Impact of KRAS alterations in pancreatic ductal adenocarcinoma (PDAC).

Abstract

4136 Background: The genomic alterations which characterize PDAC holds great promise for novel therapeutic interventions. Constitutive signaling via mutated KRAS is considered the signature pathognomonic alteration in PDAC, less than 10% of patients (pts) have tumors which are KRAS wild type (WT). We retrospectively reviewed our institutional genomic database to characterize PDAC pts with KRAS WT tumors. Methods: We reviewed electronic medical records of PDAC pts who underwent comprehensive genomic profiling (CPG) utilizing Foundation One CDx (50.6%) or TEMPUS (49.4%) between 2015-2020. Demographic and disease characteristics were compared between cohorts using Wilcoxon rank-sum test or chi-square tests. Left truncation at the time of CGP was used to account for the time of entry into the study cohort. Kaplan-Meier method was used for survival curve estimation, and log-rank test was used for between-group comparison. Cox regression was used to adjust for confounders. Results: We identified 235 patients: median age at diagnosis was 65 years and 52% were male. Clinical stages at diagnosis were localized (resectable/borderline resectable), locally advanced, or metastatic in 105 (44.7%), 61 (26.0%), and 69 (29.4%) patients, respectively. KRAS status was mutated in 212 (90%) patients: the most common alterations being G12D (48%), G12V (28%) and G12R (14%). KRAS WT status was noted in 23 (9.8%) pts, actionable genomic alterations in this subgroup are summarized in the table. Baseline demographic and treatment characteristics were similar between patients with KRAS mutated and WT tumors. Of the 23 patients with KRAS WT tumors, 16 (69.6%) completed all planned curative intent therapy compared to 121 (57.3%) of the 212 KRAS mutated pts (p=0.26). Median Overall Survival of patients with KRAS mutated tumors was 18.6 months compared to 44.1 months for WT pts (p=0.03). Adjusting for stage, WT vs. mutated status was associated with a 62% decreased hazard of death (HR 0.38 [0.18-0.83]; p=0.016). Conclusions: Patients with KRAS WT PDAC appear to have a distinct biology compared to those with KRAS mutations, meriting exploration in larger data sets. Further, comprehensive whole genome or transcriptomic characterization of KRAS WT tumors is necessary to identify putative driver alterations as well as actionable therapeutic targets.[Table: see text]

Are targeted therapies or immunotherapies effective in metastatic pancreatic adenocarcinoma?

“…For example, in a retrospective cohort of 235 patients, KRAS wild-type status was associated with a 62% decreased hazard of death [hazard ratio ((HR) = 0.38, P = 0.016]. 16 Similar findings were reported in a retrospective cohort of 741 patients with locally advanced or metastatic disease (HR = 1.26 for mutant versus wild-type KRAS ). 17…”

“…The most common are G12D and G12V, found in 44%-48% and 28%-29% of KRAS -mutated PDACs, respectively. 10 , 16 KRAS wild-type PDAC is associated with a better prognosis in most studies. For example, in a retrospective cohort of 235 patients, KRAS wild-type status was associated with a 62% decreased hazard of death [hazard ratio ((HR) = 0.38, P = 0.016].…”