Circulating tumour DNA experience in patients with cancer of unknown primary

Abstract

Background: Improving the outcome for patients diagnosed with Cancer of Unknown Primary (CUP) is an unmet clinical need where survival is usually less than 1 year. Molecular characterisation of the disease may have diagnostic and therapeutic implications. The circulating tumour DNA test - Guardant 360™ is designed to detect gene alterations with a range of clinical utility. Methods: Twenty-five patients were referred to Sarah Cannon Research Institute for the Guardant 360™ test. Panel version 2.10 reports single nucleotide variants in 73 genes, gene copy number amplifications in 18 genes, fusions/rearrangements in 6 genes as well as indels in 23 genes. The panel covers all NCCN somatic mutations. Digital Sequencing™ technology essentially eliminates false positives allowing sequencing of targeted regions at very low DNA concentrations. Variants of unknown significance (VUS) were also measured. All patients were discussed at our institutional Genomics Review Board. Results: Twenty-five patients (14 female; 11 male) were recruited from 24 August 2017 to 17 April 2018. Median age was 67 years (range 27-76). Main sites of disease were: lymph nodes (8); pelvis (8); liver (6); bone (3) and adrenal glands (2). The median turnaround time (TAT) from sample collection to report was 10 days (range 6-15). Seventeen patients (68%) had potentially actionable mutations; 4 patients had no mutations detected: 1 post resection; 2 were responding to chemotherapy; 1 was sampled prior to commencing chemotherapy. Genetic alterations detected included: BRAF V600E; KRAS; FGFR; MYC; KIT; PIK3CA and HER2. Twelve patients had ≥3 somatic mutations (including variants of uncertain significance (VUS)); ≥ 6 mutations were found in six of these patients. Conclusions: ctDNA is feasible with an acceptable TAT and the identification of significant potentially actionable targets. Targetable mutations were detected including BRAF, V600E, HER2 and FGFR. Two patients now have access to BRAF and MEK inhibitors. Twelve patients had ≥ 3 mutations that is emerging as potential biomarker of response to immunotherapy. The burden of VUS and presence of actionable targets supports more research on personalised medicine in patients with CUP.