Abstract A40: Genomic characterization of locally advanced pancreatic adenocarcinoma
Authors: Picardo Sarah L. , O'Kane Grainne , Fischer Sandra , Zhang Amy , Denroche Rob , Jang GunHo , Dodd Anna , Grant Robert , Gruenwald Barbara , Moura Shari , Wang Yifan , Elimova Elena , Prince Rebecca , Zogopoulos George , Notta Faiyaz , Wilson Julie , Gallinger Steve , Knox Jennifer 
Published: March 2020

Abstract
Introduction: Patients with locally advanced pancreatic adenocarcinoma (LAPC) historically have a poor outcome despite having localized disease. The disease course of LAPC as compared to metastatic pancreatic adenocarcinoma (MPC) is unclear. SMAD4 mutational status has been postulated as a prognostic marker in this group. Molecular characteristics of LAPC by whole-genome sequencing (WGS) have not been reported.
Methods: Patients with treatment-naive LAPC and MPC were enrolled in the COMPASS clinical trial (NCT02750657). Clinical and demographic data were collected prospectively. Biopsy samples were enriched for tumor using laser capture microdissection. WGS and RNA sequencing (RNAseq) was performed on all patients. Tumors were evaluated for mutational status of driver genes KRAS, TP53, CDKN2A, and SMAD4 as well as modified Moffitt RNA subtypes (basal-like vs. classical).
Results: Patients with LAPC (n=27) and MPC (n=163) did not differ in terms of age, gender, smoking status, or history of diabetes. Patient with LAPC had a lower BMI (p=0.005) and lower neutrophil-lymphocyte ratio (p=0.048) than those with MPC. More patients with LAPC received FOLFIRINOX chemotherapy than those with MPC (p=0.003). Patients with LAPC had similar rates of KRAS, TP53, CDKN2A, and SMAD4 mutations, including rates of biallelic inactivation, and similar levels of tumor mutational burden to patients with MPC. There was a slight increase in the number of structural variants in MPC compared to LAPC (p=0.05). LAPC patients with SMAD4 mutations had higher baseline Ca19.9 than those with wild-type SMAD4 (p=0.0048). All patients with LAPC were modified Moffitt classical subtype on RNAseq, while 77% of patients with MPC were classical subtype (p=0.0049). LAPC patients had improved overall survival compared with MPC patients on univariate analysis (p=0.04) but not on multivariate analysis. There was no difference in survival between classical subtype LAPC and MPC patients, and no difference in survival between LAPC patients with and without SMAD4 mutations.
Conclusions: Patients with LAPC have a similar molecular profile on WGS to those with MPC with similar rates of altered drivers, in particular SMAD4. Patients with LAPC are more likely to be modified Moffitt classical subtype on RNAseq and have similar survival to those with classical subtype MPC. In our series, LAPC patients with SMAD4 mutations had similar survival to those with wild-type SMAD4.
Citation Format: Sarah L. Picardo, Grainne O'Kane, Sandra Fischer, Amy Zhang, Rob Denroche, GunHo Jang, Anna Dodd, Robert Grant, Barbara Gruenwald, Shari Moura, Yifan Wang, Elena Elimova, Rebecca Prince, George Zogopoulos, Faiyaz Notta, Julie Wilson, Steve Gallinger, Jennifer Knox. Genomic characterization of locally advanced pancreatic adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A40.