Data from Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma
Year: 2023
Type: other
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%). Real-world 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 immuno-oncologic markers. Identification of KRAS WT patients in clinical practice may expand therapeutic options in a clinically meaningful manner.
Authors: 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
Institutions: Wayne State University, The Barbara Ann Karmanos Cancer Institute, Caris Life Sciences (United States), Fox Chase Cancer Center, Cedars-Sinai Medical Center, University of Minnesota, Masonic Cancer Center, Levine Cancer Institute, USA Mitchell Cancer Institute, University of South Alabama, University of Cincinnati, Medical University of South Carolina, Georgetown University, Brown University
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Funders: American Association for Cancer Research, Pancreatic Cancer Action Network, Amgen, Bristol-Myers Squibb, Minnesota Ovarian Cancer Alliance, Eli Lilly and Company, Pfizer, AstraZeneca, GlaxoSmithKline, Celgene, FibroGen, University of Minnesota, Boston Scientific Corporation, Exelixis, Novocure, Incyte, Natera, Eisai, Ipsen, Sirtex Medical, Genentech, EMD Serono, National Cancer Institute, Daiichi Sankyo Europe
OpenAlex ID: W4361954261