Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma

Philip A. Philip, Ibrahim Azar, Joanne Xiu, Michael J. Hall, Andrew Eugene Hendifar, Emil Lou, Jimmy J. Hwang, Jun Gong, Rebecca Feldman, Michelle Ellis, Phil Stafford, David Spetzler, Moh'D M. Khushman, Davendra Sohal, A. Craig Lockhart, Benjamin A. Weinberg, Wafik S. El-Deiry, John Marshall, Anthony F. Shields, W. Michael Korn

Research output: Contribution to journalArticlepeer-review

55 Scopus citations

Abstract

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

Original languageEnglish
Pages (from-to)2704-2714
Number of pages11
JournalClinical Cancer Research
Volume28
Issue number12
DOIs
StatePublished - Jun 15 2022

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