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Utility of ctDNA to support patient selection for early phase clinical trials: the TARGET study

2019; Nature Portfolio; Volume: 25; Issue: 5 Linguagem: Inglês

10.1038/s41591-019-0380-z

1546-170X

Dominic G. Rothwell, Mahmood Ayub, Natalie Cook, Fiona Thistlethwaite, Louise Carter, Emma Dean, Nigel Smith, Shaun Villa, Joanne Dransfield, Alexandra Clipson, Daniel J. White, Kamrun Nessa, Saba Ferdous, M. Howell, Avinash Gupta, Bedirhan Kilerci, Sumitra Mohan, Kris Frese, Sakshi Gulati, Crispin Miller, Allan M. Jordan, Helen Eaton, Nicholas Hickson, Ciara O’Brien, Donna M. Graham, Claire Kelly, S. Aruketty, Robert Metcalf, Jaseela Chiramel, Nadina Tinsley, Alexander J. Vickers, R Kurup, Hannah Frost, Julie Stevenson, Siobhan Southam, Dónal Landers, Andrew Wallace, Richard Marais, Andrew Hughes, Ged Brady, Caroline Dive, Matthew Krebs,

Genetic factors in colorectal cancer

Sequencing of circulating tumor DNA from cancer patients is a cost-efficient approach with turnaround time compatible with clinical practice to inform treatment decision-making in a phase 1 trial setting Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) supports blood-based genomic profiling but is not yet routinely implemented in the setting of a phase I trials clinic. TARGET is a molecular profiling program with the primary aim to match patients with a broad range of advanced cancers to early phase clinical trials on the basis of analysis of both somatic mutations and copy number alterations (CNA) across a 641 cancer-associated-gene panel in a single ctDNA assay. For the first 100 TARGET patients, ctDNA data showed good concordance with matched tumor and results were turned round within a clinically acceptable timeframe for Molecular Tumor Board (MTB) review. When a 2.5% variant allele frequency (VAF) threshold was applied, actionable mutations were identified in 41 of 100 patients, and 11 of these patients received a matched therapy. These data support the application of ctDNA in this early phase trial setting where broad genomic profiling of contemporaneous tumor material enhances patient stratification to novel therapies and provides a practical template for bringing routinely applied blood-based analyses to the clinic.