Impact of panel design and cut-off on tumour mutational burden assessment in metastatic solid tumour samples

CPCT Consortium

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15 Citations (Scopus)

Abstract

Tumour mutational burden (TMB) has emerged as a promising biomarker to predict immune checkpoint inhibitors (ICIs) response in advanced solid cancers. However, harmonisation of TMB reporting by targeted gene panels is lacking, especially in metastatic tumour samples. To address this issue, we used data of 2841 whole-genome sequenced metastatic cancer biopsies to perform an in silico analysis of TMB determined by seven gene panels (FD1CDx, MSK-IMPACT™, Caris Molecular Intelligence, Tempus xT, Oncomine Tumour Mutation Load, NeoTYPE Discovery Profile and CANCERPLEX) compared to exome-based TMB as a golden standard. Misclassification rates declined from up to 30% to <1% when the cut-point for high TMB was increased. Receiver operating characteristic analysis demonstrated that, for correct classification, the cut-point for each gene panel may vary more than 20%. In conclusion, we here demonstrate that a major limitation for the use of gene panels is inter-assay variation and the need for dynamic thresholds to compare TMB outcomes.

Original languageEnglish
Pages (from-to)953-956
Number of pages4
JournalBritish Journal of Cancer
Volume122
Issue number7
DOIs
Publication statusPublished - 31 Mar 2020

Bibliographical note

Funding Information:
Funding information Clinical studies and WGS analyses were financially supported by Hartwig Foundation and Barcode for Life. Implementation of the data portal was supported by a grant from KWF Kankerbestrijding (HMF2017-8225, GENONCO).

Funding Information:
Competing interests M.P.J.K.L. has advisory board memberships for Pfizer, Bayer, Roche, JnJ and received research grants from Astellas, JnJ, Sanofi and MSD. H.J.D. is an advisory board member for AstraZeneca. The other authors declare no competing interests.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Cancer Research UK.

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