Survival outcomes according to the tumor mutation burden and PD-L1 expression in hepatobiliary tumors.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 566-566
Author(s):  
Jorge Sánchez-García ◽  
Fidel Lopez-Verdugo ◽  
Andrew Gagnon ◽  
Diane Alonso ◽  
Shiro Fujita ◽  
...  
Keyword(s):  
Risk Factors ◽  
Checkpoint Inhibitors ◽  
Smoking Status ◽  
Immune Therapy ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Potential Biomarker ◽  
Significant Difference ◽  
Hepatobiliary Tumors ◽  
Next Generation Sequencing Ngs

566 Background: Hepatobiliary (HB) tumors are aggressive tumors with emerging evidence for increasing sensitivity to immune checkpoint inhibitors (ICI). Tumor mutation burden (TMB) was found to be a quantitative biomarker associated with production of neoantigens within the tumor and predict the sensitivity to immune therapy. Herein, we explore the TMB, microsatellite instability (MSI) and PD-L1 expression as a potential biomarker of response to immune therapy in HB tumors. Methods: We retrospectively assessed all patients with hepatobiliary malignancies who have undergone next generation sequencing (NGS) between October 2009 and June 2019. We then analysed the tumor mutation burden and PD-L1 of these tumors and also identified frequency of patients with no clinically actionable mutations. Results: In our total 61 patients with HB tumors predominantly were male (62.3%) with mean age of 63 years. Thirty-four patients had hepatocellular carcinoma, 22 patients had cholangiocarcinoma and 5 patients had gallbladder carcinoma. The most common risk factors were smoking status, cirrhosis, alcohol consumption and hepatitis C virus. The mean TMB reported was 3.2 (1.16 – 7.35). MSI was identified in 13 patients and one was indeterminate. Only 17 patients had PD-L1 positive. At least, 37 patients had one clinically actionable mutation while 24 patients had no clinically actionable mutations. Mean overall survival was 16.6 months, but no statistically significant difference was found by high PD-L1 (3 vs 3.7 months, p=0.3) expression. Conclusions: Our data suggests the TMB in HB tumors is low in general irrespective of their underlying risk factors. We also noted more than half had microsatellite stable tumors and PD-L1 expression. Future larger studies are needed to evaluate TMB, MSI and PD-L1 as a potential biomarker in hepatobiliary tumors to help select patients that will benefit from immune therapy.

Characterization of the tumor mutation burden in hepatobiliary tumors.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 295-295
Author(s):  
Ramya Thota ◽  
Bryce Christensen ◽  
Gail Fulde ◽  
Mark Andrew Lewis ◽  
Derrick S. Haslem ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Potential Biomarker ◽  
Underlying Risk Factor ◽  
Hepatobiliary Tumors ◽  
Next Generation Sequencing Ngs ◽  
Underlying Risk

295 Background: Hepatobiliary tumors are aggressive tumors with emerging evidence for increasing sensitivity to immune checkpoint inhibitors (ICI). Tumor mutation burden (TMB) was found to be a quantitative biomarker associated with production of neoantigens within the tumor and predict the sensitivity to immune therapy. Herein, we explore the TMB as a potential biomarker of response to immune therapy in hepatobiliary tumors. Methods: We retrospectively assessed all patients with hepatobiliary malignancies who have undergone next generation sequencing (NGS) between January 2013 and September 2018. We then analyzed the tumor mutation burden of these tumors and also identified frequency of patients with no clinically actionable mutations. Results: Of the 65 total patients with hepatobiliary tumors, 49 patients (75%) had at least one clinically actionable mutation while 16 patients (25%) had no clinically actionable mutations. Among 65 patients, 44 patients had hepatocellular carcinoma, 15 patients had cholangiocarcinoma and 6 patients had gallbladder carcinoma. The TMB data is available for 15 patients. The mean TMB reported was 2.7 (1.16 – 4.25), which suggests low mutation burden in general in all our HB tumors. Among the patients with available TMB, the underlying risk factor was noted as hepatitis C in 3, NASH in 1, others in 6, unknown in 5 patients. Conclusions: Our data suggests the TMB in hepatobiliary tumors is low in general irrespective of their underlying risk factors. Future larger studies are needed to evaluate TMB as a potential biomarker in hepatobiliary tumors to help select patients that will benefit from immune therapy.

Impact of prior chemotherapy or radiation therapy on tumor mutation burden in NSCLC.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2627-2627 ◽  
Author(s):  
Sushma Jonna ◽  
Ari M. Vanderwalde ◽  
Jorge J. Nieva ◽  
Kelsey Anne Poorman ◽  
Michelle Saul ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Somatic Mutations ◽  
Checkpoint Inhibitors ◽  
Smoking Status ◽  
Cytotoxic Chemotherapy ◽  
Missense Mutations ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Significant Difference ◽  
The Impact

2627 Background: Higher non-synonymous tumor mutation burden (TMB) in non-small cell lung cancer (NSCLC) is associated with a higher likelihood of response to checkpoint inhibitors. Tissue samples subject to TMB analysis may be obtained after exposure to cytotoxic chemotherapy or radiation therapy – both of which introduce somatic mutations in DNA and can influence the number of identified mutations. The role of TMB as a potential predictive marker for immunotherapy is evolving, and the impact of prior therapy on TMB could influence interpretation. Methods: Eligible cases were from patients with confirmed NSCLC, available clinical annotation and tumor molecular profiling including TMB analysis at a CLIA-certified genomics laboratory (Caris Life Sciences, Phoenix, AZ) using the Illumina NextSeq platform. TMB was calculated using only missense mutations that had not been previously reported as germline alterations. Treatment history was obtained for each patient under an IRB approved protocol to determine whether patients had had received chemotherapy or radiation therapy in the year prior to collection of the tissue subject to TMB analysis. Data analysis was performed using the chi-square test of deviance to evaluate whether TMB was statistically significantly different between groups, correcting for smoking status. Results: Out of 1,118 patients identified, 459 cases met all eligibility criteria and were evaluated. 76 patients (17%) received either chemotherapy or radiation prior to tissue collection. Samples acquired prior to any therapy had a median TMB of 10 mut/Mb vs. 11 mut/Mb in samples acquired after any therapy. After adjusting for smoking, there was no significant difference in TMB between these cohorts (p = 0.41). Secondary pair wise analysis showed no statistically significant difference in TMB from chemotherapy-naïve and chemotherapy-treated samples (p = 0.28). The same was true for radiation (p = 0.75). Collection of clinical data is ongoing and further analysis, including additional cases will be presented. Conclusions: Though cytotoxic chemotherapy and radiation therapy can introduce somatic mutations, prior exposure to either was not associated with a significant difference in TMB.

Comparison between whole exome sequencing (WES) and single nucleotide polymorphism (SNP)-based tumor mutation burden analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2634-2634
Author(s):  
Kirsten Timms ◽  
Andrey Zharkikh ◽  
Michael Perry ◽  
Nicolai Birkbak ◽  
Zoltan Szallasi ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Correlation Coefficients ◽  
Sequence Length ◽  
Tumor Mutation Burden ◽  
Germline Variants ◽  
Paired Samples ◽  
Score Threshold ◽  
Whole Exome ◽  
Mutation Burden ◽  
Significant Difference

2634 Background: Immune checkpoint inhibitors (ICI) block proteins which enable cancer cells to evade the immune system. Recent studies have shown that the higher the tumor mutation burden (TMB) the greater the likelihood of response to ICI therapy. Analysis of TMB has focused on WES of paired tumor and normal samples. This study tests the feasibility of measuring TMB from a SNP-based resequencing assay (myChoice HRD Plus). Methods: WES and myChoice HRD Plus were performed on matched tumor and normal DNA from 44 breast and 12 colon tumors. myChoice HRD Plus combines homologous recombination deficiency analysis with resequencing of 108 genes and microsatellite instability analysis. WES-based TMB was calculated by identifying all variants in paired samples, and subtracting germline variants. Two SNP-based TMB (SbTMB) methods were utilized to calculate TMB. The first used germline subtraction similar to the WES-based method. The second utilized an algorithm which removed background germline variants. Median sequence length to calculate TMB was 9.7 Mb for WES, 4.6 Mb for SbTMB (germline subtraction), and 1.9 Mb for SbTMB (algorithm). Results: Correlation coefficients for WES vs. SbTMB (germline subtraction) and SbTMB (algorithm) were 0.895 and 0.908, respectively. The two SbTMB methods had a correlation coefficient of 0.834. SbTMB measures of TMB were generally higher than WES-based TMB with a mean increase in score of 1.6 variants/Mb for SbTMB (germline subtraction; p = 4.6x10-6) and 1.5 variants/MB for SbTMB (algorithm; p = 1.2x10-5). No significant difference in magnitude of TMB score between the SbTMB measures was observed (0.04 variants/Mb; p = 0.88). Conclusions: SNP-based methods for calculating TMB produced highly concordant scores compared to WES-based methods. SbTMB assays produced elevated TMB scores, consistent with selective pressure against mutations in coding regions of genes, necessitating a higher score threshold for when using a SbTMB assay. This SbTMB analysis expands the utility of myChoice HRD Plus, and provides a method for calculation of TMB without sequencing a germline comparator.

Relationship of liver cancer with LRP1B or TP53 mutation and tumor mutation burden and survival.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1573-1573 ◽  
Author(s):  
Longrong Wang ◽  
Kai Yan ◽  
Jiamin Zhou ◽  
Ning Zhang ◽  
Miao Wang ◽  
...  
Keyword(s):  
Liver Cancer ◽  
Tp53 Mutation ◽  
Liver Tumors ◽  
Checkpoint Inhibitors ◽  
Poor Prognostic Factor ◽  
Tumor Mutation Burden ◽  
Synonymous Mutations ◽  
Clinical Cohort ◽  
Mutation Burden ◽  
Significant Difference

1573 Background: Liver cancer (LC), one of the most common causes of cancer-related deaths, is a serious medical problem due to the limited treatment options available for this disease. Immune checkpoint inhibitors (ICIs) that are proved to be beneficial in the treatment of advanced LC. Similar to observations in other cancers, these ICIs as monotherapy may benefit only a fraction of HCC patients. Tumor mutation burden (TMB) is an important predictor for efficacy of ICIs in several solid tumors. However, the research on exploring the association between TMB and mutant genes with high frequency of liver cancer is limited. Besides, previous research on prognostic factors primarily focus on pathological features, probing the effects of genetic variations are urgently needed to study. Methods: Whole-exome sequencing data of 377 liver tumors from the Cancer Genome Altas (TCGA) and next generation sequencing (NGS) data of 655 liver tumors from Chinese clinical dataset were analyzed to explore the associated between LRP1B or TP53 gene alteration and TMB. TMB was defined as total number of somatic non-synonymous mutations in coding region. Results: In total, 9.3% (35/377) of hepatic tumors in TCGA and 7.8% (51/655) in clinical cohort harboring LRP1B mutation. LRP1B mutation was significantly associated with higher TMB in both TCGA cohort (P = 0.0003) and clinical cohort (P = 0.0005). The frequency of TP53 mutation was 28.1% (106/377) in TCGA cohort, however, TP53 mutation represented a greater rate of 54.5% (357/655) in Chinese clinical cohort. TP53 mutation was also associated with higher TMB in the two cohort (P = 0.0005 for the TCGA cohort and P = 0.0010 for the clinical cohort). In addition, prognosis analysis was performed on patients in TCGA cohort. LRP1B statue resulted in significantly shorter overall survival (OS, median, 20.9 vs 61.7 months; HR, 2.22; P = 0.0012), and a decreasing trend on progression-free survival (PFS) without significant difference (median, 8.7 vs 16.6 months; HR, 1.28; P = 0.2839). TP53 mutation was an independent risk factors affecting both OS (HR 1.58, P = 0.0109) and PFS (HR 1.59, P = 0.0027), respectively. Conclusions: The results indicated that LRP1B or TP53 mutation was a poor prognostic factor in LC, and patients harboring any of these two gene mutations might easily benefit from the immunotherapy.

scholarly journals Comprehensive analysis of genomic mutation signature and tumor mutation burden for prognosis of intrahepatic cholangiocarcinoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Rui Zhang ◽  
Qi Li ◽  
Jialu Fu ◽  
Zhechuan Jin ◽  
Jingbo Su ◽  
...  
Keyword(s):  
Intrahepatic Cholangiocarcinoma ◽  
Cox Regression ◽  
Tnm Stage ◽  
Gene Set Enrichment Analysis ◽  
Functional Enrichment ◽  
Tumor Mutation Burden ◽  
Kaplan Meier ◽  
Mutation Burden ◽  
Significant Difference ◽  
Genomic Mutation

Abstract Background Intrahepatic cholangiocarcinoma (iCCA) is a highly lethal malignancy of the biliary tract. Analysis of somatic mutational profiling can reveal new prognostic markers and actionable treatment targets. In this study, we explored the utility of genomic mutation signature and tumor mutation burden (TMB) in predicting prognosis in iCCA patients. Methods Whole-exome sequencing and corresponding clinical data were collected from the ICGC portal and cBioPortal database to detect the prognostic mutated genes and determine TMB values. To identify the hub prognostic mutant signature, we used Cox regression and Lasso feature selection. Mutation-related signature (MRS) was constructed using multivariate Cox regression. The predictive performances of MRS and TMB were assessed using Kaplan–Meier (KM) analysis and receiver operating characteristic (ROC). We performed a functional enrichment pathway analysis using gene set enrichment analysis (GSEA) for mutated genes. Based on the MRS, TMB, and the TNM stage, a nomogram was constructed to visualize prognosis in iCCA patients. Results The mutation landscape illustrated distributions of mutation frequencies and types in iCCA, and generated a list of most frequently mutated genes (such as Tp53, KRAS, ARID1A, and IDH1). Thirty-two mutated genes associated with overall survival (OS) were identified in iCCA patients. We obtained a six-gene signature using the Lasso and Cox method. AUCs for the MRS in the prediction of 1-, 3-, and 5-year OS were 0.759, 0.732, and 0.728, respectively. Kaplan–Meier analysis showed a significant difference in prognosis for patients with iCCA having a high and low MRS score (P < 0.001). GSEA was used to show that several signaling pathways, including MAPK, PI3K-AKT, and proteoglycan, were involved in cancer. Conversely, survival analysis indicated that TMB was significantly associated with prognosis. GSEA indicated that samples with high MRS or TMB also showed an upregulated expression of pathways involved in tumor signaling and the immune response. Finally, the predictive nomogram (that included MRS, TMB, and the TNM stage) demonstrated satisfactory performance in predicting survival in patients with iCCA. Conclusions Mutation-related signature and TMB were associated with prognosis in patients with iCCA. Our study provides a valuable prognostic predictor for determining outcomes in patients with iCCA.

RNF43 mutations to predict survival from treatment with immune checkpoint inhibitors and are associated with a high tumor mutation burden in bladder cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16528-e16528
Author(s):  
Liping Li ◽  
Mengmei Yang ◽  
Mengli Huang
Keyword(s):  
Bladder Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Negative Regulator ◽  
Wilcoxon Test ◽  
Wild Type ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
The Impact

e16528 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1/L1 have been approved as first-line treatment for cisplatin-ineligible patients and as second-line therapy for patients with metastatic urothelial carcinoma of the bladder. Biomarkers can help select patients who are more likely to response to ICIs. RNF43 is an E3 ubiquitin ligase that acts as a negative regulator of Wnt/β-catenin signaling pathway. In colorectal cancer (CRC) patients treated with immune checkpoint inhibitors (ICIs), RNF43 mutations predicted longer overall survival (OS). The impact of RNF43 mutations on the efficiency of ICIs in bladder cancer(BLC) remains to be explored. Methods: We downloaded the mutation and clinical data of 211 BLC patients treated with ICIs from the immunotherapeutic cohort published by Samstein et al. (2019). OS analyses were conducted using Kaplan-Meier curves and log-rank tests. Wilcoxon test was used for the comparison of TMB. We also downloaded a TCGA cohort for prognostic analysis. The correlations between RNF43 and immune infiltrates were analyzed in the TIMER2.0 database. Statistical significance was set at p = 0.05. Results: RNF43 mutations were identified in 4.3%(9/211) and 3%(13/438) BLC patients in the immunotherapeutic and TCGA cohort, respectively. In the immunotherapeutic cohort, patients with RNF43 mutations had significantly longer OS (25 months vs 8 months; p = 0.015) and higher tumor mutation burden(TMB, 42.3 vs 7.9; p = 3.15E-06) than RNF43-wild-type patients. Different from this, no significant difference was found in OS between RNF43-mutant and RNF43-wild-type BLC patients with standard treatment in the TCGA cohort (p = 0.696). These results indicated that RNF43 was not a prognostic factor but a predictive biomarker of survival in BLC treated with ICIs. No difference was observed in subsets of immune cells between RNF43-mutant and the RNF43-wide-type BLC patients, including neutrophils, macrophages, CD8+ T cells, Tregs, B cells and NK cells. Conclusions: RNF43 mutations may be a predictor of survival benefit from ICIs in bladder cancer and correlated with higher TMB. Further studies in other ICI-treated cohorts are needed to confirm these results.

scholarly journals The Predictive Efficacy of Tumor Mutation Burden (TMB) on Nonsmall Cell Lung Cancer Treated by Immune Checkpoint Inhibitors: A Systematic Review and Meta-Analysis

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Zhang Nan ◽  
Wang Guoqing ◽  
Yu Xiaoxu ◽  
Mi Yin ◽  
He Xin ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Systematic Review ◽  
Cell Lung Cancer ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Nonsmall Cell Lung Cancer ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Nsclc Patients

Background. Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancer, and the majority of NSCLC patients are diagnosed at the advanced stage. Chemotherapy is still the main treatment at present, and the overall prognosis is poor. In recent years, immunotherapy has developed rapidly. Immune checkpoint inhibitors (ICIs) as the representative have been extensively applied for treating various types of cancers. Tumor mutation burden (TMB) as a potential biomarker is used to screen appropriate patients for treatment of ICIs. To verify the predictive efficacy of TMB, a systematic review and meta-analysis were conducted to explore the association between TMB and ICIs. Method. PubMed, EMBASE, Cochrane Library, and son on were systematically searched from inception to April 2020. Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were estimated. Results. A total of 11 studies consisting of 1525 nonsmall cell lung cancer (NSCLC) patients were included. Comparison of high and low TMB: pooled HRs for OS, 0.57 (95% CI 0.32 to 0.99; P = 0.046 ); PFS, 0.48 (95% CI 0.33 to 0.69; P < 0.001 ); ORR, 3.15 (95% CI 2.29 to 4.33; P < 0.001 ). Subgroup analysis values: pooled HRs for OS, 0.75 (95% CI 0.29 to 1.92, P = 0.548 ) for blood TMB (bTMB), 0.44 (95% CI 0.26 to 0.75, P = 0.003 ) for tissue TMB (tTMB); for PFS, 0.54 (95% CI 0.29 to 0.98, P = 0.044 ) and 0.43 (95% CI 0.26 to 0.71, P = 0.001 ), respectively. Conclusions. These findings imply that NSCLC patients with high TMB possess significant clinical benefits from ICIs compared to those with low TMB. As opposed to bTMB, tTMB was thought more appropriate for stratifying NSCLC patients for ICI treatment.

INITIAL EXPERIENCE IN ESTIMATING TUMOR MUTATION BURDEN IN PEDIATRIC HEPATOCELLULAR CARCINOMA

2021 ◽  
Vol 100 (3) ◽  
pp. 193-199
Author(s):  
D.G. Akhaladze ◽  
◽  
G.S. Rabaev ◽  
N.V. Zhukov ◽  
M.A. Pyatnitskiy ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Primary Tumor ◽  
Checkpoint Inhibitors ◽  
Pediatric Population ◽  
Case Series ◽  
Immune Checkpoints ◽  
Initial Experience ◽  
Tumor Mutation Burden ◽  
Detection Frequency ◽  
Mutation Burden

The level of tumor mutation burden (TMB) is a predictive factor of immune checkpoints that determines the potential effectiveness of immune checkpoint inhibitors and indications for their prescription regardless of the type of tumor in adults and children. However, the prevalence of tumors with high TMB in the pediatric population has not been well studied. Objective of the research: to assess the detection frequency of high TMB (>10 mutations per megabase) in pediatric hepatocellular carcinoma (HCC). Materials and methods of research: Next Generation Sequencing, Ion AmpliSeq™ Comprehensive Cancer Panel (409 genes) of tumor DNA samples from 4 children with HCC was performed. The calculation of the mutational load was carried out according to the work of Z.R. Chalmers et al. Results: out of 4 analyzed samples, TMB levels have lower cut-off value than needed for the immunity checkpoint inhibitors for 2 patients to administer: 5,9 mut/MB (primary tumor), 9,2 mut/MB (metastasis), while in 2 other patients the TMB has level above the threshold – 10,9 mut/MB (primary tumor) and 48,5 mut/MB (relapse metastasis), respectively. Conclusion: this paper presents the initial experience of estimation of the TMB level in children with HCC. In our case series report, the level allowing the prescription of immunotherapy (>10 mut/MB) was observed in 2 patients. Further research on a larger cohort of patients is useful to assess the role of mutational burden in disease prediction and effectiveness of immunotherapy.

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