1189O Validation of whole genome sequencing in routine clinical practice

Monkhorst, Kim; Samsom, Kris G.; Schipper, Luuk J.; Roepman, Paul; Bosch, Linda J.W.; Bruijn, Ewart de; Hoes, Louisa R.; Riethorst, Immy; Schoenmaker, Lieke; Kolk, Lizet van der; Buffart, Tineke E.; Hoeven, K. van der; Voest, Emile E.; Cuppen, Edwin; Meijer, Gerrit A.

doi:10.1016/j.annonc.2020.08.083

Cited by 7 publications

(8 citation statements)

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“…Currently, the minimum required tumor cellularity for clinical-grade WGS analysis has been further downscaled from 30% to 20% due to ongoing technical improvements and optimized data analysis (bioinformatics; ref. 54), resulting in a current successful analysis of 71% (55).…”

Section: Clinmentioning

confidence: 99%

Patients with Biallelic BRCA1/2 Inactivation Respond to Olaparib Treatment Across Histologic Tumor Types

Wijngaart

Hoes

Henegouwen

et al. 2021

Clinical Cancer Research

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Purpose: To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with BRCA1/2 mutations, regardless of histologic tumor type. Patients and Methods: Patients with treatment-refractory BRCA1/2-mutated cancer were included for treatment with off-label olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In Drug Rediscovery Protocol (DRUP), patients with treatment-refractory solid malignancies receive off-label drugs based on tumor molecular profiles while whole-genome sequencing (WGS) is performed on baseline tumor biopsies. The primary endpoint was clinical benefit (CB; defined as objective response or stable disease ≥ 16 weeks according to RECIST 1.1). Per protocol patients were enrolled using a Simon-like two-stage model. Results: Twenty-four evaluable patients with nine different tumor types harboring BRCA1/2 mutations were included, 58% had CB from treatment with olaparib. CB was observed in patients with complete loss of function (LoF) of BRCA1/2, while 73% of patients with biallelic BRCA LoF had CB. In 17 patients with and seven without current labeled indication, 10 and four patients had CB, respectively. Treatment resistance in four patients with biallelic loss might be explained by an additional oncogenic driver which was discovered by WGS, including Wnt pathway activation, FGFR amplification, and CDKN2A loss, in three tumor types. Conclusions: These data indicate that using PARPis is a promising treatment strategy for patients with non–BRCA-associated histologies harboring biallelic BRCA LoF. WGS allows to accurately detect complete LoF of BRCA and homologous repair deficiency (HRD) signature as well as oncogenic drivers that may contribute to resistance, using a single assay.

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Section: Clinmentioning

confidence: 99%

Patients with Biallelic BRCA1/2 Inactivation Respond to Olaparib Treatment Across Histologic Tumor Types

Wijngaart

Hoes

Henegouwen

et al. 2021

Clinical Cancer Research

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“…If costs for WGS remained at €2500, identifying 2.7% more patients eligible for targeted therapy could result in cost effectiveness if monthly treatment costs to treat these additional patients decreased substantially (31.1%). It has been suggested that there are more targets available or under investigation in incurable cancers that are not detected by SoC and that can be targeted with systemic treatments [3,6,11,26,55,56]. Additionally, WGS can detect non-hotspot targets within known genes, e.g.…”

Section: Discussionmentioning

confidence: 99%

“…It has been suggested that there are more targets available or under investigation in incurable cancers that are not detected by SoC and that can be targeted with systemic treatments [ 3 , 6 , 11 , 26 , 55 , 56 ]. Additionally, WGS can detect non-hotspot targets within known genes, e.g.…”

Section: Discussionmentioning

confidence: 99%

“…The following targets were considered in the model: EGFR mutations (exon 19, 21, T790M, non-classic, and other); ALK rearrangements; ROS1 rearrangements; BRAF (V600) mutations; MET proto-oncogene ( MET ) (amplifications and exon 14 skipping); rearranged during transfection proto-oncogene ( RET ) rearrangement; neurotrophic tropomyosin receptor kinase ( NTRK ) (kinase 1, 2, and 3) gene fusions; KRAS mutation in exon 2, 3, and 4; and PD-L1 expression level. Molecular targets in the aforementioned genes with targeted therapies available in routine practice that are currently missed in SoC (because of technical and/or analysis challenges) but that can be reliably detected with WGS were labelled as ‘target X’ [ 26 ]. For the base-case analysis, WGS was assumed to be capable of identifying a proportion of 0.5% target X, based on expert opinion (PR).…”

Section: Methodsmentioning

confidence: 99%

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Early Cost Effectiveness of Whole-Genome Sequencing as a Clinical Diagnostic Test for Patients with Inoperable Stage IIIB,C/IV Non-squamous Non-small-Cell Lung Cancer

et al. 2021

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Background Advanced non-small-cell lung cancer (NSCLC) harbours many genetic aberrations that can be targeted with systemic treatments. Whole-genome sequencing (WGS) can simultaneously detect these (and possibly new) molecular targets. However, the exact added clinical value of WGS is unknown. Objective The objective of this study was to determine the early cost effectiveness of using WGS in diagnostic strategies compared with currently used molecular diagnostics for patients with inoperable stage IIIB,C/IV non-squamous NSCLC from a Dutch healthcare perspective. Methods A decision tree represented the diagnostic pathway, and a cohort state transition model represented disease progression. Three diagnostic strategies were modelled: standard of care (SoC) alone, WGS as a diagnostic test, and SoC followed by WGS. Treatment effectiveness was based on a systematic review. Probabilistic cost-effectiveness analyses were performed, and threshold analyses (using €80,000 per quality-adjusted life-year [QALY]) was used to explore the early cost effectiveness of WGS. Results WGS as a diagnostic test resulted in more QALYs (0.002) and costs (€1534 [incremental net monetary benefit -€1349]), and SoC followed by WGS resulted in fewer QALYs (-0.002) and more costs (€1059 [-€1194]) compared with SoC alone. WGS as a diagnostic test was only cost effective if it was priced at €2000 per patient and identified 2.7% more actionable patients than SoC alone. Treating these additional identified patients with new treatments costing >€4069 per month decreased the probability of cost effectiveness. Conclusions Our analysis suggests that providing WGS as a diagnostic test is cost effective compared with SoC followed by WGS and SoC alone if costs for WGS decrease and additional patients with actionable targets are identified. This costeffectiveness model can be used to incorporate new findings iteratively and to support ongoing decision making regarding the use of WGS in this rapidly evolving field.

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“…There are challenges to equitable reimbursement and subsequent access to NGS across Europe, as highlighted in our expert panel discussions and summarized in Table S4 [42]. Key general challenges include:…”

Section: Key Challenges To the Supply Of Tests 221 Reimbursementmentioning

confidence: 99%

Identifying the Steps Required to Effectively Implement Next-Generation Sequencing in Oncology at a National Level in Europe

Horgan¹,

Curigliano

Rieß

et al. 2022

JPM

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Next-generation sequencing (NGS) may enable more focused and highly personalized cancer treatment, with the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines now recommending NGS for daily clinical practice for several tumor types. However, NGS implementation, and therefore patient access, varies across Europe; a multi-stakeholder collaboration is needed to establish the conditions required to improve this discrepancy. In that regard, we set up European Alliance for Personalised Medicine (EAPM)-led expert panels during the first half of 2021, including key stakeholders from across 10 European countries covering medical, economic, patient, industry, and governmental expertise. We describe the outcomes of these panels in order to define and explore the necessary conditions for NGS implementation into routine clinical care to enable patient access, identify specific challenges in achieving them, and make short- and long-term recommendations. The main challenges identified relate to the demand for NGS tests (governance, clinical standardization, and awareness and education) and supply of tests (equitable reimbursement, infrastructure for conducting and validating tests, and testing access driven by evidence generation). Recommendations made to resolve each of these challenges should aid multi-stakeholder collaboration between national and European initiatives, to complement, support, and mutually reinforce efforts to improve patient care.

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1189O Validation of whole genome sequencing in routine clinical practice

Cited by 7 publications

References 0 publications

Patients with Biallelic BRCA1/2 Inactivation Respond to Olaparib Treatment Across Histologic Tumor Types

Patients with Biallelic BRCA1/2 Inactivation Respond to Olaparib Treatment Across Histologic Tumor Types

Early Cost Effectiveness of Whole-Genome Sequencing as a Clinical Diagnostic Test for Patients with Inoperable Stage IIIB,C/IV Non-squamous Non-small-Cell Lung Cancer

Identifying the Steps Required to Effectively Implement Next-Generation Sequencing in Oncology at a National Level in Europe

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