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.

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 genomic alterations as biomarkers of immune checkpoint inhibitor (ICI) response in metastatic urothelial carcinoma (mUC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 400-400
Author(s):  
Matthew Labriola ◽  
Jason Zhu ◽  
Rajan Gupta ◽  
Shannon McCall ◽  
Jennifer Jackson ◽  
...  
Keyword(s):  
Clinical Information ◽  
Personal Genome ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Potential Biomarker ◽  
Wide Range ◽  
Metastatic Urothelial Carcinoma ◽  
Underlying Mechanisms ◽  
Fgfr3 Mutations

400 Background: ICIs have expanded therapeutic options for mUC patients (pts); however, biomarkers such as PD-L1 have not served as reliable predictors of treatment efficacy. High tumor mutation burden (TMB) has been previously described as a potential biomarker for predicting ICI response in several indications, but its utility is still being explored in mUC. Here, we compare the genomic landscapes and clinical outcomes of mUC pts following ICI therapy using an investigational solid tissue-based next-generation sequencing assay to assess TMB and identify genetic correlates of ICI response. Methods: 20 pts with mUC treated with ICIs at Duke Cancer Institute were identified. Tumor samples were retrospectively evaluated with a Personal Genome Diagnostics Assay for somatic variants across > 500 genes, as well as TMB and microsatellite status. Tumor samples were also stained for PD-L1 status using the Dako 22C3 IHC assay. Deidentified clinical information was extracted from the medical record and tumor response was evaluated using RECIST 1.1 criteria. Results: Pts were grouped by overall response following ICI therapy as either responders (“R”, n = 6) or non-responders (“NR”, n = 13). Pts exhibited a wide range of TMB scores (0.7 to 30.4 mutations/Mb), with a mean TMB score of 9.60 vs. 3.87 mut/Mb in R vs NR groups, respectively; however, this difference was not statistically significant ( p = 0.284). 18 pts were evaluated for PD-L1 status, with only 2 positive samples (one in each group). Rs had significantly more mutations in histone methylation genes (KDM6A, KMT2C, and KMT2D), (67% vs 15% in NRs, p = 0.0039). FGFR3 mutations were also more frequent in R vs NR (67% vs 5%, p = 0.0339). Finally, there was a higher frequency of mutations in TP53 and BRCA1 in the NRs. Conclusions: In this mUC cohort, neither TMB nor PD-L1 correlated with response to ICI therapy. Histone modifying genes and FGFR3 mutations were more frequent in responders, whereas BRCA1 and TP53 mutations were enriched in non-responders, warranting future prospective studies to understand underlying mechanisms of ICI response and resistance in mUC.

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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