TY - JOUR
T1 - Molecular Characterization of KRAS Wild-type Tumors in Patients with Pancreatic Adenocarcinoma
AU - Philip, Philip A.
AU - Azar, Ibrahim
AU - Xiu, Joanne
AU - Hall, Michael J.
AU - Hendifar, Andrew Eugene
AU - Lou, Emil
AU - Hwang, Jimmy J.
AU - Gong, Jun
AU - Feldman, Rebecca
AU - Ellis, Michelle
AU - Stafford, Phil
AU - Spetzler, David
AU - Khushman, Moh'D M.
AU - Sohal, Davendra
AU - Lockhart, A. Craig
AU - Weinberg, Benjamin A.
AU - El-Deiry, Wafik S.
AU - Marshall, John
AU - Shields, Anthony F.
AU - Korn, W. Michael
N1 - Funding Information:
J. Xiu reports other support from Caris Life Sciences during the conduct of the study. A.E. Hendifar reports other support from PANCAN and Merck, grants and personal fees from Ipsen, and personal fees from AbbVie and Novartis outside the submitted work. E. Lou reports research grants from the American Association for Cancer Research (AACR-Novocure Tumor-Treating Fields Research Award) and the Minnesota Ovarian Cancer Alliance; honorarium and travel expenses from GlaxoSmithKline and Novocure, LLC; honorarium (donated to lab) for discussion organized by Antidote Education and funded by Daiichi Sankyo; consultancy with Nomocan Pharmaceuticals (unpaid); scientific advisory board membership with Minnetronix, LLC (unpaid); consultant and speaker honorarium from Boston Scientific US; University of Minnesota membership in the Caris Life Sciences Precision Oncology Alliance (unpaid); and institutional principal investigator for clinical trials sponsored by Celgene, Novocure, Intima Biosciences, and the NCI. J.J. Hwang reports personal fees from Bristol Myers Squibb, Bayer, Eisai, Taiho, Pfizer, Incyte, and Deciphera outside the submitted work. J. Gong reports personal fees from EMD Serono, Elsevier, Exelixis, QED Therapeutics, Natera, Basilea, HalioDx, Eisai, Janssen, Aveo, and Bayer outside the submitted work. D. Sohal reports speakers bureau with Incyte and Genentech; consulting with AstraZeneca; and research funding from Ability Pharma Amgen, Apexigen, AstraZeneca, Bristol Myers Squibb, FibroGen, Genentech, Merck, Rafael, and Roche (institution). B.A. Weinberg reports personal fees from Lilly, Taiho, Sirtex, Daiichi Sankyo, and AstraZeneca outside the submitted work. J. Marshall reports personal fees from Caris, Indivumed, Bayer, Taiho, and Pfizer during the conduct of the study. A.F. Shields reports personal fees and other support from Caris Life Sciences outside the submitted work. W.M. Korn reports other support from Caris Life Sciences outside the submitted work. No disclosures were reported by the other authors.
Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/6/15
Y1 - 2022/6/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85131903186&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-3581
DO - 10.1158/1078-0432.CCR-21-3581
M3 - Article
C2 - 35302596
AN - SCOPUS:85131903186
SN - 1078-0432
VL - 28
SP - 2704
EP - 2714
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 12
ER -