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589 Background: Spatiotemporal heterogeneity, paucity of actionable targets, and complexity of the tumor microenvironment (TME) are major barriers to therapeutic advances in pancreatic ductal adenocarcinoma (PDAC). We reconstructed the transcriptomic data from a heterogeneous cohort of PDAC patients (pts) to examine the TME and identify putative therapeutic strategies. Methods: Transcriptomic profiling and targeted gene sequencing data (Tempus) on primary or metastatic specimens from PDAC pts treated at the Medical College of Wisconsin (MCW) between 2015-2020 were analyzed. Mutation calling, expression analysis, cell type deconvolution from the transcriptome, and TME reconstruction were performed using BostonGene’s automated pipelines. Mann-Whitney U test and Fisher's exact test were used to assess statistical significance. Results: The cohort (N = 79) comprised of resectable (19%), borderline resectable (37%), locally advanced (24%) and metastatic (20%) PDAC pts. The most frequently used tumor sites for transcriptomic profiling were pancreas primary (59%), liver (16%), lung (10%) and peritoneum (10%). Four distinct subtypes were identified based on the BostonGene classification of the transcriptomic TME– Immune Enriched (IE; 14%), Fibrotic (F; 28%), Immune Enriched & Fibrotic (IEF; 36%), and Immune Depleted (ID; 22%). Analyses of the cellular composition of the TME subtypes with RNA-seq-based deconvolution showed that T-cell fractions (CD4, CD8) were higher in the IE/IEF subtypes compared to the F/ID subtypes (CD8 means: 6.4% vs 2.9%, p < 0.001; CD4 means: 15.1% vs. 7.6%, p < 0.001), while fibroblast content was higher in the F/IEF subtypes compared to the IE/ID subtypes (37.4% vs 18.4%; p < 0.001). KRAS wild-type (WT) tumors were enriched in the IEF subtype (58%), while KRAS mutated tumors comprised all four transcriptomic subtypes. Primary PDACs that underwent radiotherapy were significantly more enriched in fibroblasts compared to samples from the TCGA cohort that did not undergo radiotherapy (means: 30%(MCW) vs. 20% (TCGA), p < 0.001). Primary PDACs were enriched in the IEF subtype (46%), while liver and lung metastases were enriched in the ID (74%) and IE subtypes (70%), respectively. When pts were dichotomized to short (< 400 days) versus long (> 800 days) survivors, tumors from pts with longer survival demonstrated a trend towards enrichment in CD4/CD8 T cells and IE subtype that did not meet statistical significance. Conclusions: Lung metastases and KRAS WT PDACs harbor an immunogenic TME while liver metastases harbor an immune-cold TME, highlighting the biologic heterogeneity of PDAC. The efficacy of immunotherapeutic strategies in PDAC pts who demonstrate an IE/IEF transcriptomic subtype merits prospective evaluation. The four distinct subtypes identified by TME transcriptomic classification highlight the possibility of personalized immunotherapeutic strategies in PDAC.

4136 Background: The genomic alterations which characterize PDAC holds great promise for novel therapeutic interventions. Constitutive signaling via mutated KRAS is considered the signature pathognomonic alteration in PDAC, less than 10% of patients (pts) have tumors which are KRAS wild type (WT). We retrospectively reviewed our institutional genomic database to characterize PDAC pts with KRAS WT tumors. Methods: We reviewed electronic medical records of PDAC pts who underwent comprehensive genomic profiling (CPG) utilizing Foundation One CDx (50.6%) or TEMPUS (49.4%) between 2015-2020. Demographic and disease characteristics were compared between cohorts using Wilcoxon rank-sum test or chi-square tests. Left truncation at the time of CGP was used to account for the time of entry into the study cohort. Kaplan-Meier method was used for survival curve estimation, and log-rank test was used for between-group comparison. Cox regression was used to adjust for confounders. Results: We identified 235 patients: median age at diagnosis was 65 years and 52% were male. Clinical stages at diagnosis were localized (resectable/borderline resectable), locally advanced, or metastatic in 105 (44.7%), 61 (26.0%), and 69 (29.4%) patients, respectively. KRAS status was mutated in 212 (90%) patients: the most common alterations being G12D (48%), G12V (28%) and G12R (14%). KRAS WT status was noted in 23 (9.8%) pts, actionable genomic alterations in this subgroup are summarized in the table. Baseline demographic and treatment characteristics were similar between patients with KRAS mutated and WT tumors. Of the 23 patients with KRAS WT tumors, 16 (69.6%) completed all planned curative intent therapy compared to 121 (57.3%) of the 212 KRAS mutated pts (p=0.26). Median Overall Survival of patients with KRAS mutated tumors was 18.6 months compared to 44.1 months for WT pts (p=0.03). Adjusting for stage, WT vs. mutated status was associated with a 62% decreased hazard of death (HR 0.38 [0.18-0.83]; p=0.016). Conclusions: Patients with KRAS WT PDAC appear to have a distinct biology compared to those with KRAS mutations, meriting exploration in larger data sets. Further, comprehensive whole genome or transcriptomic characterization of KRAS WT tumors is necessary to identify putative driver alterations as well as actionable therapeutic targets.[Table: see text]

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