Comparison of mutational landscape in primary and metastatic pancreatic tumors.

781 Background: Genomic profiling has brought to the forefront the clinical relevance of intratumoral heterogeneity. Oncogenic KRAS mutation is the most common driver event in pancreatic ductal adenocarcinoma (PDAC), but little is known about how KRAS alteration may cooperate with other genetic lesions to support dissemination and growth of metastatic disease. Therefore, an improved understanding of molecular events affecting the clinical course of KRAS -altered PDAC is needed to identify biomarkers of early disease and expand the repertoire of targeted therapies. Methods: We retrospectively analyzed tissue samples from PDAC patients using the OncoExTra tumor-normal whole exome and whole transcriptome test between April 2018 and May 2024. The prevalence of actionable somatic alterations was determined overall and by specimen location (primary vs. metastatic). Fisher’s exact test with FDR-based correction for multiple testing was used to identify co-alterations with KRAS and 19 DNA damage response (DDR) gene alterations. Results: PDAC samples from 434 patients (51.2% female; mean age 65.4±10.9 years) were analyzed. KRAS alterations were detected in 369 (85.0%) samples: 198 (45.6%) primary and 239 (55.1%) metastatic. KRAS G12D (32.7%) and KRAS G12V (29.5%) were the most common KRAS mutations. The frequency of KRAS alterations was 85.9% and 84.5% in primary and metastatic samples, respectively. TP53 alterations occurred in 68.2% samples overall and in 64.6% and 71.1% of primary and metastatic samples, respectively. Examination of co-alterations in KRAS -altered versus KRAS -WT samples uncovered enrichment of TP53 alterations in KRAS -altered (277 samples, 75.1%) compared to KRAS -WT samples (19 samples, 29.2%) ( p <0.001). Also, BRAF mutations and SND1:BRAF fusions exclusively occurred in metastatic KRAS -WT samples, although the number of events was small ( n =4 and n =2, respectively). We also found that MTAP was significantly co-altered in metastatic KRAS -WT samples (n=6, 16.2%) compared to KRAS -altered samples (6 samples, 3.0%) ( p =0.004). A total of 21.9% of all PDAC samples had an alteration in at least 1 DDR gene. No associations were observed between KRAS alteration status and alteration in DDR genes. However, TP53 alterations were more frequent in non-DDR-altered samples ( p <0.001), while CDKN2B alterations were enriched in DDR-altered samples ( p =0.025). Conclusions: We observed expected rates of alterations in known PDAC driver genes and uncovered higher co-occurrence of KRAS and TP53 alteration in metastatic samples. Additionally, TP53 alterations were less frequent in DDR-altered samples. Our findings suggest that a number of therapy approaches including BRAF, WEE1, PARP, and KRAS inhibitors as well as epigenetic modulators, alone or in combination, could improve clinical outcomes in PDACs with specific mutational profiles.