Wayne State University, School of Medicine, Karmanos Cancer Center, Detroit, Michigan.
Caris Life Sciences, Phoenix, Arizona.
Clin Cancer Res. 2022 Jun 13;28(12):2704-2714. doi: 10.1158/1078-0432.CCR-21-3581.
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.
Tumor tissue obtained from surgical or biopsy material was subjected to next-generation DNA/RNA sequencing, microsatellite instability (MSI) and mismatch repair status determination.
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.
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.
KRAS 突变（MT）是胰腺导管腺癌（PDAC）的主要致癌驱动因素。一小部分 PDAC 存在 KRAS 野生型（WT）。我们旨在描述 KRAS WT PDAC 的分子特征，以揭示新的发病驱动因素并提供靶向治疗。
对来自手术或活检材料的肿瘤组织进行下一代 DNA/RNA 测序、微卫星不稳定性（MSI）和错配修复状态确定。
在研究的 2483 名患者（男性占 53.7%，中位年龄 66 岁）中，266 个肿瘤（10.7%）为 KRAS WT。KRAS WT PDAC 中最常突变的基因是 TP53（44.5%），其次是 BRAF（13.0%）。在 DNA 损伤修复（BRCA2、ATM、BAP1、RAD50、FANCE、PALB2）、染色质重塑（ARID1A、PBRM1、ARID2、KMT2D、KMT2C、SMARCA4、SET2D）和细胞周期控制途径（CDKN2A、CCND1、CCNE1）中经常检测到多个基因突变。KRAS WT（15.8%）和 MT（17%）肿瘤之间 PD-L1 表达无统计学差异。然而，KRAS WT PDAC 更可能是 MSI-高（4.7%比 0.7%；P<0.05）、肿瘤突变负担高（4.5%比 1%；P<0.05），并且表现出 CD8+T 细胞、自然杀伤细胞和髓样树突状细胞的浸润增加。KRAS WT PDAC 存在 BRAF（6.6%）、FGFR2（5.2%）、ALK（2.6%）、RET（1.3%）和 NRG1（1.3%）的基因融合，以及 FGFR3（1.8%）、NTRK（1.8%）和 MET（1.3%）的扩增。真实世界的证据表明，KRAS WT 患者在总体队列以及接受吉西他滨/ nab-紫杉醇或 5-FU/奥沙利铂治疗的患者中均具有生存优势。
KRAS WT PDAC 占 PDAC 的 10.7%，并富含可靶向的改变，包括免疫肿瘤标志物。在临床实践中识别 KRAS WT 患者可能会以有临床意义的方式扩大治疗选择。
