Correlative analysis of circulating tumor (ct) DNA and tumor mutational analysis (TMA) in patients with advanced pancreatobilliary malignancies (PBM).

Abstract

235 Background: Tumor archival tissue (TT) MA of PBM is challenging due to insufficient specimen acquired from fine needle aspirations. This is a barrier to analyzing specimens for targeted therapy (clinical trial enrollment). The correlation of cell free ctDNA and TMA has not been studied extensively. We hypothesize that somatic TMA correlates with ctDNA and will be a surrogate for enrollment to targeted trials. Methods: We retrospectively identified PBM patients evaluated in the Phase I Program and analyzed ctDNA and TT. ctDNA was extracted from plasma, genomic alterations were analyzed by parallel sequencing of amplified target genes (73 genes) using Illumina Hi Seq (Guardant360). Direct sequence analysis was performed on genomic DNA isolated from FFPE TT using the Illumina MiSeq platform, 592-whole gene targets (Caris MI/X). The primary objective was to correlate the mutation concordance rate (mCR, common mutations/all mutations) between ctDNA and TT. We utilized Stata 15 for descriptive analysis, Spearman correlation coefficient, and Wilcoxon Sign Rank test for statistical analysis. Results: Between 03/2016-08/2017, 28 patients (M:F 1:1) were identified, 89.2% had pancreatic adenocarcinoma, 54% were treatment naïve and age ranged from 52-83 years old. The mCR for ctDNA was 31% (21/67) and the mCR for TT was 38% (21/55). These mCRs were highly correlative with a Spearman’s Rho = 0.89, (p < 0.0001). The mCR in ctDNA was compared to mCR in TT using Wilcoxon Sign Rank Test and was found to not be statistically different (p = 0.69). Adequate TT for MA occurred in 64 % (18/28) of patients. Percentage of DNA alterations found was 89.3% (25/28) in ctDNA and 94.4% (17/18) in TT. Moreover, 61% (11/18) of patients had at least 1 shared mutation. Percentages of driver mutations identified were 92% (23/25) in ctDNA and 100% (17/17) in TT. The most common driver mutations in ctDNA were TP53, KRAS, SMAD4, and NF1. The most common driver mutations in TT were KRAS, TP53, CDKN2A, and SMAD4. Conclusions: There was a statistically significant correlation between mCR of ctDNA and TMs in PBM (p < 0.0001).