Dataset Information

Association of MUC16 Mutation With Response to Immune Checkpoint Inhibitors in Solid Tumors.

ABSTRACT: Importance:As the third most frequently mutated gene in cancers, the association between MUC16 mutation and response to immune checkpoint inhibitors (ICIs) in solid tumors remains unclear. Objective:To examine whether MUC16 mutation is associated with genomic factors in ICI response in solid tumors and with outcomes in ICI-treated patients. Design, Setting, and Participants:This cohort study used multidimensional genomic data of 10?195 patients from The Cancer Genome Atlas (TCGA) across 30 solid tumor types, 56 patients from a non-small cell lung cancer (NSCLC) cohort, and 145 patients from a melanoma cohort. Genomic factors associated with ICI response covered tumor mutational burden, neoantigens, immune-related gene signatures, and tumor immune microenvironment. Both NSCLC and melanoma cohorts included ICI-treated patients. The TCGA cohort was used to examine the association of MUC16 mutation with genomic factors. Two ICI-treated cohorts were used to explore the significance of outcomes associated with MUC16 mutation, using Kaplan-Meier curves and Cox models with adjusting for potential confounders. Gene set enrichment analysis was used to identify MUC16 mutation-associated biological processes. Data were obtained from October 1 through October 10, 2019, and were analyzed from October 11 through December 31, 2019. Main Outcomes and Measures:Genomic factors associated with ICI response, overall survival, and clinical response. Results:Of the 10?195 patients, 4821 (47.6%) were men (median [interquartile range {IQR}] age, 60 [50-70] years). MUC16 was mutated in 2006 of 10?195 patients (19.68%). In this pan-cancer data set, patients with MUC16 mutation had higher tumor mutational burden (median [IQR], 230 [93-595] mutations vs 48 [25-92] mutations; difference, 182 mutations; 95% CI, 164-199 mutations; P?

SUBMITTER: Zhang L

PROVIDER: S-EPMC7450349 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Association of MUC16 Mutation With Response to Immune Checkpoint Inhibitors in Solid Tumors.

Zhang Lei L Han Xiaohong X Shi Yuankai Y

JAMA network open 20200803 8

<h4>Importance</h4>As the third most frequently mutated gene in cancers, the association between MUC16 mutation and response to immune checkpoint inhibitors (ICIs) in solid tumors remains unclear.<h4>Objective</h4>To examine whether MUC16 mutation is associated with genomic factors in ICI response in solid tumors and with outcomes in ICI-treated patients.<h4>Design, setting, and participants</h4>This cohort study used multidimensional genomic data of 10 195 patients from The Cancer Genome Atlas ...[more]

PMID: 32845327

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Project description:Predictive biomarkers of response to immune checkpoint inhibitors (ICI) help to identify cancer patients who will benefit from immunotherapy. Protein kinase, DNA-activated, catalytic subunit (PRKDC) is an important gene for DNA double-strand break (DSB) repair and central T-cell tolerance. We aimed to investigate the association between PRKDC mutations and tumor mutation burden (TMB), tumor microenvironment (TME), and response to ICI. Whole-exome sequencing data of 4023 solid tumor samples from the Cancer Genome Atlas (TCGA) and panel-based sequencing data of 3877 solid tumor samples from Geneplus-Beijing, China, were used to analyze the TMB. The mRNA expression data of 3541 solid tumor samples from TCGA were used to explore the effect of PRKDC mutations on the TME. Four ICI-treated cohorts were analyzed for verifying the correlation between PRKDC mutations and the response to ICI. In both the TCGA and Geneplus datasets, we found that the TMB in PRKDC mutation samples was significantly higher than in PRKDC wild-type samples (P < 0.05 and P < 0.0001, respectively). Further, TCGA datasets showed that PRKDC mutation samples were associated with a significantly increased expression of CD8+ T cells, NK cells, immune checkpoint, chemokines, etc. compared to PRKDC wild-type samples (P < 0.05). In ICI-treated cohorts, we also found the PRKDC mutations were associated with increased survival (median PFS, not reached vs. 6.8 months, HR, 0.2893; 95% CI, 0.1255-0.6672; P = 0.0650, Hellmann cohort; median OS, 1184 days vs. 250 days, HR, 0.5126; 95% CI, 0.2715-0.9679; P = 0.1020, Allen cohort), and the increase was significant in multivariate analysis (HR, 0.361; 95% CI, 0.155-0.841; P = 0.018, Allen cohort; HR, 0.240 95% CI, 0.058-0.998; P = 0.050, Hellmann cohort). In summary, we found that PRKDC mutation often appeared to co-exist with deficiency in some other DNA damage repair mechanism and is nonetheless one of the important factors associated with increased TMB, inflamed TME, and better response to ICI.

Project description:BackgroundA large proportion of patients eventually experience disease progression despite treatment with immune checkpoint inhibitors (ICIs), but subsequent treatment options are limited for this population. Retreatment with the same or different types of ICIs is a possible strategy, but the clinical efficacy and safety data are limited. This systematic review aims to evaluate the efficacy and safety of ICIs retreatment in patients with solid tumors after disease progression to previous ICIs.MethodsWe searched MEDLINE, EMBASE, the Cochrane Library, and major meeting libraries for prospective studies. The primary outcomes included the objective response rate (ORR), disease control rate (DCR), median overall survival (mOS), and the incidence of grade ⩾3 immune-related adverse events (irAEs).ResultsWe identified 22 prospective studies including 1865 patients. For disease progression after CTLA-4 inhibitors, three studies evaluated anti-CTLA-4 retreatment. The ORR was 12-23%, the DCR was 48.4-67.7%, and the mOS was 12 months. The incidence of grade ⩾3 irAEs was 5.9-25%. Four studies evaluated anti-programmed cell death protein 1 (PD-1) retreatment. The ORR was 22-36%, the DCR was 40-64%, and the mOS was 13.4-20.6 months. The incidence of grade ⩾3 irAEs was <10%. For disease progression after PD-(L)1 inhibitors, 13 studies evaluated anti-PD-(L)1 retreatment. The ORR was 5-53%, the DCR was 38-83%, and the mOS was 13.9 months. The incidence of grade ⩾3 irAEs was 0-15% for patients retreated with single anti-PD-(L)1 agent, but was higher (0-64%) for those retreated with ICIs combined with other agents. Two studies evaluated anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) retreatment. The ORR was 0-22.4%, the DCR was 50-72%, and the mOS was 4-21 months. The incidence of grade ⩾3 irAEs was 26-61%.ConclusionRetreatment with ICIs is feasible for cancer patients considering its encouraging efficacy and tolerable safety. Further prospective trials are needed to explore more promising strategies and identify suitable populations for retreatment.

Project description:ImportanceCopy number alterations in programmed cell death ligand 1 (PDL1 or CD274), programmed cell death 1 ligand 2 (PDCD1LG2 or PDL2), and Janus kinase 2 (JAK2) genes (chromosome 9p24.1) characterize Hodgkin lymphoma, resulting in high response rates to programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade. The prevalence and utility of PDL1 amplification as a response biomarker to PD-1/PD-L1 blockade are unknown in other tumors.ObjectivesTo examine the prevalence of PDL1 amplification and its utility as a response biomarker to PD-1/PD-L1 blockade in solid tumors.Design, setting, and participantsThis retrospective study (October 1, 2012, to October 1, 2017) used a deidentified tumor database from a commercial company and annotated clinical records from a subset of patients treated at a university tertiary referral center. The study analyzed 118 187 tumors from the deidentified database, including a clinically annotated subgroup of 2039 malignant tumors.InterventionsComprehensive genomic profiling was performed on all samples to determine PDL1 amplification, microsatellite instability, and tumor mutational burden (TMB). A subset of patients was treated with PD-1/PD-L1 blockade.Main outcomes and measuresThe prevalence of PDL1 amplification was determined among 118 187 patient samples that underwent next-generation sequencing. Solid tumors treated with checkpoint blockade were evaluated for response and progression-free survival (PFS).ResultsOf the 118 187 deidentified tumor samples, PDL1 amplifications were identified in 843 (0.7%), including more than 100 types of solid tumors. Most PDL1-amplified tumors (84.8%) had a low to intermediate TMB. PDL1 amplification did not always correlate with high-positive PD-L1 expression by immunohistochemical analysis. Six of 9 patients (66.7%) from 1 center with PDL1-amplified solid tumors had objective responses after checkpoint blockade administration. The median PFS among all treated patients was 15.2 months. Responders included 1 patient with glioblastoma (PFS, ≥5.2 months), 2 patients with head and neck squamous cell cancer (PFS, ≥9 and 15.2 months), 2 patients with metastatic basal cell cancer (PFS, 3.8 and ≥24.1 months), and 1 patient with urothelial cancer (PFS, ≥17.8 months).Conclusions and relevanceThe results of this study suggest that PDL1 amplification occurs in a small subset of malignant tumors. Additional large-scale, prospective studies of PDL1-amplified cancers are warranted to confirm the responses to checkpoint blockade described herein, even in the absence of microsatellite instability, high PD-L1 expression, and a high TMB.

Dataset Information

Association of MUC16 Mutation With Response to Immune Checkpoint Inhibitors in Solid Tumors.

Publications

Association of MUC16 Mutation With Response to Immune Checkpoint Inhibitors in Solid Tumors.

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