Optimising fusion detection through sequential DNA and RNA molecular profiling of non-small cell lung cancer

Moore, David A.; Benafif, Sarah; Poskitt, Benjamin; Argue, Stephanie; Lee, Siow Ming; Ahmad, Tanya; Papadatos-Pastos, Dionysis; Jamal‐Hanjani, Mariam; Bennett, Philip C.; Förster, Martin

doi:10.1016/j.lungcan.2021.08.008

Cited by 13 publications

(6 citation statements)

References 11 publications

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“…Our results are in line with other publications showing that comprehensive NGS strategies outperformed single-gene tests with respect to diagnostic yield. [5][6][7][8]17,18 Differences in diagnostic costs varied per study. However, these publications differ from the current study.…”

Section: Discussionmentioning

confidence: 99%

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Cost-Effectiveness of Parallel Versus Sequential Testing of Genetic Aberrations for Stage IV Non–Small-Cell Lung Cancer in the Netherlands

Wolff

Steeghs

Mfumbilwa

et al. 2022

JCO Precision Oncology

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PURPOSE A large number of targeted treatment options for stage IV nonsquamous non–small-cell lung cancer with specific genetic aberrations in tumor DNA is available. It is therefore important to optimize diagnostic testing strategies, such that patients receive adequate personalized treatment that improves survival and quality of life. The aim of this study is to assess the efficacy (including diagnostic costs, turnaround time (TAT), unsuccessful tests, percentages of correct findings, therapeutic costs, and therapeutic effectiveness) of parallel next generation sequencing (NGS)–based versus sequential single-gene–based testing strategies routinely used in patients with metastasized non–small-cell lung cancer in the Netherlands. METHODS A diagnostic microsimulation model was developed to simulate 100,000 patients with prevalence of genetic aberrations, extracted from real-world data from the Dutch Pathology Registry. These simulated patients were modeled to undergo different testing strategies composed of multiple tests with different test characteristics including single-gene and panel tests, test accuracy, the probability of an unsuccessful test, and TAT. Diagnostic outcomes were linked to a previously developed treatment model, to predict average long-term survival, quality-adjusted life-years (QALYs), costs, and cost-effectiveness of parallel versus sequential testing. RESULTS NGS-based parallel testing for all actionable genetic aberrations is on average €266 cheaper than single-gene–based sequential testing, and detects additional relevant targetable genetic aberrations in 20.5% of the cases, given a TAT of maximally 2 weeks. Therapeutic costs increased by €8,358, and 0.12 QALYs were gained, leading to an incremental cost-effectiveness ratio of €69,614/QALY for parallel versus sequential testing. CONCLUSION NGS-based parallel testing is diagnostically superior over single-gene–based sequential testing, as it is cheaper and more effective than sequential testing. Parallel testing remains cost-effective with an incremental cost-effectiveness ratio of 69,614 €/QALY upon inclusion of therapeutic costs and long-term outcomes.

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Section: Discussionmentioning

confidence: 99%

“… 13 In the model, all genetic aberrations are assumed to be mutually exclusive. 17 , 18 PD-L1 expression was deduced from pathology reports obtained from PALGA between July 2017 and December 2018. 14 …”

Section: Methodsmentioning

confidence: 99%

Cost-Effectiveness of Parallel Versus Sequential Testing of Genetic Aberrations for Stage IV Non–Small-Cell Lung Cancer in the Netherlands

Wolff

Steeghs

Mfumbilwa

et al. 2022

JCO Precision Oncology

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“…Molecular genotyping is now currently used to guide clinical care of patients with lung adeno carcinoma, due to clinical trials that demonstrated superior efficacy of targeted kinase inhibitor compared to standard chemotherapy with marked improvement in survival. Therefore, accurate tissue handling and processing is essential to identify the response biomarkers and to define the optimal therapy for patients [8][9][10]. ALK rearrangements are observed in 2-7% of non-smoking young patients with a solid-pattern dominant adenocarcinoma histology [7].…”

Section: Discussionmentioning

confidence: 99%

Alectinib rescue therapy in advanced ALK rearranged lung adenocarcinoma: a case report

Cesaro

Caterino²,

Perrotta³

et al. 2022

Monaldi Arch Chest Dis

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Alectinib is a highly selective tyrosine kinase inhibitor of anaplastic lymphoma kinase (ALK) that is approved as first-line treatment in adult patients with ALK-positive non-small cell lung cancer (NSCLC) and as second-line in patients previously treated with crizotinib, and has been shown in the literature to significantly prolong progression-free survival compared to chemotherapy in patients with advanced non-small cell lung cancer. The authors describe a clinical case of a 24-year-old woman with malignant massive pleural effusion caused by ALK rearranged pulmonary adenocarcinoma with pleural and pericardial metastasis, in which, despite a dramatic clinical debut, the correct and timely management of the diagnostic and therapeutic path allowed for extraordinary therapeutic success.

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“…RNA‐based targeted NGS approaches have been found to be effective in identifying gene fusions and exon‐skipping and are more accurate compared with DNA‐based assays 17,19–22 . In several reports, additional RNA‐based NGS assays were suggested to detect targetable kinase gene fusions and exon‐skipping in samples without detectable pathogenic driver mutations or with a failure to yield optimal outcomes by DNA‐based assays 23–25 . Moreover, RNA‐based NGS has been recommended by the NCCN guidelines for gene fusion and exon‐skipping analysis.…”

Section: Introductionmentioning

confidence: 99%

“…17,[19][20][21][22] In several reports, additional RNA-based NGS assays were suggested to detect targetable kinase gene fusions and exon-skipping in samples without detectable pathogenic driver mutations or with a failure to yield optimal outcomes by DNA-based assays. [23][24][25] Moreover, RNA-based NGS has been recommended by the NCCN guidelines for gene fusion and exon-skipping analysis. However, RNA-based NGS is rarely used for somatic SNV or indel identification because RNA is unstable, has varying expression levels, and lacks double-stranded context and stable evidence.…”

Section: Introductionmentioning

confidence: 99%

A unified DNA‐ and RNA‐based NGS strategy for the analysis of multiple types of variants at the dual nucleic acid level in solid tumors

Chen,

Wang,

Zhang

et al. 2023

Clinical Laboratory Analysis

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BackgroundTargeted next‐generation sequencing (NGS) is a powerful and suitable approach to comprehensively identify multiple types of variants in tumors. RNA‐based NGS is increasingly playing an important role in precision oncology. Both parallel and sequential DNA‐ and RNA‐based approaches are expensive, burdensome, and have long turnaround times, which can be impractical in clinical practice. A streamlined, unified DNA‐ and RNA‐based NGS approach is urgently needed in clinical practice.MethodsA DNA/RNA co‐hybrid capture sequencing (DRCC‐Seq) approach was designed to capture pre‐capture DNA and RNA libraries in a single tube and convert them into one NGS library. The performance of the DRCC‐Seq approach was evaluated by a panel of reference standards and clinical samples.ResultsThe average depth, DNA data ratio, capture ratio, and target coverage 250 (×) of the DNA panel data had a negative correlation with an increase in the proportion of RNA probes. The SNVs, indels, fusions, and MSI status were not affected by the proportion of RNA probes, but the copy numbers of the target genes were higher than expected in the standard materials, and many unexpected gene amplifications were found using D:R (1:2) and D:R (1:4) probe panels. The optimal ratio of DNA and RNA probes in the combined probe panel was 1:1 using the DRCC‐Seq approach. The DRCC‐Seq approach was feasible and reliable for detecting multiple types of variants in reference standards and real‐world clinical samples.ConclusionsThe DRCC‐Seq approach is more cost‐effective, with a shorter turnaround time and lower labor requirements than either parallel or sequential targeted DNA NGS and RNA NGS. It is feasible to identify multiple genetic variations at the DNA and RNA levels simultaneously in clinical practice.

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Optimising fusion detection through sequential DNA and RNA molecular profiling of non-small cell lung cancer

Cited by 13 publications

References 11 publications

Cost-Effectiveness of Parallel Versus Sequential Testing of Genetic Aberrations for Stage IV Non–Small-Cell Lung Cancer in the Netherlands

Cost-Effectiveness of Parallel Versus Sequential Testing of Genetic Aberrations for Stage IV Non–Small-Cell Lung Cancer in the Netherlands

Alectinib rescue therapy in advanced ALK rearranged lung adenocarcinoma: a case report

A unified DNA‐ and RNA‐based NGS strategy for the analysis of multiple types of variants at the dual nucleic acid level in solid tumors

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