Abstract 1349: Personalized circulating tumor DNA profiling in malignant pleural mesothelioma

Background:Malignant pleural mesothelioma (MPM) is an aggressive tumor associated with exposure to asbestos and is rising in incidence worldwide. A lack of early detection methods and treatment successes have maintained a dismal prognosis of just 12 - 16 months. Circulating tumor DNA (ctDNA) is emerging as an important stratification biomarker in other thoracic malignancies, however research in this area has been lacking in MPM. Homozygous deletion of CDKN2A is one of the few established negatively prognostic molecular markers in MPM.Methods and Results:We conducted multiregional whole exome sequencing (m-WES) on tumor tissue (4 or 5 regions) and matched germline DNA from 11 patients with MPM that received surgery (extended pleurectomy decortication) as their primary treatment modality. Using a validated bioinformatics pipeline (developed as part of the TRACERx study), clonal single nucleotide variants (SNVs) and/or indels (present within all tumor regions) were selected from m-WES data for patient-specific assay design. Variants were prioritized for selection based on tumor driver status and higher mean variant allele frequencies (VAFs) amongst tumor regions. A minimum of 10 ng cfDNA isolated from pre-surgical blood was analyzed for ctDNA detection using Droplet Digital PCR (ddPCR), with positivity being defined as ≥ 3 mutant droplets and a plasma VAF ≥ 0.1%. Four out of eleven (36.4%) patients were ctDNA-positive using this patient-specific approach with VAFs ranging between 0.16% and 2.96%. Two additional patients had one or two positive mutant droplets, but these were excluded as potential false positives. In this pilot study, ctDNA-positive patients had significantly shorter survival than ctDNA-negative patients (P = 0.047), although this failed to reach significance by Cox regression analysis, likely due to a small sample size. Furthermore, in this cohort ctDNA status was a stronger prognostic biomarker than CDKN2A deletion status.Conclusions:Considering the short survival of patients with MPM despite surgery, we consider ctDNA-based analyses could be used to stratify patients regarding surgery, where risk-benefit would be marginal for those ctDNA-positive. This study provides proof-of-principle that the detection of tumor DNA from minimally invasive sources is possible in MPM and has alluded to how this could potentially impact clinical decision-making.Citation Format: Luke J. Martinson, Annabel J. Sharkey, Alan G. Dawson, Robert K. Hastings, Gareth Wilson, David Waller, Apostolos Nakas, Charles Swanton, Jacqui A. Shaw, Dean A. Fennell. Personalized circulating tumor DNA profiling in malignant pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1349.