Genomic analysis of paired primary and metastatic pancreatic ductal adenocarcinoma tumors.

758 Background: The genomics of pancreatic ductal adenocarcinoma (PDAC) have been increasingly understood allowing for improvements in treatment, yet the clinical relevance of PDAC evolution is less well studied. The aim of this study is to evaluate genomic differences and clinical correlations between primary pancreatic tumors and paired metastases using a targeted sequencing panel. Methods: Patients who underwent surgical resection for PDAC with recurrent disease who had targeted genomic sequencing of both the primary tumor and a metastasis were included. Genomic alterations were determined using a panel of cancer-related genes (MSK-IMPACT). OncoKB was used to annotate driver alterations. MATH scores were used to quantify intratumoral heterogeneity. Comparison between paired samples was performed and association with clinical variables was assessed. Results: There were 55 patients included; 20% (n=11) received neoadjuvant therapy, 91% (n=50) had adjuvant therapy and 36% (n=20) had adjuvant radiation. The most common sites of metastasis sequenced were lung (36%, n=20), liver (35%, n=19) and local (13%, n=7). There was concordance between the first site of recurrence and site sequenced in 93% (n=51) of cases with a median time between resection and biopsy of recurrence of 25 months. The most commonly altered genes are KRAS (96%), TP53 (83%), CDKN2A (40%), SMAD4 (25%) and RNF43 (13%). The majority of alterations are shared between the primary tumor and metastasis. Clonal mutations were defined as cancer cell fraction (CCF) >0.8. The majority of shared mutations are clonal; 52% of mutations are clonal in both the primary and metastasis, and clonality is preserved in 76% of shared mutations in metastases. The most commonly shared alterations are in driver genes and the majority are clonal- TP53 (80%), KRAS (78%), CDKN2A (77%) and SMAD4 (64%). The proportion of clonal mutations among drivers is higher than variants of unknown significance (p=0.005). There are 31 mutations private to the metastasis in 19 patients, 12 of which are clonal (39%). Mutations private to the metastasis are more common in patients who received adjuvant systemic therapy (p=0.035); however this was not seen when comparing patients who received adjuvant radiation to those who did not (p=0.38). MATH scores are higher in the metastasis as compared to the primary in all patients (p=0.0096), including those who received adjuvant treatment (p=0.002), indicating increased intratumoral heterogeneity in metastases. Conclusions: A targeted sequencing panel demonstrates that the majority of driver mutations are clonal and preserved between the primary tumor and metastasis. Additional private mutations and increased intratumoral heterogeneity are noted in metastasis, and our data suggests that this may be associated with exposure to systemic therapy.