Frequency and incidence of oncogenic <i>RAS</i> mutations in patients with metastatic pancreatic ductal adenocarcinoma: Derived from the real-world evidence database Foundation Medicine Insights.

Abstract

777 Background: Approximately 60,000 patients are diagnosed with pancreatic cancer in the United States annually, with half of all cases diagnosed at the metastatic stage. 1 The most common type, pancreatic ductal adenocarcinoma (PDAC), accounts for ~90% of all pancreatic cancers 2 and is characterized by frequent KRAS oncogenic mutations. Newer investigational therapeutics target HRAS and NRAS, in addition to KRAS. To comprehensively characterize the incidence of RAS mutations in patients with PDAC, we analyzed mutational frequency data from the Foundation Medicine Insights (FMI) database. Methods: NGS-based comprehensive genomic profiling (CGP) data from 27,298 PDAC tissue samples were accessed from the FMI database (May 7, 2024 data cut). Only ‘short variants’ in RAS genes ( KRAS , NRAS , and HRAS) occurring at amino acid positions G12, G13, or Q61 that had a frequency 0.1% or greater were included. To estimate the number of new US cases of RAS -mutant PDAC, pancreatic cancer incidence estimates 3 were adjusted by the derived RAS mutational frequency values. All incidence estimates were rounded to the nearest 100. Results: Oncogenic RAS mutations were identified in 92% of PDAC patients, with nearly all being KRAS (91.8%) and the remaining NRAS (0.2%). No HRAS mutations passed our minimum frequency threshold requirement. Individual RAS mutations with frequency &gt;1% included KRAS G12D (39.9%), KRAS G12V (28.6%), KRAS G12R (14.6%), KRAS Q61H (4.2%), KRAS G12C (1.7%), and KRAS Q61R (1.4%). Applying these RAS mutation rates to reported PDAC incidence, we estimate that ~56,000 new patients with PDAC in USA per year will have tumors harboring an oncogenic RAS mutation, including ~51,000 of those with a RAS G12 mutation specifically. Conclusions: Oncogenic RAS mutations are identified from NGS testing in nearly all patients with advanced PDAC. Both the frequency and diversity of RAS mutations in PDAC suggest that PDAC is largely a RAS-driven cancer and that targeting RAS may be useful broadly in this disease. Mutational frequency and incidence at G12, G13, and Q61 amino acid positions in KRAS and NRAS among patients with PDAC. RAS G12 RAS G13 RAS Q61 RAS mutant Mutational Frequency KRAS 85.7% 0.8% 6.3% 91.8% NRAS 0.1% Below threshold 0.1% 0.2% Incidence KRAS 51,300 600 3,700 55,600 NRAS 100 Below threshold 100 200