Abstract Introduction: While type 2 diabetes mellitus (T2DM) has been shown to be both a risk factor and consequence of pancreatic ductal adenocarcinoma (PDAC), the bidirectional relationship between T2DM and PDAC remains to be fully understood. Due to spatial proximity of insulin-producing beta cells, PDAC tumor cells are presumably exposed to a highly concentrated insulin microenvironment, which may contribute to the dysregulation of the insulin receptor gene INSR. There are two isoforms of insulin receptor: IR-A and IR-B. IR-A activity has been associated with oncogenic function and is upregulated in several cancer types. This leads to questions regarding the role of INSR and more specifically, how the ratio of the two isoforms may potentiate tumor aggressiveness in PDAC. Results: Using data from whole-genome and RNA sequencing of metastatic PDAC (mPDAC) from both the PanGen (n=70; NCT01855477) and Personalized Oncogenomics (n=22; NCT02155621) trials, we identified somatic copy loss of INSR in 39/92 (42%) patient tumors, with the majority of such cases (35/39; 90%) showing heterozygous copy loss. There was no statistical association between INSR copy status and PDAC transcriptomic subtypes. INSR expression was lower in basal-like versus classical subtype tumors (p=1.1e-4), and INSR expression was further attenuated in basal-like tumors with heterozygous copy loss of INSR (p=0.0041). The ratio of IR-A:IR-B expression was heterogenous across samples, and heightened IR-A:IR-B ratio was significantly (p<0.05) associated with expression of genes linked to the PI3K-Akt signaling axis (CCDC88A, THEM4) and glucose metabolism (HK1, G6PC, PKLR) in basal-like tumors. Interestingly,HK1 and IGF1R were significantly upregulated, independent of IR-A:IR-B ratio, among basal-like (p 9.1e-9 and p=1.4e-5, respectively) compared to classical subtype tumors. Conclusion: These data indicate that heightened IR-A:IR-B ratio is associated with the expression of key pathways converging on PI3K signalling and glucose metabolism in mPDAC, while highlighting that several IR-A:IR-B-associated gene correlations are unique to basal-like tumors. Such findings warrant further investigation of relative INSR isoform expression in mPDAC and pre-clinical models to elucidate the role of the oncogenic isoform, IR-A, in driving tumor aggressiveness in basal-like subtype tumors. Citation Format: Lan V. Tao, James T. Topham, Joanna M. Karasinska, Erica S. Tsang, Andrew Metcalfe, Hassan Ali, Dawn Ashforth, Rachel Goodwin, Patricia A. Tang, Oliver F. Bathe, Janessa Laskin, Marco Marra, Daniel J. Renouf, David F. Schaeffer. Elucidating the role of insulin receptor isoform expression in metastatic pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B066.