Prospective analysis of 895 patients on a UK Genomics Review Board

Abstract

Background: The increasing frequency and complexity of cancer genomic profiling represents a challenge for the oncology community. Results from next-generation sequencing-based clinical tests require expert review to determine their clinical relevance and to ensure patients are stratified appropriately to established therapies or clinical trials.

Methods: The Sarah Cannon Research Institute UK/UCL Genomics Review Board (GRB) was established in 2014 and represents a multidisciplinary team with expertise in molecular oncology, clinical trials, clinical cancer genetics and molecular pathology. Prospective data from this board were collated.

Results: To date, 895 patients have been reviewed by the GRB, of whom 180 (20%) were referred for clinical trial screening and 62 (7%) received trial therapy. For a further 106, a clinical trial recommendation was given.

Conclusions: Numerous challenges are faced in implementing a GRB, including the identification of potential germline variants, the interpretation of variants of uncertain significance and consideration of the technical limitations of pathology material when interpreting results. These challenges are likely to be encountered with increasing frequency in routine practice. This GRB experience provides a model for the multidisciplinary review of molecular profiling data and for the linking of molecular analysis to clinical trial networks.

Keywords: clinical genetics; genomic medicine; molecular oncology; molecular tumour board.

Figure 1

Consort diagram of the stratification of patients reviewed by the Genomics Review Board (GRB) for standard therapy, to trials for targeted therapies and general recommendations returned to the treating clinician. In total, 62 patients received trial therapy (8 under compassionate access programmes). 19 of these patients were enrolled to trial directly following on from the GRB as a result of variants detected from molecular profiling. SCRI, Sarah Cannon Research Institute.

Figure 2

Number of reported cases with driver mutations in commonly affected cancer genes reported from Sarah Cannon Molecular Diagnostics multigene panel results.

Figure 3

Total number of KRAS variants identified and discussed by the Genomics Review Board from all Sarah Cannon Molecular Diagnostics reports. All recognised driver mutations in grey, variants of unknown clinical significance in black. KRAS variants identified as likely formalin fixation artefacts excluded.

Figure 4

MET variants identified in Sarah Cannon Molecular Diagnostics multigene panel testing with variant allele frequencies (VAFs). Several of these variants are consistently reported close to 50% VAF, which suggests these are likely single-nucleotide polymorphisms rather than tumour-specific mutations.

Figure 5

Proportion of cases demonstrating formalin-fixed, paraffin-embedded artefact from the six main referring institutions referring samples to Sarah Cannon Molecular Diagnostics which were then discussed at the Genomics Review Board (range, 0%–26.9%).