DNA damage response and repair (DDR) gene mutations and correlation with tumor mutation burden (TMB) in non-small cell lung cancer (NSCLC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9100-9100 ◽  
Author(s):  
Hirva Mamdani ◽  
Jerry Chen ◽  
Seongho Kim ◽  
Yahya Ibrahim ◽  
Mohammad Fahad Bin Asad ◽  
...  
Keyword(s):  
Dna Repair ◽  
Immune Checkpoint ◽  
Gene Mutations ◽  
Predictive Biomarker ◽  
Immune Checkpoint Blockade ◽  
Parp Inhibition ◽  
Tumor Evolution ◽  
Immune Biomarkers ◽  
Dna Repair Deficiency ◽  
Brca1 Brca2

9100 Background: Loss of DNA repair fidelity is a common feature of human cancers and can drive genomic instability and tumor evolution. DNA repair deficiency has also emerged as a predictive biomarker of response to PARP inhibition and more recently to immune checkpoint inhibition. Information on relationship between DNA repair defects and TMB in NSCLC is limited. Methods: We analyzed molecular profiles of 5667 NSCLC tumors harboring mutations in DDR genes ( ATM, ATR, BARD1, BLM, BRCA1/2, BRIP1, CHEK1/2, ERCC2/3, FANCA/C/D2/E/F/G/L, MLH1, MSH2/6, MRE11, NBN, PALB2, POLE, PTEN, RAD50/51, WRN). Profiles included next-generation sequencing of 592 genes, TMB, and PD-L1 (22c3) by immunohistochemistry. Association of DDR gene mutations with immune biomarkers (TMB and PD-L1) was assessed. Results: Of the 5667 samples, 54% (n = 3060) had high TMB (defined as ≥10 mutations/Mb) with median TMB of 14 (range, 10-168). Among the remaining 46% (n = 2607) with low TMB, median TMB was 7 (range, 1-9). PD-L1 expression was high (≥50%) in 33% (n = 1878), intermediate (1-49%) in 26% (n = 1446), and negative ( < 1%) in 41% (n = 2343). Among all DDR mutated pts, 19% (n = 1058) had both high PD-L1 and high TMB, 35% (n = 2002) had high TMB alone, 15% (n = 820) had high PD-L1 alone. Most commonly mutated genes were RAD50 (52%), WRN (29%), CHEK2 (20%), ATM (19%), MRE11 (19%), and ATR (18%). Genes with a high likelihood of being associated with high TMB were ATM, ATR, BARD1, BRCA1, BRCA2, ERCC2, ERCC3, FANCA, MSH2, PALB2, and POLE. Strongest association was seen with BRCA1 (OR 1.81, 95% CI 1.47-2.22), PALB2 (OR 1.76, 95% CI 1.40-2.21), and POLE (OR 1.71, 95% CI 1.45-2.01). DDR genes mutations were not mutually exclusive - 77.5% (n = 4397) had 2 or more mutated genes. Tumors with ≥3 mutated genes were more likely to be associated with high TMB. No such correlation was observed with PD-L1 expression. Conclusions: The majority of NSCLC pts harboring DDR gene mutations have high TMB. Presence of ≥3 gene mutations and BRCA1, PALB2, and POLE mutations strongly correlate with high TMB. These patients may represent a unique subset that is more likely to benefıt from immune checkpoint blockade and PARP inhibition.

scholarly journals Mutations Associated with No Durable Clinical Benefit to Immune Checkpoint Blockade in Non-S-Cell Lung Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1397
Author(s):  
Guangsheng Zhu ◽  
Dian Ren ◽  
Xi Lei ◽  
Ruifeng Shi ◽  
Shuai Zhu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Lung Cancer ◽  
Immune Checkpoint ◽  
Clinical Benefit ◽  
Gene Mutations ◽  
Predictive Biomarker ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Related Gene ◽  
Nsclc Patients

(1) Background: The immune checkpoint blockade (ICB) has shown promising efficacy in non-small-cell lung cancer (NSCLC) patients with significant clinical benefits and durable responses, but the overall response rate to ICBs is only 20%. The lack of responsiveness to ICBs is currently a central problem in cancer immunotherapy. (2) Methods: Four public cohorts comprising 2986 patients with NSCLC were included in the study. We screened 158 patients with NSCLC with no durable clinical benefit (NDB) to ICBs in the Rizvi cohort and identified NDB-related gene mutations in these patients using univariate and multivariate Cox regression analyses. Programmed death-ligand 1 (PD-L1) expression, tumor mutation burden (TMB), neoantigen load, tumor-infiltrating lymphocytes, and immune-related gene expression were analyzed for identifying gene mutations. A comprehensive predictive classifier model was also built to evaluate the efficacy of ICB therapy. (3) Results: Mutations in FAT1 and KEAP1 were found to correlate with NDB in patients with NSCLC to ICBs; however, the analysis suggested that only mutation in FAT1 was valuable in predicting the efficacy of ICB therapy, and that mutation in KEAP1 acted as a prognostic but not a predictive biomarker for NSCLC. Mutations in FAT1 were associated with a higher TMB and lower multiple lymphocyte infiltration, including CD8 (T-Cell Surface Glycoprotein CD8)+ T cells. We established a prognostic model according to PD-L1 expression, TMB, smoking status, treatment regimen, treatment type, and FAT1 mutation, which indicated good accuracy by receiver operating characteristic (ROC) analysis (area under the curve (AUC) for 6-months survival: 0.763; AUC for 12-months survival: 0.871). (4) Conclusions: Mutation in FAT1 may be a predictive biomarker in patients with NSCLC who exhibit NDB to ICBs. We proposed an FAT1 mutation-based model for screening more suitable NSCLC patients to receive ICBs that may contribute to individualized immunotherapy.

HLA-A*03 is a Predictive Biomarker of Poor Response to Immune Checkpoint Blockade in Cancer

2021 ◽  
Author(s):  
Vivek Naranbhai ◽  
Mathias Viard ◽  
Michael Dean ◽  
Stefan Groha ◽  
David A. Braun ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Poor Response ◽  
Predictive Biomarker ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade

scholarly journals Germline HLA-B evolutionary divergence influences the efficacy of immune checkpoint blockade therapy in gastrointestinal cancer

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Zhihao Lu ◽  
Huan Chen ◽  
Xi Jiao ◽  
Yujiao Wang ◽  
Lijia Wu ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Gene Mutations ◽  
Human Leukocyte ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Cancer Center ◽  
Driver Gene ◽  
Evolutionary Divergence ◽  
Rna Profiling ◽  
Gi Cancer

Abstract Background The human leukocyte antigen class I (HLA-I) genotype has been linked with differential immune responses to infectious disease and cancer. However, the clinical relevance of germline HLA-mediated immunity in gastrointestinal (GI) cancer remains elusive. Methods This study retrospectively analyzed the genomic profiling data from 84 metastatic GI cancer patients treated with immune checkpoint blockade (ICB) recruited from Peking University Cancer Hospital (PUCH). A publicly available dataset from the Memorial Sloan Kettering (MSK) Cancer Center (MSK GI cohort) was employed as the validation cohort. For the PUCH cohort, we performed HLA genotyping by whole exome sequencing (WES) analysis on the peripheral blood samples from all patients. Tumor tissues from 76 patients were subjected to WES analysis and immune oncology-related RNA profiling. We studied the associations of two parameters of germline HLA as heterozygosity and evolutionary divergence (HED, a quantifiable measure of HLA-I evolution) with the clinical outcomes of patients in both cohorts. Results Our data showed that neither HLA heterozygosity nor HED at the HLA-A/HLA-C locus correlated with the overall survival (OS) in the PUCH cohort. Interestingly, in both the PUCH and MSK GI cohorts, patients with high HLA-B HED showed a better OS compared with low HLA-B HED subgroup. Of note, a combinatorial biomarker of HLA-B HED and tumor mutational burden (TMB) may better stratify potential responders. Furthermore, patients with high HLA-B HED were characterized with a decreased prevalence of multiple driver gene mutations and an immune-inflamed phenotype. Conclusions Our results unveil how HLA-B evolutionary divergence influences the ICB response in patients with GI cancers, supporting its potential utility as a combinatorial biomarker together with TMB for patient stratification in the future.

Immune checkpoint inhibitor sensitivity of DNA repair deficient tumors

Immunotherapy ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 1205-1213
Author(s):  
Pauline Rochefort ◽  
Françoise Desseigne ◽  
Valérie Bonadona ◽  
Sophie Dussart ◽  
Clélia Coutzac ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Repair ◽  
Immune Checkpoint ◽  
Genome Stability ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Excision Repair ◽  
Checkpoint Inhibitors ◽  
Repair Deficiency ◽  
Dna Repair Deficiency

Faithful DNA replication is necessary to maintain genome stability and implicates a complex network with several pathways depending on DNA damage type: homologous repair, nonhomologous end joining, base excision repair, nucleotide excision repair and mismatch repair. Alteration in components of DNA repair machinery led to DNA damage accumulation and potentially carcinogenesis. Preclinical data suggest sensitivity to immune checkpoint inhibitors in tumors with DNA repair deficiency. Here, we review clinical studies that explored the use of immune checkpoint inhibitor in patient harboring tumor with DNA repair deficiency.

scholarly journals Role of tumor gene mutations in treatment response to immune checkpoint blockades

2019 ◽  
Vol 2 (2) ◽  
pp. 100-109 ◽  
Author(s):  
Manni Wang ◽  
Liu Yu ◽  
Xiawei Wei ◽  
Yuquan Wei
Keyword(s):  
Gene Expression ◽  
Treatment Response ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Immune Checkpoint ◽  
Gene Mutations ◽  
Immune Checkpoint Blockade ◽  
Recent Developments ◽  
Tumor Gene

AbstractEarly studies shed light on the immune suppression of immune checkpoint molecules in the cancer microenvironment, with later studies applying immune checkpoint blockade (ICB) in treatment of various malignancies. Despite the encouraging efficacy of ICBs in a substantial subset of cancer patients, the treatment response varies. Gene mutations of both tumor cells and immune cells in the tumor microenvironment have recently been identified as potential predictors of the ICB response. Recent developments in gene expression profiling of tumors have allowed identification of a panel of mutated genes that may affect tumor cell response to ICB treatment. In this review, we discuss the association of the ICB response with gene expression and mutation profiles in tumor cells, which it is hoped will help to optimize the clinical application of ICBs in cancer patients.

scholarly journals Circulating Tumor Cell PD-L1 Expression as Biomarker for Therapeutic Efficacy of Immune Checkpoint Inhibition in NSCLC

Cells ◽  
2019 ◽  
Vol 8 (8) ◽  
pp. 809 ◽  
Author(s):  
Kloten ◽  
Lampignano ◽  
Krahn ◽  
Schlange
Keyword(s):  
Lung Cancer ◽  
Immune Checkpoint ◽  
Advanced Nsclc ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarker ◽  
Immune Checkpoint Blockade ◽  
Tissue Samples ◽  
Programmed Death ◽  
Nsclc Patients

Over the last decade, the immune checkpoint blockade targeting the programmed death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis has improved progression-free and overall survival of advanced non-small cell lung cancer (NSCLC) patients. PD-L1 tumor expression, along with tumor mutational burden, is currently being explored as a predictive biomarker for responses to immune checkpoint inhibitors (ICIs). However, lung cancer patients may have insufficient tumor tissue samples and the high bleeding risk often prevents additional biopsies and, as a consequence, immunohistological evaluation of PD-L1 expression. In addition, PD-L1 shows a dynamic expression profile and can be influenced by intratumoral heterogeneity as well as the immune cell infiltrate in the tumor and its microenvironment, influencing the response rate to PD-1/PD-L1 axis ICIs. Therefore, to identify subgroups of patients with advanced NSCLC that will most likely benefit from ICI therapies, molecular characterization of PD-L1 expression in circulating tumor cells (CTCs) might be supportive. In this review, we highlight the use of CTCs as a complementary diagnostic tool for PD-L1 expression analysis in advanced NSCLC patients. In addition, we examine technical issues of PD-L1 measurement in tissue as well as in CTCs.

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