PCF-SELECT ctDNA targeted sequencing panel

• PCF-SELECT has been developed by world-leading academics with funding from CRUK: Dr Francesca Demichelis (Computational Oncology Laboratory at the Centre for Integrative Biology at the University of Trento) and Professor Gert Attard (Treatment Resistance Group at the UCL Cancer Institute).
• The panel has been designed for use in treatment selection for mCRPC patients, both for standard of care treatments and the clinical evaluation of experimental therapies, including drugs targeting DNA repair deficiency, immune checkpoints and the PI3K/AKT pathway.
• Although currently optimised for prostate cancer, the approach could be applied to other cancer types, as well as for diverse applications including stratification, monitoring and prognostication.
• Key benefits of this technology include detection of a breadth of genomic alterations at high sensitivity; a computational approach to minimise false positives; enrichment for informative SNPs; and a need for only low amounts of plasma DNA.

Liquid biopsies offer a minimally invasive solution to detect genomic aberrations, enabling tumour characterization and serial testing. Biological and technical challenges towards accurate detection of genomic lesions in metastatic prostate cancer plasma DNA include the broad range of tumour fractions, intra-patient genomic heterogeneity, frequent aneuploidy, and common imbalanced copy number changes.

There is currently no actionable way to detect mono-allelic deletions or loss of heterozygosity genes in plasma, which are informative for therapy selection, when the ctDNA content is low in circulation. Other known methods, including using coverage ratios, can do so when the ctDNA content is >10-20% or not at all. With an increasing number of effective treatments for metastatic prostate cancers, there is an urgent need for molecular biomarkers that allow improved sequencing of therapies and selection of agents for distinct molecular subtypes.

PCF-SELECT is a ctDNA plasma targeted next generation sequencing (NGS) panel for use prior to each change of treatment for metastatic castration-resistant prostate cancer (mCRPC). It has been designed to detect genomic aberrations informative for therapeutic selection, including drugs targeting DNA repair deficiency, immune checkpoints and the PI3K/AKT pathway, both for standard of care treatments and the clinical evaluation of experimental therapies. The customised design has been optimised together with a computational approach to quantitate tumour fraction that is prognostic and allows reporting of genomic calls weighted for risk of false negatives.

The performance of PCF-SELECT and associated computational method, including the ability to detect lesions at low ctDNA level and with complex copy number states, has been verified using synthetic simulations, serial mCRPC patient samples and comparisons with independent standard assays.