1%-10.3%) using the alternative TMB-H cutoff of 13 or more mut/Mb.

Association of TMB-H With OS

A total of 2517 patients were included in the primary analysis of OS after excluding 69 patients (2.7%) who received immunotherapy before the index date and 3 patients (0.1%) who died before January 1, 2012. Of 320 patients in the TMB-H group, 140 (43.8%) had an OS event, and of 2197 patients in the non–TMB-H group, 956 (43.5%) had an OS event. In the primary analysis population, OS across all cancer types was similar among patients with TMB-H and without TMB-H, with median OS of 8.4 (95% CI, 7.4-11.4) months in the TMB-H group and 10.5 (95% CI, 9.5-11.5) months in the non–TMB-H group (Figure 2 and Table 2). The hazard ratio (HR) for OS for TMB-H vs non–TMB-H groups was 1.11 (95% CI, 0.93-1.33) in unadjusted analyses and 0.94 (95% CI, 0.77-1.13) in adjusted analyses (Table 2). Consistent with the overall cohort, across each individual tumor type, the unadjusted and adjusted HRs for OS contained 1 (Table 2).

Sensitivity analyses were conducted to evaluate whether the outcome was affected by the criteria used for analysis. These sensitivity analyses were conducted at both TMB-H cutoffs (ie, ≥10 mut/Mb and ≥13 mut/Mb), using the F1 or F1CDx tested population vs patients tested using any FMI bait set, including and excluding patients with MSI-H cancers, and alternative index dates for calculation of OS (using the first observed antineoplastic treatment date or FMI report date). At the alternative TMB-H cutoff of ≥13 mut/Mb, the adjusted HR for OS was 0.84 (95% CI, 0.67-1.05). The 95% CIs of the HRs for sensitivity analyses all contained 1, suggesting there was no association in OS between patients with different TMB status across these tumor types in either unadjusted or unadjusted analyses (Figure 3).


This retrospective cohort study using a real-world data set evaluated prevalence of TMB-H (defined as ≥10 mut/Mb) and its association with OS (ie, its prognostic association) among patients with 1 of 10 rare solid tumor types who were not treated with immunotherapy. Median TMB ranged from 1.7 mut/Mb among patients with thyroid cancer, salivary cancer, and mesothelioma to 8.7 mut/Mb among patients with SCLC. Prevalence of TMB-H varied widely across tumor types, ranging from 1.2% in patients with mesothelioma to 40.0% in patients with SCLC. Prevalence of TMB-H exceeded 10% in 7 of 10 tumor types evaluated. These results indicate marked differences in TMB-H prevalence rates across a wide range of cancers.

We found no difference when comparing HRs for OS across all patients and within each tumor group. Sensitivity analyses, which evaluated the effect of using a different cutoff for TMB-H (≥13 mut/Mb), including patients with MSI-H tumors, including patients tested with any FMI bait set, and calculating OS from the first observed antineoplastic treatment date, similarly found no difference in OS for patients with TMB-H tumors vs those with non–TMB-H tumors. Based on these findings, TMB-H was not associated with overall survival among patients with these cancer types when not treated with immunotherapy.

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Evidence from other studies regarding associations between OS and TMB-H in patients not treated with immunotherapy has been equivocal.2228 For example, higher TMB (ie, >100 somatic nonsynonymous mutations) was associated with more favorable OS vs lower TMB in patients with ovarian cancer who had not received immunotherapy.25,27 In contrast, a 2018 study22 reported that a very high TMB (ie, >62 mut/Mb) was associated with shorter OS in patients with resected NSCLC who had not received chemotherapy or immunotherapy before surgery. Consistent with our finding for SCLC, in which no association was found between TMB-H and OS based on HR estimates for OS comparing patients with TMB-H vs without TMB-H, previous studies have found no association between TMB-H and improved OS in SCLC,17 gastroesophageal adenocarcinoma,29 and across a selection of 10 tumor types not included in our study: bladder, breast, colorectal, esophagogastric, head and neck, renal cell carcinomas, glioma, melanoma, and NSCLC.1 These differences could result from different study populations, treatment settings, TMB testing assays, or TMB-H definition.

An association between TMB-H and improved efficacy of immunotherapies has been reported in several tumor types, suggesting TMB-H may be a potential biomarker associated with response to these treatments.7,13,30 An analysis of the KEYNOTE-158 study using the F1CDx assay evaluated associations between TMB and outcomes with pembrolizumab monotherapy. Findings from the KEYNOTE-158 study18 indicated an improved ORR among patients with TMB-H (≥10 mut/Mb) after pembrolizumab monotherapy in the same tumor types as those included in the current study, reporting an ORR of 29% among patients with TMB-H (28% when MSI-H patients were excluded) compared with 6% for patients without TMB-H. Median OS for TMB-H was 11.7 (95% CI, 9.1-19.1) months compared with 12.8 (95% CI, 11.1-14.1) months for patients without TMB-H,19 although the many potential confounding factors associated with assessments in such pooled estimates of OS must be noted. In the context of a single-group study, such as KEYNOTE-158,18 it can be difficult to evaluate whether differences in outcomes (or lack thereof) are representative of a predictive or prognostic association. Our results suggest that assessment of any difference in outcomes by TMB status in KEYNOTE-158 was not confounded by a prognostic association of TMB-H.

The association between TMB-H and clinical outcomes may further be strengthened by co-occurrence of another marker of genomic instability, such as MSI-H.21,31 Chalmers et al21 reported that 97% of specimens with MSI-H also had TMB-H and that such co-occurrences are observed more frequently in certain cancer types, especially in gastrointestinal cancers, but rarely in melanoma and lung carcinoma. As such, comparative analysis of biomarkers associated with treatment response and their association with rare solid tumor types may help provide accurate and improved usage of immunotherapies.

Consistent with our findings, evidence from previous studies suggests that prevalence of TMB-H varies widely among tumor types,3,4 with cancers related to chronic mutagenic exposures, such as lung (tobacco) and malignant melanoma (ultraviolet light), exhibiting the highest prevalence of TMB-H.3,4 Yarchoan et al3 recently reported frequencies of TMB-H in 9887 FFPE clinical cancer specimens in 35 tumor types, including most tumor types evaluated in this study, using the F1 assay. Their studies showed the highest prevalence of TMB-H was reported in 41% of SCLCs, followed by 17% of cervical cancers, 15% of anal cancers, 9% of NET, 8% of endometrial cancers, and 1% of mesotheliomas.3 In this study, prevalence of TMB-H observed in the NET cohort (29.3%) was higher possibly owing to the anatomic site distribution of the NETs: of 164 patients with NETs, 90 had lung large cell NET, of whom approximately half had TMB-H.

Strengths of this investigation include use of patient-level data from routine clinical practice. Additionally, this study used analytically and clinically validated assays, which are highly concordant with respect to assessment of TMB.32


This study has some limitations, including the small sample size of patients with TMB-H-for some tumor types and potential differences in immunotherapy usage across tumor types. Further research would be needed to explore whether the prognostic association of TMB varies by tumor type or TMB-H cutoff. Because TMB is a continuous variable, dichotomization of TMB in this study has inherent limitations,33 and future analyses will need to consider whether there are dose-dependent associations of TMB across different tumor types. The population, clinical characteristics, and outcomes in this study were captured from EHRs of a nationwide network of community and academic oncology practices, and thus treatments or outcomes that occurred outside the FH network and were not documented in the patient’s record may be missing. Furthermore, because this study relied on structured EHR data for cohort selection, there may be unmeasured confounders in the comparison, including certain data elements not ascertainable without EHR review, such as date of diagnosis, stage, additional therapies (eg, radiation therapy), or comorbidities. Because of the lack of availability of the diagnosis date, a novel index date (FMI report date) was used for primary analysis. Sensitivity analyses using an alternative date of first documented antineoplastic therapy showed similar results. Prior to conducting this analysis, we compared HRs and 95% CIs for OS using structured index dates (ie, date of first antineoplastic, FMI report date) vs abstractor confirmed index dates (ie, advanced diagnosis date, first-line start date) across several other FH-FMI clinicogenomic data sets with abstractor confirmed data available and found that the structured and abstractor-confirmed index dates yielded similar results. As a result, we used the structured index date of FMI report date for this analysis. Other limitations include the potential for differences in characteristics for patients included in this study (ie, those for whom TMB testing was performed) and the broader population of patients with cancer and that MSI-H status was not ascertained in one-third of patients. Additionally, this study was not designed to evaluate whether specific mutations or types of mutations (eg, frameshift vs nonframeshift) were associated with prognosis.


This diagnostic/prognostic study found that prevalence of TMB-H varied widely across a range of solid tumors, and there was no association between TMB-H status and OS across the evaluated tumor types. These findings indicate that TMB-H does not have a prognostic association among patients with these tumor types in the absence of immunotherapy.

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Article Information

Accepted for Publication: September 14, 2020.

Published: October 29, 2020. doi:10.1001/jamanetworkopen.2020.25109

Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License. © 2020 Shao C et al. .

Corresponding Author: Changxia Shao, PhD, 770 Sumneytown Pike, Mailstop WP37A-250, West Point, PA 19486 ([email protected]).

Author Contributions: Drs Castellanos and Li had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Shao, Pruitt, Frampton, Snow, Zhou.

All authors.

Shao, Fabrizio.

Shao, Li, Huang, Pruitt, Castellanos, Frampton, Carson, Snow, Singal, Alexander, Jin, Zhou.

Li, Huang, Castellanos, Frampton.

Shao, Zhou.

Shao, Castellanos, Singal, Fabrizio, Alexander, Zhou.

Shao, Frampton, Carson, Alexander, Jin, Zhou.

Conflict of Interest Disclosures: Dr Shao reported owning stock in Merck and Co outside the submitted work. Dr Li reported receiving personal fees from Foundation Medicine and having equity ownership in F. Hoffmann-La Roche outside the submitted work. Dr Huang reported owning stock in Merck and Co outside the submitted work. Dr Castellanos reported owning equity in Flatiron Health and stock from Roche outside the submitted work. Dr Carson reported receiving personal fees from Tempus Labs and Flatiron Health outside the submitted work. Dr Snow reported receiving personal fees from and owning stock in Roche and owning equity in Flatiron Health outside the submitted work. Dr Fabrizio reported having a patent for Methods and Systems for Evaluating Tumor Mutational Burden pending. Dr Alexander reported receiving personal fees from Roche during the conduct of the study and grants from Eli Lilly and Co, Puma, and Celgene outside the submitted work. Dr Zhou reported receiving stock and stock options in Merck and Co outside the submitted work. No other disclosures were reported.

Funding/Support: Funding for this research was provided by Merck Sharp and Dohme, a subsidiary of Merck and Co.

Role of the Funder/Sponsor: Representatives of Merck and Co (including the authors) participated in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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Additional Contributions: Medical writing and editorial assistance was provided by Christabel Wilson, MSc (ICON, North Wales, Pennsylvania). This assistance was funded by Merck Sharp and Dohme, a subsidiary of Merck and Co. Additional study assistance was provided by Deepti Aurora-Garg, PhD; Razvan Cristescu, PhD; Sumesh Kachroo, PhD; and Jared Lunceford, PhD (Merck and Co, Kenilworth, New Jersey).


[NEW] TMB Consortium Develops a TMB Calibration Tool | tmb life care – Sonduongpaper

Estimation of tumour mutational burden (TMB) varies across different panels, with panel size, gene content, and bioinformatics pipelines contributing to empirical variability. Statistical calibration can achieve more consistent results across panels and allows for comparison of TMB values across various panel assays. The TMB Harmonization Project leveraged the expertise and insight of 16 different diagnostic laboratories to objectively evaluate the empirical variability across panel TMB values and to propose best practices for panel TMB alignment. The aim is to provide data and guidance that will help improve the consistency and reliability of panel tissue TMB estimation across platforms and facilitate the use of this complex biomarker in clinical decision making. To promote reproducibility and comparability across assays, the TMB Consortium developed a software tool and made it publicly available. The findings are described in an article published on 30 September 2021 in the Annals of Oncology.

The Friends of Cancer Research TMB Harmonization Consortium consists of several diagnostic manufacturers, academics, pharmaceutical companies, the US National Cancer Institute, Frederick National Laboratory for Cancer Research, and the US Food and Drug Administration. They previously reported results from the first phase of the TMB harmonisation project where the variability across 11 commercial and academic panel assays was described and Consortium-endorsed recommendations were proposed for the analytical validation of TMB assays. Furthermore, the TMB Consortium partnered with Quality in Pathology in Germany, to complement its approach and enrich its perspective on the variability in TMB estimates across laboratories through a technical comparability study.

TMB measurements aid in identifying patients who are likely to benefit from immunotherapy. However, there is empirical variability across panel assays and factors contributing to this variability have not been comprehensively investigated. In this study, the TMB Consortium set out to characterise the empirical variability in TMB measurements across platforms using a common set of cell lines and clinical samples tested across 16 panel assays from 16 participating laboratories.

They aimed to elucidate how certain factors such as panel size, gene content and bioinformatics pipelines impact TMB estimates, and to investigate the use of a calibration tool based on TCGA data and human tumour derived cell lines that will facilitate comparability across different panel assays.

The study team processed 29 tumour samples and 10 human-derived cell lines and distributed to 16 laboratories and each of them used their own bioinformatics pipelines to calculate TMB and compare to whole exome results. Additionally, theoretical positive percent agreement and negative percent agreement of TMB were estimated. The impact of filtering pathogenic and germline variants on TMB estimates was assessed. Calibration curves specific to each panel assay were developed to facilitate translation of panel TMB values to whole exome sequencing (WES) TMB values.

Panel sizes greater than 667Kb are necessary to maintain adequate positive percent agreement and negative percent for calling TMB high versus TMB low across the range of cut-offs used in practice. Failure to filter pathogenic variants when estimating panel TMB resulted in overestimating TMB relative to WES for all assays. Filtering out potential germline variants at >0% population minor allele frequency resulted in the strongest correlation to WES TMB.

Application of a calibration approach derived from TCGA data, tailored to each panel assay, reduced the spread of panel TMB values around the WES TMB as reflected in lower root mean squared error (RMSE) for 26 of 29 of the clinical samples (90%), although RMSE across samples at the laboratory level was less often reduced.

In this work the TMB Consortium demonstrated that the utilisation of a calibration tool based on a universal reference standard derived from TCGA data can enhance comparability of TMB across different panel assays. 

The Friends of Cancer Research TMB Harmonization initiative uses a distributed research model and costs incurred are supported by each participating organisation. Additional sources of funding were provided by AstraZeneca, Bristol-Myers Squibb, EMD Serono, Genentech and Merck & Company Inc.


Vega DM, Yee LM, McShane LM, et al. Aligning Tumor Mutational Burden (TMB) quantification across diagnostic platforms: Phase 2 of the Friends of Cancer Research TMB Harmonization Project. Annals of Oncology; Published online 30 September 2021. DOI: https://doi.org/10.1016/j.annonc.2021.09.016


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Hướng dẫn sử dụng máy đo huyết áp điện tử bắp tay Omron HEM-7121

Máy đo huyết áp điện tử Omron HEM7121
Giới thiệu sản phẩm
Tỷ lệ tăng huyết áp ở nước ta ngày càng tăng do lối sống hiện đại vội vã, bận rộn, thói quen sinh hoạt không điều độ. Nhiều người bị huyết áp không hề biết mình bị cho đến khi xảy ra tai biến hay các biến chứng về bệnh, lúc đó thì đã quá muộn. Chính vì vậy, chăm sóc sức khỏe bằng cách theo dõi huyết áp hàng ngày qua đó thay đổi lại lối sống, chế độ ăn uống luyện tập là cách đơn giản để “hạ gục” hoàn toàn bệnh tật.
Chi tiết sản phẩm: https://sieuthiyte.com.vn/maydohuyetapdientubaptayomronhem7121156.html
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Hướng dẫn sử dụng máy đo huyết áp điện tử bắp tay Omron HEM-7121




Chương trình Shark Tank phiên bản đặc biệt lần đầu tiên xuất hiện tại MB Ageas Life.
Liệu Startup HULK có chinh phục được dàn cá mập lão luyện của chúng ta?
Hãy cùng chờ đón những điều bất ngờ trong chương trình “Shark Tank by MBAL”, ra mắt vào ngày 21/10/2021 tới đây!
mbal starktank amazer


SISTAR’s fans singing ‘Give It To Me’ make SISTAR chills! 《Fantastic Duo》판타스틱 듀오 EP14

Fantastic Duo 판타스틱 듀오 EP14 20160717 SBS
쌍문동 애봉이, 씨스타로 인생역전, 영광 굴비소녀는 ‘Give It To Me ’ 불렀고, 씨스타의 멤버들은 소름이 돋으며 환호를 보낸다.
“Shall we sing a song together?”
What if you can received a love call from the top singers in Korea?
Anyone who has a smart phone can sing duet songs with Korea’s top singers in “Fantastic Duo”! Incredible collaboration and Amazing duet performances of singers and their fans starts here.
SBS Mucis Show ‘Singers in My Hands Fantastic Duo’ to be aired for the first time on April 17 2016 and it aris on every Sunday at 4:50pm.
☞ Visit ‘Fantastic Duo’ official website and get more information:
☞ Enjoy watching other best clips of ‘Fantastic Duo’ to follow:

SISTAR's fans singing ‘Give It To Me’ make SISTAR chills! 《Fantastic Duo》판타스틱 듀오 EP14

นอกจากการดูบทความนี้แล้ว คุณยังสามารถดูข้อมูลที่เป็นประโยชน์อื่นๆ อีกมากมายที่เราให้ไว้ที่นี่: ดูวิธีอื่นๆWiki

ขอบคุณมากสำหรับการดูหัวข้อโพสต์ tmb life care

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