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Thymic malignancies: next-generation sequencing as a tool to select patients for targeted therapies and immunotherapies?

ABSTRACT: The management of thymic malignancies is based on multidisciplinary discussion. Systemic agents may be administered as an exclusive treatment if local treatment is not achievable. Novel and innovative agents are used based on the results of next-generation sequencing that may report the activation of targetable signaling pathways both in thymomas and thymic carcinomas. Phase II trials reported the antitumor activity of PI3K/mTOR inhibitors, CDK inhibitors, and antiangiogenic agents in advanced, refractory, or metastatic thymic epithelial tumors. The use of immune checkpoint inhibitors is challenging given the frequent association of those tumors with auto-immune disorders. Meanwhile, a better understanding of systemic treatment sequences in a real-life setting is mandatory to analyze the actual indication of each agent, define the potential biomarkers for the selection of patients, and develop individualized decision-making to optimize the survival of patients.

SUBMITTER: Girard N

PROVIDER: S-EPMC8794339 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Thymic malignancies: next-generation sequencing as a tool to select patients for targeted therapies and immunotherapies?

Girard Nicolas N

Mediastinum (Hong Kong, China) 20190926

The management of thymic malignancies is based on multidisciplinary discussion. Systemic agents may be administered as an exclusive treatment if local treatment is not achievable. Novel and innovative agents are used based on the results of next-generation sequencing that may report the activation of targetable signaling pathways both in thymomas and thymic carcinomas. Phase II trials reported the antitumor activity of PI3K/mTOR inhibitors, CDK inhibitors, and antiangiogenic agents in advanced, ...[more]

PMID: 35118264

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Project description:BackgroundTargeted next-generation sequencing (NGS) enables rapid identification of common and rare genetic variation. The detection of variants contributing to therapeutic drug response or adverse effects is essential for implementation of individualized pharmacotherapy. Successful application of short-read based NGS to pharmacogenes with high sequence homology, nearby pseudogenes and complex structure has been previously shown despite anticipated technical challenges. However, little is known regarding the utility of such panels to detect copy number variation (CNV) in the highly polymorphic cytochrome P450 (CYP) 2D6 gene, or to identify the promoter (TA)7 TAA repeat polymorphism UDP glucuronosyltransferase (UGT) 1A1*28. Here we developed and validated PGxSeq, a targeted exome panel for pharmacogenes pertinent to drug disposition and/or response.MethodsA panel of capture probes was generated to assess 422 kb of total coding region in 100 pharmacogenes. NGS was carried out in 235 subjects, and sequencing performance and accuracy of variant discovery validated in clinically relevant pharmacogenes. CYP2D6 CNV was determined using the bioinformatics tool CNV caller (VarSeq). Identified SNVs were assessed in terms of population allele frequency and predicted functional effects through in silico algorithms.ResultsAdequate performance of the PGxSeq panel was demonstrated with a depth-of-coverage (DOC) ≥ 20× for at least 94% of the target sequence. We showed accurate detection of 39 clinically relevant gene variants compared to standard genotyping techniques (99.9% concordance), including CYP2D6 CNV and UGT1A1*28. Allele frequency of rare or novel variants and predicted function in 235 subjects mirrored findings from large genomic datasets. A large proportion of patients (78%, 183 out of 235) were identified as homozygous carriers of at least one variant necessitating altered pharmacotherapy.ConclusionsPGxSeq can serve as a comprehensive, rapid, and reliable approach for the detection of common and novel SNVs in pharmacogenes benefiting the emerging field of precision medicine.

Project description:BackgroundInfections in patients with hematological malignancies (HM) are a significant cause of morbidity and mortality. Timely and effective empirical anti-infective treatment can reduce the infection-related mortality rate. Targeted next-generation sequencing (tNGS) offers a rapid diagnostic approach for identifying diverse pathogens in these patients. However, relevant research is still limited to adult patients with HM.MethodsWe conducted a retrospective analysis of adult HM patients admitted to our hospital from March 2023 to September 2023, focusing on their clinical characteristics and the results of both tNGS and conventional microbiological tests (CMTs). We evaluated the performance of tNGS and CMTs in pathogenic diagnosis and described the distribution characteristics of pathogens in adult HM patients with infections.ResultsThe study included 209 samples collected from 137 patients. Results showed that the overall pathogen detection rate differed significantly between tNGS and CMTs (60.3% vs. 24.4%, p < 0.001). The sensitivity (69.7% vs. 35.9%), negative predictive value (NPV) (48.2% vs. 42.4%), and accuracy (66.5% vs. 56.5%) of pathogen detection were notably superior with tNGS compared to CMTs. Among the 142 samples with clinically diagnosed infections, tNGS combined with CMTs identified a definite or probable microbial etiology in 114 samples (80.3%). Of the 36 samples with concordant positive results from both tNGS and CMTs, 72.2% (26/36) exhibited full or partial agreement. Our study further showed the highest detection rate for viral infections (57.0%), predominantly for Epstein-Barr virus (DNA-V, 18.3%). Followed by bacterial infections (46.5%), the detection rate of Gram-negative bacteria (G+, 35.9%) was higher than that of Gram-positive bacteria (G-, 21.8%) in this study. Klebsiella pneumoniae (G-, 12.7%) had the highest detection rate among these emerging bacteria, followed by Pseudomonas aeruginosa (G-, 10.6%) and Enterococcus faecium (G+, 7.7%). Bacterial-viral coinfections were the most common type of mixed infection (35.5%).ConclusionIn conclusion, tNGS outperforms CMTs in both sensitivity and pathogen spectrum. Therefore, it can serve as an adjunct to CMTs to facilitate the precise adjustment of anti-infective regimens for adult HM patients. Our findings establish a basis for formulating empirical anti-infective therapy strategies tailored to the pathogen distribution in this patient population.

Dataset Information

Thymic malignancies: next-generation sequencing as a tool to select patients for targeted therapies and immunotherapies?

Publications

Thymic malignancies: next-generation sequencing as a tool to select patients for targeted therapies and immunotherapies?

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