scholarly journals Tumor Mutational Burden as a Pan-cancer Biomarker for Immunotherapy: The Limits and Potential for Convergence

Cancer Cell ◽  
2020 ◽  
Vol 38 (5) ◽  
pp. 624-625
Author(s):  
Antonio Passaro ◽  
Albrecht Stenzinger ◽  
Solange Peters
Keyword(s):  
Cancer Biomarker ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Pan Cancer

Abstract A027: Analytic validation of a pan-cancer tumor mutational burden assay

2018 ◽  
Author(s):  
Monica Nesselbush ◽  
Sian Jones ◽  
Laurel Keefer ◽  
Naomi Sengamalay ◽  
Victor Velculescu ◽  
...  
Keyword(s):  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Cancer Tumor ◽  
Pan Cancer

scholarly journals Cancer-Specific Thresholds Adjust for Whole Exome Sequencing–Based Tumor Mutational Burden Distribution

2019 ◽  
pp. 1-12
Author(s):  
Evan M. Fernandez ◽  
Kenneth Eng ◽  
Shaham Beg ◽  
Himisha Beltran ◽  
Bishoy M. Faltas ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Disease Stage ◽  
Cancer Type ◽  
Primary Tumors ◽  
Mutational Burden ◽  
Whole Exome ◽  
Significant Difference ◽  
Tumor Mutational Burden ◽  
Pan Cancer

PURPOSE To understand the clinical context of tumor mutational burden (TMB) when comparing a pan-cancer threshold and a cancer-specific threshold. MATERIALS AND METHODS Using whole exome sequencing data from primary tumors in The Cancer Genome Atlas (n = 3,534) and advanced and/or metastatic tumors from Weill Cornell Medicine Advanced (n = 696), TMB status was determined using a pan-cancer and cancer-specific threshold. Survival curves, number of samples classified as TMB high, and predicted neoantigens were used to evaluate the differences between thresholds. RESULTS The distribution of TMB varied dramatically among cancer types. A cancer-specific threshold was able to adjust for the different TMB distributions, whereas the pan-cancer threshold was often too stringent. The dynamic nature of the cancer-specific threshold resulted in more tumors being classified as TMB high compared with the static pan-cancer threshold. In addition, no significant difference in survival outcomes was found with the cancer-specific threshold compared with the pan-cancer threshold. Furthermore, the cancer-specific threshold maintained higher predicted neoantigen load for the TMB-high samples compared with the TMB-low samples, even when the threshold was lower than the pan-cancer threshold. CONCLUSION TMB is determined within the context of cancer type, metastatic state, and disease stage. Compared with a pan-cancer threshold, a cancer-specific threshold classifies more patients as TMB high while maintaining clinical outcomes that are not significantly different. Furthermore, the cancer-specific threshold identifies patients with a high number of predicted neoantigens. Because of the potential impact in the care of patients with cancer, TMB status should be determined in a cancer-specific manner.

scholarly journals Pan-cancer analysis of the effect of biopsy site on tumor mutational burden observations

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Simon Papillon-Cavanagh ◽  
Julia F. Hopkins ◽  
Shakti H. Ramkissoon ◽  
Lee A. Albacker ◽  
Alice M. Walsh
Keyword(s):  
Predictive Biomarker ◽  
Collection Site ◽  
Measurement Variability ◽  
Mutational Burden ◽  
Biopsy Site ◽  
Specific Manner ◽  
Tumor Mutational Burden ◽  
Nsclc Patients ◽  
Pan Cancer ◽  
Shed Light

Abstract Background Tumor mutational burden (TMB) has been proposed as a predictive biomarker of response to immunotherapy. Efforts to standardize TMB scores for use in the clinic and to identify the factors that could impact TMB scores are of high importance. However, the biopsy collection site has not been assessed as a factor that may influence TMB scores. Methods We examine a real-world cohort comprising 137,771 specimens across 47 tissues in 12 indications profiled by the FoundationOne assay (Foundation Medicine, Cambridge, MA) to assess the prevalence of biopsy sites for each indication and their TMB scores distribution. Results We observe a wide variety of biopsy sites from which specimens are sent for genomic testing and show that TMB scores differ in a cancer- and tissue-specific manner. For example, brain or adrenal gland specimens from NSCLC patients show higher TMB scores than local lung specimens (mean difference 3.31 mut/Mb; p < 0.01, 3.90 mut/Mb; p < 0.01, respectively), whereas bone specimens show no difference. Conclusions Our data shed light on the biopsied tissue as a driver of TMB measurement variability in clinical practice.

scholarly journals Pan-cancer analysis of tumor mutational burden and homologous recombination DNA damage repair by targeted next-generation sequencing

2020 ◽  
Author(s):  
Hai-Yun Wang ◽  
Ling Deng ◽  
Ying-Qing Li ◽  
Xiao Zhang ◽  
Ya-Kang Long ◽  
...  
Keyword(s):  
Dna Damage ◽  
Treatment Response ◽  
Targeted Next Generation Sequencing ◽  
Mutational Burden ◽  
Damage Repair ◽  
Tumor Mutational Burden ◽  
Cancer Types ◽  
Gene Panels ◽  
Pan Cancer ◽  
Generation Sequencing

Abstract Background: Current variability in methods for tumor mutational burden (TMB) estimation and reporting urges the need for a homogeneous TMB assessment. Here we compared the TMB distributions in different cancer types using two customized targeted panels commonly used in clinical practice. Methods: TMB spectrum of the 295- and 1021-Gene panels in multiple cancer types were compared using targeted next-generation sequencing (NGS). Then the TMB distributions across a diverse cohort of 2,332 cancer cases were investigated for their associations to clinical features. Treatment response data was collected for 222 patients who received immune-checkpoint inhibitors (ICIs) and their homologous recombination DNA damage repair (HR-DDR) and PD-L1 expression were additionally assessed, and compared with TMB and response rate. Results: The median TMB between the gene panels were similar despite wide range in TMB values. Highest TMB was 8 and 10 in patients with squamous cell carcinoma and esophageal carcinoma according to the classification of histopathology and cancer types, respectively. Patients with high TMB and HR-DDR positive status could benefit from ICIs therapies (23 patients versus 7 patients with treatment response, P = 0.004). Additionally, PD-L1 expression was not associated with TMB and treatment response among patients receiving ICIs. Conclusions: Targeted NGS assays demonstrated advantageous ability to evaluate TMB in pan-cancer samples as a tool to predict response to ICIs. Also, TMB integrated with HR-DDR positive status could be a significant biomarker for predicting ICIs response in patients.

scholarly journals What is the burden of proof for tumor mutational burden in gliomas?

2020 ◽  
Author(s):  
Mustafa Khasraw ◽  
Kyle M Walsh ◽  
Amy B Heimberger ◽  
David M Ashley
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Solid Tumors ◽  
Treatment Options ◽  
Burden Of Proof ◽  
Predictive Biomarkers ◽  
Cns Tumors ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Pan Cancer

Abstract The treatment of patients with a variety of solid tumors has benefitted from immune checkpoint inhibition targeting the anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis. The US Food and Drug Administration (FDA) granted accelerated approval of PD-1 inhibitor, pembrolizumab, for the treatment of adult and pediatric patients with high tumor mutational burden (TMB-H), solid tumors that have progressed following prior treatment, and who have no other treatment options, including the extension to tumors of the central nervous system (CNS). In general, pan-cancer approvals are viewed positively to empower patients and clinicians. There are subsets (eg, BRAF, NTRK) for which this pathway for approval is appropriate. However, the pan-cancer FDA approval of pembrolizumab raises several concerns regarding the generalizability of the evidence to other tumor types, including managing patients with gliomas and other CNS tumors. The cutoff for TMB-H is not well defined. There are intrinsic immunological differences between gliomas and other cancers types, including the immunosuppressive glioma microenvironment, the tumor’s effects on systemic immune function, and the transformation of the T-cell populations to an exhausted phenotype in glioma. Here, we address the caveats with pan-cancer approvals concerning gliomas and complexities of the unique CNS immune environment, discuss potential predictive biomarkers, including TMB, and explain why the recent approval should be applied with caution in CNS tumors.

scholarly journals Clinically significant genomic alterations in the Chinese and Western patients with intrahepatic cholangiocarcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shifeng Xu ◽  
Yuan Guo ◽  
Yanwu Zeng ◽  
Zhijian Song ◽  
Xiaodan Zhu ◽  
...  
Keyword(s):  
Future Development ◽  
Intrahepatic Cholangiocarcinoma ◽  
Chinese Patients ◽  
Cancer Genes ◽  
Genomic Alterations ◽  
Driver Genes ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Clinically Significant ◽  
Pan Cancer

Abstract Background The goal of this study is to disclose the clinically significant genomic alterations in the Chinese and Western patients with intrahepatic cholangiocarcinoma. Methods A total of 86 Chinese patients were enrolled in this study. A panel of 579 pan-cancer genes was sequenced for the qualified samples from these patients. Driver genes, actionability, and tumor mutational burden were inferred and compared to a cohort of Western patients. Results Totally, 36 and 12 driver genes were identified in the Chinese and Western cohorts, respectively. Of them, seven driver genes (IDH1, KRAS, TP53, BAP1, PBRM1, ARID1A, and NRAS) were shared by the two cohorts. Four driver genes (SPTA1, ARID2, TP53, and GATA1) were found significantly correlated with the tumor mutational burden. For both cohorts, half of the patients had actionable mutations. The two cohorts shared the most actionable genes but differed much in their frequency. Though KRAS mutations were at the first and second actionable rank respectively for the Chinese and Western populations, they were still at a relatively low level of actionable evidence. Conclusions The study on the clinical significance of genomic alterations directs the future development of precision medicine for intrahepatic cholangiocarcinoma treatment.

Sign in / Sign up

Export Citation Format

Share Document