Up-front cell-free DNA next generation sequencing improves target identification in UK first line advanced non-small cell lung cancer (NSCLC) patients.

BACKGROUND: Genomic sequencing is necessary for first-line advanced non-small cell lung cancer (aNSCLC) treatment decision-making. Tissue next generation sequencing (NGS) is standard but tissue quantity, quality, and time-to-results remains problematic. Here, we compare upfront cell-free-DNA (cfDNA) NGS clinical utility against routine tissue testing in patients with aNSCLC. METHODS: cfDNA-NGS was performed in consecutive, newly identified aNSCLC patients between December 2019-October 2021 alongside routine tissue genotyping. Variants were interpreted using AMP/ASCO/CAP guidelines. The primary endpoint was tier-1 variants detected on cfDNA-NGS. cfDNA-NGS results were compared to tissue results. RESULTS: Of 311 patients, 282 (91%) had an informative cfDNA-NGS test; 118 (38%) patients had a tier-1 variant identified by cfDNA-NGS. Of 243 patients with paired tissue-cfDNA tests, 122 (50%) tissue tests were informative; 85 (35%) tissue tests identified a tier-1 variant. cfDNA-NGS detected 39 additional tier-1 variants compared to tissue alone, increasing the tier-1 detection rate by 46% (from 85 to 124). The sensitivity of cfDNA-NGS relative to tissue was 75% (25% tissue tier-1 variants were not detected on cfDNA-NGS); 33% of cfDNA tier-1 variants were not identified on tissue tests. Median time from request-to-report was shorter for cfDNA-NGS versus tissue (8 versus 22 days; p < 0.0001). A total of 245 (79%) patients received first-line systemic-therapy: 49 (20%) with cfDNA-NGS results alone. Median time from sampling-to-commencement of first-line treatment was shorter for cfDNA-NGS blood draw versus first tissue biopsy (16 versus 35 days; p < 0.0001). CONCLUSIONS: cfDNA-NGS increased the tier-1 variant detection rate with high concordance with tissue, and halves time-to-treatment. 'Plasma-first' upfront cfDNA-NGS use should be considered routinely for aNSCLC.

Prospective analysis of 895 patients on a UK Genomics Review Board.

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.