Abstract 4255: Concurrent KRAS and TP53 mutations in pancreatic cancer real-world data (RWD) highlight convergent tumor evolutionary patterns

Abstract

Abstract Pancreatic cancer is one of the most fatal of all cancers. Pancreatic adenocarcinomas have been historically difficult to treat, in part due to lack of early detection, and due to their resistance to conventional chemotherapy. There has recently been an improved understanding of the biologic processes driving pancreatic tumorigenesis, and an increase in clinical trial options available to patients, especially in the context of KRAS mutation positive pancreatic ductal adenocarcinoma (PDAC). KRAS is a known driver of pancreatic cancer initiation, with concurrent loss of TP53 in many cases. Among all mutated genes in pancreatic cancer, KRAS, TP53, CDKN2A, and SMAD4 are most frequently reported, followed by CDKN2B and ARID1A among others. Mutations in TP53 commonly found in pancreatic cancer are either missense or truncating. The specific type of mutation may be important to note since point mutations may produce dysfunctional proteins that acquire gain of functions that are tumor-promoting, although the most well-agreed upon effects of TP53 mutations stem from the absence or decrease of its normal physiologic functions including cell cycle arrest, apoptosis promotion, DNA damage response triggering, maintenance of cell polarity, and maintenance of genomic stability. Here we present an in-depth multi-dimensional analysis of 29 pancreatic adenocarcinoma patients, consisting of 11 patients with KRAS G12D mutations, 5 patients with KRAS G12V mutations, 3 patients with non-canonical KRAS mutations, and 10 patients with no KRAS mutations identified in their tumors. Individual TP53 mutations were highlighted in the context of associated KRAS mutations and tumor genomic landscape at the time of testing. Real-world data was collected with patient consent through community embedded Oncology Clinical Team (ceOCT) facilitated engagement. Tumor evolution prediction rules were constructed based on mutational landscapes of the 29 patients and evidence published in peer-reviewed journals. Pancreatic cancer patient data from the AACR GENIE Cohort v12.0-public database and the cBioportal for Cancer Genomics public site was subsequently used for testing predicted tumor evolutionary trajectories. Here we describe multiple independent combinations of KRAS and TP53 mutations leading to convergent functional outcomes for tumor cells, in the context of patient-specific gene mutation landscapes. Recurrent patterns of paired mutations with common cellular function dysregulation outcomes highlight core underlying mechanisms of pancreatic tumor evolution. Citation Format: Kaumudi Bhawe, Adrienne Nugent, Deb Christensen, Lauren Levine, Emma Shtivelman. Concurrent KRAS and TP53 mutations in pancreatic cancer real-world data (RWD) highlight convergent tumor evolutionary patterns. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4255.