Exploring the mutational and molecular profile of pancreatic cancer: A comprehensive genomics approach.

Abstract

e16417 Background: Pancreatic cancer is an aggressive and often fatal malignancy, with its asymptomatic nature complicating diagnosis and treatment. Therapeutic options for advanced or metastatic cases remain limited. Understanding the genomic and molecular characteristics of pancreatic cancer is critical for uncovering its mechanisms and driving the development of novel therapies. Methods: A cohort of 261 pancreatic cancer patients were profiled for genomic alterations using NGS-based broad gene panel (1212 genes). The screening included testing for immunotherapy biomarkers – TMB, MSI and PD-L1 expression. Results: Pathogenic variants were identified in 48.3% of the patients, across 70 genes; 68.6% of these genes were tumor suppressors. Predominantly mutated genes include KRAS (40.6%), TP53 (39.5%), CDKN2A (9.2%), SMAD4 (7.7%), ARID1A (4.6%), ATM (3.4%), and BRCA2 (3.4%). Common KRAS mutations were p.G12D (10%), p.G12V (8.3%), and p.G12R (3.4%). Recurrently amplified genes included ERBB2, CCND1 , and FGFR3 /4, while notable gene fusions such as FGFR3-TACC3, HP-HPR, and SAMD5 - SASH1 were also identified. The most frequently altered pathways were cell cycle control (34.2%), RAS/RAF/MAPK (28.6%), DNA damage response (10.7%), and chromatin remodelling (8.5%). Co-occurring mutations were most common in the cell cycle control and RAS/RAF/MAPK pathway (33%). Further, 6.1% of patients had high TMB (> 10 mut/Mb), 2.9% had MSI-H, and PD-L1 expression was detected in 5.8% of the cohort (> 1%). Comprehensive genomic profiling detected therapeutic relevant variants in 58.6% of the cohort, which included 17.6% patients eligible for FDA approved (level 1) therapy and 41.8% were eligible for therapy studied in clinical trials (level 3 therapy). Conclusions: There are limited standard of care targeted therapy for pancreatic cancer. Considering the molecular complexity and inter-patient heterogeneity, every exercise on understanding the molecular drivers may help in better patient stratification for appropriate therapy and designing clinical trials. This study indicates that nearly 32% of pancreatic cancer patients may benefit from targeted therapy, by screening for therapeutically relevant biomarkers as part of broad comprehensive genomic profiling which will help in improving clinical outcomes. Mutated genes targeted by FDA approved drugs/drug combinations (Level 1) Mutated genes targeted by drugs/drug combinations in clinical trials (Level 3) BRAF (p.V600E) (Tier 2 AMP) APC JAK1 BRCA1 (n=4) (Tier 1 AMP) ARID1A KMT2C BRCA2 (n=10) (Tier 1 AMP) ARID2 RNF43 EGFR (Tier 2 AMP) ATRX SETD2 KRAS (Tier 2 AMP) AXIN1 SLX4 MLH1 (Tier 1 AMP) BRAF (non-p.V600E) SMAD4 PIK3CA (Tier 2 AMP) CDKN2A PTEN (Tier 2 AMP) CTNNB1 RAD50 (Tier 2 AMP) FANCA RAD54L (Tier 2 AMP) FANCC ERBB2 (Tier 2 AMP) NRAS BRIP1 (Tier 2 AMP) POLD1 ATM (Tier 2 AMP) PTCH1 MSH2 (Tier 2 AMP) RAF1 MSH3 (Tier 2 AMP) TP53