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Validation of whole genome sequencing in routine clinical practice

Date

19 Sep 2020

Session

Proffered Paper - Translational research

Presenters

Kim Monkhorst

Citation

Annals of Oncology (2020) 31 (suppl_4): S725-S734. 10.1016/annonc/annonc262

Authors

K. Monkhorst1, K. Samsom1, L. Schipper2, P. Roepman3, L. Bosch4, E. de Bruijn3, L.R. Hoes2, I. Riethorst3, L. Schoenmaker3, L. van der Kolk5, T. Buffart6, K. van der Hoeven3, E.E. Voest7, E. Cuppen3, G. Meijer8

Author affiliations

  • 1 Pathology Department, NKI-AVL - Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, 1066 CX - Amsterdam/NL
  • 2 Molecular Oncology Dept., NKI-AVL - Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, 1066 CX - Amsterdam/NL
  • 3 Medical Department, Hartwig Medical Foundation, 1098XH - Amsterdam/NL
  • 4 Translational Gastrointestinal Oncology, Netherlands Cancer Institute, 1066CX - Amsterdam/NL
  • 5 Family Cancer Clinic, NKI-AVL - Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, 1066 CX - Amsterdam/NL
  • 6 Gastrointestinal Oncology, NKI-AVL - Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, 1066 CX - Amsterdam/NL
  • 7 Molecular Oncology, Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL), 1066 CX - Amsterdam/NL
  • 8 Pathology Dept, NKI-AVL - Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, 1066 CX - Amsterdam/NL
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Resources

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Abstract 1189O

Background

Clinical-grade Whole Genome Sequencing (cWGS) is currently being implemented in routine practice. In the WIDE study (WGS Implementation in standard cancer Diagnostics for Every cancer patient), cWGS is performed on a prospective cohort of 1,200 patients (stage IV solid tumors). Here we report the results on feasibility and clinical validity (primary endpoints) of the first 600 patients.

Methods

cWGS was conducted independently of, but in parallel with, validated Standard-of-Care (SOC) diagnostics. For 47% of patients, this included SOC molecular diagnostics (MolDx). cWGS and MolDx results were compared and discussed in a dedicated tumor board. Initial discordances were further evaluated by additional tests.

Results

cWGS was successfully performed in 69% (414/602) of patients with a technical success rate of 96% (414/433). Ineligibility for cWGS was mostly caused by an insufficient number of tumor cells (<20%) in the received biopsy (86%, 145/169). MolDx was performed in 47% (283/602) and was successful in 95% (267/283) of patients. cWGS showed a median turn-around-time (TAT) of 14 days, which decreased incrementally by continuous improvements to the clinical procedure and cWGS pipeline. In total, 480 genomic biomarkers for clinical validation were identified by SOC MolDx. cWGS showed an error rate of 4.2% (20/480) compared to a SOC MolDx error rate of 1% (5/480). Most of the biomarkers that were not reported by cWGS (19 of 20) were present in the raw data but not reliably identified due to very low variant allele frequencies. Improvements to further increase the sensitivity are currently being implemented with an anticipated reduction of the cWGS error rate to 2%. Overall, cWGS identified a clinically actionable (routine practice and experimental) biomarker in 74% of all patients tested. Compared to SOC MolDx, cWGS identified one or more additional treatment options in 69% (197/287) of patients. Interestingly, in patients that were not tested by SOC MolDx, actionable variants were identified in 60% (76/126).

Conclusions

Based on the first 600 patients of the WIDE study, cWGS was found to be clinically feasible in routine molecular diagnostics in a comprehensive cancer center setting and has added value by providing additional treatment options for the majority of patients.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Gerrit Meijer, Emile Voest and Kim Monkhorst.

Funding

The Netherlands Organisation for Health Research and Care innovation (ZonMW) and Hartwig Medical Foundation.

Disclosure

K. Monkhorst: Honoraria (self), Advisory/Consultancy, Research grant/Funding (self), Travel/Accommodation/Expenses: F. Hoffmann-La Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Research grant/Funding (self): PDGx; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Advisory/Consultancy: Pfizer; Advisory/Consultancy: BMS; Advisory/Consultancy: Abbvie; Advisory/Consultancy: Diaceutics; Travel/Accommodation/Expenses: Takeda. All other authors have declared no conflicts of interest.

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Q&A and live discussion

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Session: Proffered Paper - Translational research

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Q&A and live discussion

Presenter: Samra Turajlic

Session: Proffered Paper - Translational research

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Webcast

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