Assessment of Blood Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Patients With Non–Small Cell Lung Cancer With Use of a Next-Generation Sequencing Cancer Gene Panel

Wang, Zhijie; Duan, Jianchun; Cai, Shangli; Han, Miao; Hua, Dong; Zhao, Jun; Zhu, Bo; Wang, Shuhang; Zhuo, Minglei; Sun, Jianping; Wang, Qiming; Bai, Hua; Han, Jiefei; Tian, Yanhua; Lü, Jing; Xu, Tingting; Zhao, Xiaochen; Wang, Guoqiang; Cao, Xi; Li, Fugen; Wang, Dalei; Chen, Yuejun; Bai, Yuezong; Zhao, Jing; Zhao, Zhengyi; Zhang, Yuzi; Xiong, Lei; He, Jie; Gao, Shugeng; Wang, Jie

doi:10.1001/jamaoncol.2018.7098

Cited by 411 publications

(342 citation statements)

References 23 publications

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“…For this reason, they compare TCGA WES-based TMB with panel-based TMB with or without inclusion of EGFR and/or KRAS mutations. Although similar results are yielded, the raised issue is an important point to be further investigated in panel-based TMB quantification [49]. TMB quantification from liquid biopsies suffers from ctDNA detection limits, which also depend on tumor size and number of cancer cells, but these results encourage to further explore and more extensively validate this approach.…”

Section: Tmb Quantification Beyond Tissue Biopsies and Current Gene Pmentioning

confidence: 63%

“…As for synonymous mutations, it is claimed that, although not biologically meaningful, their inclusion may reduce sampling noise and improve the approximation of TMB across the whole genome. Indeed, several works compared TMB quantification with or without synonymous variants and observed that, when including synonymous variants, panel-based TMB shows increased correlation with WES-based TMB values [35,49] and stronger association with clinical response [9]. Starting from the [74] above observations, we can infer that some recommendations to build a standardized and robust analysis pipeline for TMB quantification are starting to emerge at least for the following points: i. germline variants can be most efficiently identified and removed by matched normal sequencing and, if this is not possible, the largest available germline variant databases should be used for in silico filtering, especially for non-caucasian ancestries; ii.…”

Section: Need For Standardization Of Tmb Quantification and Reportingmentioning

confidence: 99%

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Tumor mutational burden quantification from targeted gene panels: major advancements and challenges

Fancello

Gandini

Pelicci

et al. 2019

j. immunotherapy cancer

266

233

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Tumor mutational burden (TMB), the total number of somatic coding mutations in a tumor, is emerging as a promising biomarker for immunotherapy response in cancer patients. TMB can be quantitated by a number of NGS-based sequencing technologies. Whole Exome Sequencing (WES) allows comprehensive measurement of TMB and is considered the gold standard. However, to date WES remains confined to research settings, due to high cost of the large genomic space sequenced. In the clinical setting, instead, targeted enrichment panels (gene panels) of various genomic sizes are emerging as the routine technology for TMB assessment. This stimulated the development of various methods for panel-based TMB quantification, and prompted the multiplication of studies assessing whether TMB can be confidently estimated from the smaller genomic space sampled by gene panels. In this review, we inventory the collection of available gene panels tested for this purpose, illustrating their technical specifications and describing their accuracy and clinical value in TMB assessment. Moreover, we highlight how various experimental, platform-related or methodological variables, as well as bioinformatic pipelines, influence panel-based TMB quantification. The lack of harmonization in panel-based TMB quantification, of adequate methods to convert TMB estimates across different panels and of robust predictive cutoffs, currently represents one of the main limitations to adopt TMB as a biomarker in clinical practice. This overview on the heterogeneous landscape of panel-based TMB quantification aims at providing a context to discuss common standards and illustrates the strong need of further validation and consolidation studies for the clinical interpretation of panel-based TMB values. Electronic supplementary material The online version of this article (10.1186/s40425-019-0647-4) contains supplementary material, which is available to authorized users.

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Section: Tmb Quantification Beyond Tissue Biopsies and Current Gene Pmentioning

confidence: 63%

Section: Need For Standardization Of Tmb Quantification and Reportingmentioning

confidence: 99%

Tumor mutational burden quantification from targeted gene panels: major advancements and challenges

Fancello

Gandini

Pelicci

et al. 2019

j. immunotherapy cancer

266

233

View full text Add to dashboard Cite

show abstract

“…Recent studies have found that changes in plasma cfDNA concentration and bTMB in plasma cfDNA may be used as molecular biomarkers for predicting therapeutic effects in ICI therapy, 29,30 all of which support the exploration of immunotherapy-related molecular biomarkers based on liquid biopsy. 31 In the early study of small samples, it has been found that CTC PD-L1 expression can be detected in peripheral blood of tumor patients.…”

Section: Discussionmentioning

confidence: 87%

<p>Detection of PD-L1 Expression and Its Clinical Significance in Circulating Tumor Cells from Patients with Non-Small-Cell Lung Cancer</p>

Cheng¹,

Wang²,

Lv³

et al. 2020

CMAR

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Background: The expression of programmed cell death ligand 1(PD-L1) is related to the efficacy of immune checkpoint inhibitors on patients with non-small cell lung cancer (NSCLC), but tumor tissue (TT) samples are difficult to obtain, and initial TT samples are difficult to reflect the spatial-temporal heterogeneity. Therefore, we explored the feasibility of separating circulating tumor cells (CTCs) and detecting PD-L1 expression on CTCs. Patients and Methods: Peripheral blood specimens were sampled from 66 NSCLC patients, and CTCs were separated by membrane filtration based on size. For 59 patients with paired TT specimens, the expression of PD-L1 in their CTCs and TTs was determined using the immunohistochemistry and immunocytochemistry based on 28-8 antibody, respectively. The PD-L1 expression in TTs was set as a gold standard for calculation of sensitivity, specificity, consistency, positive predictive value (PPV), and negative predictive value (NPV), and the Cohen kappa coefficient for CTCs and paired TTs was calculated. In addition, the T-test, Chi-square test, and Mann-Whitney U-test were adopted to analyze the correlation of clinical pathological features and prognosis with PD-L1 expression. Results: Sensitivity, specificity, concordance, PPV and NPV of detecting PD-L1 in CTCs of the 41 initial treated patients were 88.89%, 73.91%, 80%, 72.73% and 89.47%, respectively, and the Cohen kappa coefficient of CTC and paired TTs was 0.613. The univariate analysis of survival showed that the progression-free survival time of initial treated patients with positive PD-L1 expression was shorter than that of those with negative PD-L1 expression in CTCs or TTs (P>0.05), and the positive PD-L1 expression in CTCs or TTs had nothing to do with age, sex, smoking status, histological type, and stage (P > 0.05). Conclusion: The study confirms the feasibility of CTC PD-L1 detection in peripheral blood and lays a foundation for exploring real-time and individualized immunotherapy molecular biomarkers.

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“…In addition, the evaluation of tumor mutational burden (TMB), which is the number of somatic mutations in the genome coding regions (Mut/Mb), has been explored and is currently been tested in the cfDNA, to identify patients who can benefit from immunotherapy [99][100][101][102]. However, the first results on the concordance between tissue and cfDNA are contrasting [103].…”

Section: Resultsmentioning

confidence: 99%

Liquid Biopsy in Non-Small Cell Lung Cancer: Highlights and Challenges

Rijavec

Coco

Genova

et al. 2019

Cancers

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Non-small cell lung cancer is one leading cause of death worldwide, and patients would greatly benefit from an early diagnosis. Since targeted and immunotherapies have emerged as novel approaches for more tailored treatments, repeated assessments of the tumor biology have become pivotal to drive clinical decisions. Currently, tumor tissue biopsy is the gold standard to investigate potentially actionable biomarkers, but this procedure is invasive and may prove inadequate to represent the whole malignancy. In this regard, liquid biopsy represents a minimally invasive and more comprehensive option for early detection and investigation of this tumor. Today, cell-free DNA is the only approved circulating marker to select patients for a targeted therapy. Conversely, the other tumor-derived markers (i.e., circulating tumor cells, miRNAs, exosomes, and tumor educated platelets) are still at a pre-clinical phase, although they show promising results for their application in screening programs or as prognostic/predictive biomarkers. The main challenges for their clinical translation are the lack of reliable cutoffs and, especially for miRNAs, the great variability among the studies. Moreover, no established tool has been approved for circulating tumor cells and exosome isolation. Finally, large prospective clinical trials are mandatory to provide evidence of their clinical utility.

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Assessment of Blood Tumor Mutational Burden as a Potential Biomarker for Immunotherapy in Patients With Non–Small Cell Lung Cancer With Use of a Next-Generation Sequencing Cancer Gene Panel

Abstract: This study explores whether blood tumor mutational burden estimated by a next-generation sequencing gene panel is associated with clinical outcomes of patients with non–small cell lung cancer treated with anti–programmed cell death 1 and anti–programmed cell death ligand 1 agents.

Cited by 411 publications

References 23 publications

Tumor mutational burden quantification from targeted gene panels: major advancements and challenges

Tumor mutational burden quantification from targeted gene panels: major advancements and challenges

<p>Detection of PD-L1 Expression and Its Clinical Significance in Circulating Tumor Cells from Patients with Non-Small-Cell Lung Cancer</p>

Liquid Biopsy in Non-Small Cell Lung Cancer: Highlights and Challenges

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