Data from Molecular Characterization of <i>KRAS</i> Wild-type Tumors in Patients with Pancreatic Adenocarcinoma

Abstract

<div>AbstractPurpose:<p><i>KRAS</i> mutation (MT) is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC). A small subset of PDACs harbor <i>KRAS</i> wild-type (WT). We aim to characterize the molecular profiles of <i>KRAS</i> WT PDAC to uncover new pathogenic drivers and offer targeted treatments.</p>Experimental Design:<p>Tumor tissue obtained from surgical or biopsy material was subjected to next-generation DNA/RNA sequencing, microsatellite instability (MSI) and mismatch repair status determination.</p>Results:<p>Of the 2,483 patients (male 53.7%, median age 66 years) studied, 266 tumors (10.7%) were <i>KRAS</i> WT. The most frequently mutated gene in <i>KRAS</i> WT PDAC was <i>TP53</i> (44.5%), followed by <i>BRAF</i> (13.0%). Multiple mutations within the DNA-damage repair (<i>BRCA2, ATM, BAP1, RAD50, FANCE, PALB2</i>), chromatin remodeling (<i>ARID1A, PBRM1, ARID2, KMT2D, KMT2C, SMARCA4, SETD2</i>), and cell-cycle control pathways (<i>CDKN2A, CCND1, CCNE1</i>) were detected frequently. There was no statistically significant difference in PD-L1 expression between <i>KRAS</i> WT (15.8%) and MT (17%) tumors. However, <i>KRAS</i> WT PDAC were more likely to be MSI-high (4.7% vs. 0.7%; <i>P</i> < 0.05), tumor mutational burden–high (4.5% vs. 1%; <i>P</i> < 0.05), and exhibit increased infiltration of CD8<sup>+</sup> T cells, natural killer cells, and myeloid dendritic cells. <i>KRAS</i> WT PDACs exhibited gene fusions of <i>BRAF</i> (6.6%), <i>FGFR2</i> (5.2%), <i>ALK</i> (2.6%), <i>RET</i> (1.3%), and <i>NRG1</i> (1.3%), as well as amplification of <i>FGF3</i> (3%), <i>ERBB2</i> (2.2%), <i>FGFR3</i> (1.8%), <i>NTRK</i> (1.8%), and <i>MET</i> (1.3%). Real-world evidence reveals a survival advantage of <i>KRAS</i> WT patients in overall cohorts as well as in patients treated with gemcitabine/nab-paclitaxel or 5-FU/oxaliplatin.</p>Conclusions:<p>KRAS WT PDAC represents 10.7% of PDAC and is enriched with targetable alterations, including immuno-oncologic markers. Identification of KRAS WT patients in clinical practice may expand therapeutic options in a clinically meaningful manner.</p></div>