Background: Locally advanced pancreatic cancer (LAPC) accounts for approximately 30% of pancreatic ductal adenocarcinomas (PDAC). Optimal management for LAPC is controversial and combination treatments are extrapolated from treatment guidelines for metastatic disease. The biological underpinnings of LAPC remain unclear, although the loss of tumor suppressor SMAD4 has been associated with metastatic disease. Here we characterize the genomic landscape of LAPC in a large series of prospectively sequenced PDAC. Methods: Clinical, genomic and survival data were obtained from the COMPASS trial (NCT02750657), a prospective multi-institutional study that included patients with treatment-naïve advanced PDAC, with predominantly metastatic cases due to ease of biopsy. Fresh tumor tissue was acquired by percutaneous core biopsy for real-time whole genome sequencing (WGS) and RNA sequencing (RNAseq). Laser capture micro-dissection was performed for all cases. Response to therapy was assessed every 8 weeks, and patients were followed prospectively. Results: Of 268 patients (268 with available WGS and 253 with RNAseq), 37 (14%) had LAPC. Baseline epidemiological variables were similar, with no differences between sex, age, smoking status, or history of diabetes. Patients with LAPC had a lower BMI (median 22 vs 24, p=0.005) and lower baseline CA19-9 (median 488 vs 2551, p=0.002) than metastatic cases. All patients with LAPC had a low (<2 points) Gustave Roussy Immune Score, previously shown to be prognostic in our dataset. Driver alternations were similar in LAPC and metastatic cases with no differences in SMAD4 loss between the two groups; however, major imbalances in mutant KRAS were absent in the LAPC group. The burden of SNVs, indels and SVs was significantly lower in LAPC (Table). All LAPC cases demonstrated a classical RNA subtype, compared to 23% in metastatic cases (p=0.0008). Median OS measured 12.5 and 8.3 months for LAPC and metastatic cases, respectively (HR 0.65, 95% CI 0.48-0.89, p=0.003). In addition, when measuring CD8+ T cell infiltration by IHC using median cut-off values, primary site biopsies had a higher CD8+ T cell infiltrate compared to metastatic sites (77% vs 56% CD8-high, respectively, p=0.01). Conclusions: These integrated genomic, RNA subtyping and early immunophenotyping results suggest that LAPC demonstrate less genomic instability and classical programming. Further study will delineate how these genomic differences, along with better clinical features, may influence treatment decision-making and design of future clinical trials. Clinical trial information: NCT02750657.

m=mutation.