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Tumor Mutational Burden Determined by Panel Sequencing Predicts Survival After Immunotherapy in Patients With Advanced Gastric Cancer.

ABSTRACT: Objective: Panel-based sequencing is widely used to measure tumor mutational burden (TMB) in clinical trials and is ready to enter routine diagnostics. However, cut-off points to distinguish "TMB-high" from "TMB-low" tumors are not consistent and the clinical implications of TMB in predicting responses to immune checkpoint blockade (ICB) in gastric cancer are not clearly defined. We aimed to assess whether TMB is associated with the response to immunotherapy and to examine its relation with other biomarkers of immunotherapy response in advanced gastric cancer. Design: In total, 63 patients with advanced gastric cancer treated with ICB were included in the study. Panel-based TMB in gastric tumor samples, treatment responses to ICB, clinicopathological data, and time to progression were retrospectively analyzed. Microsatellite instability (MSI) status, Epstein-Barr virus (EBV) positivity, and programmed death-ligand 1 (PD-L1) combined positive score (CPS) were also analyzed. Results: TMB ranged from 0 to 446 mutations/megabase (mt/mb) and was significantly associated with MSI (P < 0.001), PD-L1 CPS (P = 0.022), response to ICB (P = 0.04), chemotherapy (P = 0.02) and older patient age (?65 years; P = 0.0014). The cut-off point of 14.31 mt/mb determined by log-rank statistics for progression-free survival divided the tumors into eight (12.7%) TMB-high and 55 (87.3%) TMB-low tumors. The median TMB of the chemo-refractory group was significantly higher (8.43 mt/mb) compared to that of chemo-naïve group (3.42 mt/mb) (P = 0.02). Patients with TMB-high tumors showed prolonged progression-free survival in univariate [HR, 0.32; 95% confidence interval (CI), 0.12-0.90] and multivariate (HR, 0.21; 95% CI, 0.07-0.69) analyses. In area under the receiver operating curve (AUC) analysis of TMB, PD-L1, EBV, MSI, and their combination, the AUC value was the highest for EBV (0.97), followed by MSI (0.96), PD-L1 (0.81), the combination (0.78), and TMB (0.56). Conclusion: In addition to EBV, MSI, and PD-L1 CPS, TMB could be used as a predictive biomarker in patients with advanced gastric cancer treated with ICB and may aid clinical decision making.

SUBMITTER: Kim J

PROVIDER: S-EPMC7082319 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Tumor Mutational Burden Determined by Panel Sequencing Predicts Survival After Immunotherapy in Patients With Advanced Gastric Cancer.

Kim Jinchul J Kim Binnari B Kang So Young SY Heo You Jeong YJ Park Se Hoon SH Kim Seung Tae ST Kang Won Ki WK Lee Jeeyun J Kim Kyoung-Mee KM

Frontiers in oncology 20200313

<b>Objective:</b> Panel-based sequencing is widely used to measure tumor mutational burden (TMB) in clinical trials and is ready to enter routine diagnostics. However, cut-off points to distinguish "TMB-high" from "TMB-low" tumors are not consistent and the clinical implications of TMB in predicting responses to immune checkpoint blockade (ICB) in gastric cancer are not clearly defined. We aimed to assess whether TMB is associated with the response to immunotherapy and to examine its relation wi ...[more]

PMID: 32232003

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Project description:BackgroundTumor mutational burden (TMB) is a promising biomarker for stratifying patient subpopulation who would benefit from immune checkpoint blockade (ICB) therapies. Although great efforts have been made for standardizing TMB measurement, mutation calling and TMB quantification can be challenging in samples with low tumor content including liquid biopsies. The effect of varying tumor content on TMB estimation by different assay methods has never been systematically investigated.MethodWe established a series of reference standard DNA samples derived from 11 pairs of tumor-normal matched human cell lines across different cancer types. Each tumor cell line was mixed with its matched normal at 0% (control), 1%, 2%, 5%, and 10% mass-to-mass ratio to mimic the clinical samples with low tumor content. TMB of these reference standards was evaluated by both ∼1000× whole-exome sequencing (wesTMB) and targeted panel sequencing (psTMB) at four different vendors. Both regression and classification analyses of TMB were performed for theoretical investigation and clinical practice purposes.ResultsLinear regression model was established that demonstrated in silico psTMB determined by regions of interest (ROI) as a great representative of wesTMB based on TCGA dataset. It was also true in our reference standard samples as the predicted psTMB interval based on the observed wesTMB captured the intended 90% of the in silico psTMB values. Although ∼1000× deep WES was applied, reference standard samples with less than 5% of tumor proportions are below the assay limit of detection (LoD) of wesTMB quantification. However, predicted wesTMB based on observed psTMB accurately classify (>0.97 AUC) for TMB high and low patient stratification even in samples with 2% of tumor content, which is more clinically relevant, as TMB determination should be a qualitative assay for TMB high and low patient classification. One targeted panel sequencing vendor using an optimized blood psTMB pipeline can further classify TMB status accurately (>0.82 AUC) in samples with only 1% of tumor content.ConclusionsWe developed a linear model to establish the quantitative correlation between wesTMB and psTMB. A set of DNA reference standards was produced in aid to standardize TMB measurements in samples with low tumor content across different targeted sequencing panels. This study is a significant contribution aiming to harmonize TMB estimation and extend its future application in clinical samples with low tumor content including liquid biopsy.

Project description:BackgroundSerum tumor markers including AFU, AFP, CEA, CA199, CA125 and CA724, are of great importance in the diagnosis, prognostic prediction and recurrence monitoring of gastrointestinal malignancies. However, their significance in gastric cancer (GC) patients with neoadjuvant therapy (NCT) is still uncertain. The aim of this study was to evaluate the predictive value of these six tumor markers in locally advanced GC patients who underwent NCT and curative surgery.MethodsIn total, 290 locally advanced GC patients who underwent NCT and D2 radical gastrectomy were retrospectively analyzed. Data on their tumor markers before (pre-) and after (post-) NCT and pathological characteristics were extracted from the database of our hospital. The optimal cutoff values of the six tumor markers were calculated by the ROC curve and Youden index. Their predictive significance was analyzed and survival curves for overall survival (OS) were obtained by the Kaplan-Meier method. Associations between categorical variables were explored by the chi-square test or Fisher's exact test. Multivariate analyses were performed by the Cox regression model.ResultsPre- and post-CA199, -CA125 and -CA724 could predict overall survival (all P < 0.05), but only the change (diff-) of CA199 was related to prognosis (P = 0.05). In the multivariable analysis, pre- (P = 0.014) and post-CA724 (P = 0.036) remained significant, though diff-CA724 was not an independent prognostic factor (P = 0.581). In addition, pre- and post-CA199, -CA125 and -CA724 were associated with lymph node metastasis (N- vs N+) and pathological stage (I-II vs III) (all P < 0.05). Moreover, post-CA724 was related to the vascular or lymphatic invasion (P = 0.019), while pre-CA724 was not (P = 0.082). However, AFU, AFP and CEA showed no association with survival (P > 0.05).ConclusionsCA724 is an independent factor for prognosis and could be used to predict ypN and ypTNM stage in locally advanced GC patients undergoing NCT and curative resection.

Project description:BackgroundImmune checkpoint blockade is effective against many cancer types, but few patients achieve a complete response (OR). Therefore, effective prognostic biomarkers are needed for metastatic gastric cancer (GC) patients after immune treatment. The present study assessed the value of hematological parameters as markers of the effectiveness of immune checkpoint blockade among metastatic GC patients.MethodsThis retrospective study included patients with metastatic GC who underwent multiline chemotherapy including at least two courses of immunotherapy between September 2018 and December 2020. Patient and tumor characteristics were tested for prognostic significance by analysis of variance or chi-square test. Kaplan-Meier and Cox analyses were performed to identify factors associated with progression-free survival (PFS).ResultsSixty-one GC patients (mean age 55.61±11.97 years, range 23-80 years, 24 females, and 37 males) were included, and 27, 9 and 25 cases had organ only, peritoneum only, and simultaneous organ and peritoneum metastasis, respectively. Gastrectomy was performed in 24 cases, and there was no operative treatment in the other 37 cases, while all patients received two or more lines of chemotherapy. After immune treatment, 13 patients achieved a partial response (PR), 16 stable disease (SD), and 32 progressive disease (PD). The median PFS was 4.93±3.47 months. An alkaline phosphatase (ALP) level >225 U/L, a lactate dehydrogenase level (LDH) >299 U/L, and a body mass index (BMI) >24 kg/m2 were associated with a short PFS (P=0.01, P=0.008, and P=0.039, respectively). A Cox multivariate proportional hazard model indicated that higher ALP level was a significant prognostic indicator for adverse PFS.ConclusionsOur data show an ALP cutoff of 225 U/L offered good prognostic sensitivity for HER2-negative metastatic GC. ALP measurement represents a convenient, cost-effective, and relatively sensitive screening tool, and prospective studies involving its evaluation in addition to other biomarkers in metastatic GC patients are indicated.

Dataset Information

Tumor Mutational Burden Determined by Panel Sequencing Predicts Survival After Immunotherapy in Patients With Advanced Gastric Cancer.

Publications

Tumor Mutational Burden Determined by Panel Sequencing Predicts Survival After Immunotherapy in Patients With Advanced Gastric Cancer.

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