Validation of a Targeted Next-Generation Sequencing Panel for Tumor Mutation Burden Analysis

Fenizia, Francesca; Alborelli, Ilaria; Costa, José Luís; Vollbrecht, Claudia; Bellosillo, Beatríz; Dinjens, Winand N.M.; Endris, Volker; Heydt, Carina; Leonards, Katharina; Merkelback-Bruse, Sabine; Pfarr, Nicole; Marion, Ronald van; Allen, Christopher; Chaudhary, Ruchi; Gottimukkala, Rajesh; Hyland, Fiona; Wong-Ho, Elaine; Jermann, Philip; Machado, José Carlos; Hummel, Michael; Normanno, Nicola

doi:10.1016/j.jmoldx.2021.04.008

Cited by 4 publications

(2 citation statements)

References 31 publications

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“…Third, unlike the FoundationOne and MSK-IMPACT panel tests, which were approved by the FDA, the assay that was adopted in this study (Oncomine Tumor Mutational Load assay) has not yet been validated for clinical use. However, previous studies revealed good concordance with TMB assessment by whole exome sequencing [ 58 , 59 ], and a recent study that was conducted by the Onconetwork Immuno-Oncology Consortium showed that the platform that we used demonstrated robustness and reproducibility for TMB evaluation [ 60 ]. Fourth, data on TMB levels at the time of disease progression and blood TMB levels were not analyzed.…”

Section: Discussionmentioning

confidence: 82%

High Tumor Mutation Burden Is Associated with Poor Clinical Outcome in EGFR-Mutated Lung Adenocarcinomas Treated with Targeted Therapy

2022

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This study aimed to determine the association between TMB and treatment outcomes in patients with epidermal growth factor receptor (EGFR)-mutated lung cancer that were treated with tyrosine kinase inhibitors (TKIs). The TMB was assessed using a 409-gene targeted next-generation sequencing panel. We compared the response rate (RR), progression-free survival (PFS), overall survival (OS), and frequency of secondary T790M mutations among the different TMB groups. The median TMB of the study population (n = 88) was 3.36/megabases. We divided 52 (59%) and 36 (41%) patients into the low and high TMB groups, respectively. A high TMB level was significantly associated with liver metastasis and more advanced stage (all p < 0.05). RR was significantly lower in the high TMB group than that of the low TMB group (50.0% vs. 80.7%, all p = 0.0384). In multivariate analysis, high TMB was independently associated with a shorter PFS (hazard ratio [HR] = 1.80, p = 0.0427) and shorter OS (HR = 2.05, p = 0.0397) than that of the low TMB group. Further, high TMB was independently associated with decreased T790M mutation development. These results suggest that high TMB may be a predictive biomarker for adverse treatment outcomes and represent a patients’ subgroup warranting tailored therapeutic approaches.

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Section: Discussionmentioning

confidence: 82%

High Tumor Mutation Burden Is Associated with Poor Clinical Outcome in EGFR-Mutated Lung Adenocarcinomas Treated with Targeted Therapy

2022

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“…In this respect, it has long been demonstrated that dMMR/MSI CRC have a high TMB as consequence of the defect of the MMR DNA repair mechanism. However, significant difference in the TMB values among dMMR/MSI CRC have been described [ 50 ]. In this regard, it has been demonstrated that the TMB count is widely variable among dMMR/MSI tumors according to both types of MMR defect and site of origin.…”

Section: Tumor Heterogeneity (True Primary Resistance): Biological Ch...mentioning

confidence: 99%

Resistance to immune checkpoint inhibitors in colorectal cancer with deficient mismatch repair/microsatellite instability: misdiagnosis, pseudoprogression and/or tumor heterogeneity?

Normanno,

Caridi,

Fassan

et al. 2024

Exploration of Targeted Anti-Tumor Therapy

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Colorectal carcinoma (CRC) with deficiency of the deficient mismatch repair (dMMR) pathway/ microsatellite instability (MSI) is characterized by a high mutation load and infiltration of immune cells in the tumor microenvironment. In agreement with these findings, clinical trials have demonstrated a significant activity of immune checkpoint inhibitors (ICIs) in dMMR/MSI metastatic CRC (mCRC) patients and, more recently, in CRC patients with early disease undergoing neoadjuvant therapy. However, despite high response rates and durable clinical benefits, a fraction of mCRC patients, up to 30%, showed progressive disease when treated with single agent anti-programmed cell death 1 (PD-1) antibody. This article discusses the three main causes that have been associated with early progression of dMMR/MSI mCRC patients while on treatment with ICIs, i.e., misdiagnosis, pseudoprogression and tumor heterogeneity. While pseudoprogression probably does not play a relevant role, data from clinical studies demonstrate that some dMMR/MSI CRC cases with rapid progression on ICIs may be misdiagnosed, underlining the importance of correct diagnostics. More importantly, evidence suggests that dMMR/MSI mCRC is a heterogeneous group of tumors with different sensitivity to ICIs. Therefore, we propose novel diagnostic and therapeutic strategies to improve the outcome of dMMR/MSI CRC patients.

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Molecular testing in gynecologic cancer

Kerr,

Shahi

2024

Diagnostic Molecular Pathology

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Validation of a Targeted Next-Generation Sequencing Panel for Tumor Mutation Burden Analysis

Cited by 4 publications

References 31 publications

High Tumor Mutation Burden Is Associated with Poor Clinical Outcome in EGFR-Mutated Lung Adenocarcinomas Treated with Targeted Therapy

High Tumor Mutation Burden Is Associated with Poor Clinical Outcome in EGFR-Mutated Lung Adenocarcinomas Treated with Targeted Therapy

Resistance to immune checkpoint inhibitors in colorectal cancer with deficient mismatch repair/microsatellite instability: misdiagnosis, pseudoprogression and/or tumor heterogeneity?

Molecular testing in gynecologic cancer

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