Association of co-occurring KRAS and gain of function TP53 mutations with aggressive metastasis through comprehensive genomic profiling of pancreatic ductal adenocarcinoma.

e16379 Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of malignancy. Although tissue genomics has been valuable in understanding driver mutations in PDAC, it is limited to impart subclonal mutations. ctDNA-based liquid biopsy represents a wider mutational profile, accounts for mutational heterogeneity, and better accessibility. Here we compared comprehensive mutational profiling (CGP) of advanced PDAC patients from tissue and blood samples to evaluate its relation to the disease stage. Methods: In a retrospective study, 145 Pts with advanced PDAC and on SOC underwent targeted hybrid-capture-based CGP using an OncoIndx CGP comprising 1080 genes on tumor tissue or plasma ctDNA. Enriched libraries were sequenced at an average depth of 5500 X on Illumina Nextseq 2000 platform. Raw sequenced reads were processed for variant calling using a proprietary iCare. Variants were called according to ClinVar, ACMG, and AMP databases. Results: Out of 145 patients sequenced, 104 showed the presence of at least one pathogenic mutation. 46 % (48/104) of samples were blood, 34 % (36/104) were tissue and 19 % (20/104) were paired. We observed 90 % concordance between Lbx and Tbx for KRAS and TP53 variants. TP53 mutation was the most frequent, occurring in 70 % pts with equivalent distribution in tissue and blood. Nearly 55 % TP53 variants were gain of function (GOF) while 45 % were loss of function. KRAS was the 2 nd most frequent mutation (66 % Pts) with the codon 12 variant being the most frequent (57.7 %), and showing comparable distribution between KRAS:p.G12D (55 %) and KRAS:p.G12V (45%). Rare variants including codon 61 (KRAS:p.Q61H) and 146 (KRAS:p.A59T) were detected in 5 pts, while N and HRAS variants were combined present in 14 % pts, and were mutually exclusive with KRAS (P = 0.043). TP53 and KRAS variants showed high mutual co-occurrence (Fisher test; P = 0.0042, OR = 2.1). KRAS:p. G12D and TP53 GOF variants strongly correlated with aggressive metastasis (Speareman Rho = 0.8, P = 0.037), and were detected primarily in Lbx. Additionally, Lbx revealed the presence of HRR mutations (BRCA1, BRIP1, and RAD54L) in 9.6 % pts. 21 % Pts showed presence of amplified ERBB2, while 24 % showed either CCND1 or CCND2 amplification. When present, co-occurring KRAS, SMAD4 and TP53 mutations were associated with distant metastasis (P = 0.04). Conclusions: The genomic profile of advanced PDAC patients revealed a complex mutational landscape. Notably, ctDNA exhibited greater tumor mutational heterogeneity compared to tissue DNA samples and detected additional actionable pathogenic variants. Co-occurring KRAS and TP53 GOF variants and the presence of LOF SMAD4 variants along with ERBB2 amplification showed a strong association with distant metastasis, suggesting their prognostic value in advanced PDAC.