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

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.

Multiparametric Mapping Magnetic Resonance Imaging of Pancreatic Disease.

BACKGROUND: Current magnetic resonance imaging (MRI) of pancreatic disease is qualitative in nature. Quantitative imaging offers several advantages, including increased reproducibility and sensitivity to detect mild or diffuse disease. The role of multiparametric mapping MRI in characterizing various tissue types in pancreatic disease such as chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC) has rarely been evaluated. PURPOSE: To evaluate the feasibility of multiparametric mapping [T1, T2, and apparent diffusion coefficient (ADC)] in defining tissue characteristics that occur in CP and PDAC to improve disease diagnosis. MATERIALS AND METHODS: Pancreatic MRI was performed in 17 patients with PDAC undergoing therapy, 7 patients with CP, and 29 healthy volunteers with no pancreatic disease. T1 modified Look-Locker Inversion Recovery (T1 MOLLI), T2-prepared gradient-echo, and multi-slice single-shot echo-planar diffusion weighted imaging (SS-EPI DWI) sequences were used for data acquisition. Regions of interest (ROIs) of pancreas in PDAC, CP, and control subjects were outlined by an experienced radiologist. One-way analysis of variance (ANOVA) was used to compare the difference between groups and regions of the pancreas, and Tukey tests were used for multiple comparison testing within groups. Receiver operator characteristic (ROC) curves were analyzed, and the areas under the curves (AUCs) were calculated using single parameter and combined parameters, respectively. RESULTS: T1, T2, and ADC values of the entire pancreas among PDAC, CP, and control subjects; and between upstream and downstream portions of the pancreas in PDAC patients were all significantly different (p < 0.05). The AUC values were 0.90 for T1, 0.55 for T2, and 0.71 for ADC for independent prediction of PDAC. By combining T1, T2, and ADC, the AUC value was 0.94 (sensitivity 91.54%, specificity 85.81%, 95% CI: 0.92-0.96), which yielded higher accuracy than any one parameter only (p < 0.001). CONCLUSION: Multiparametric mapping MRI is feasible for the evaluation of the differences between PDAC, CP, and normal pancreas tissues. The combination of multiple parameters of T1, T2, and ADC provides a higher accuracy than any single parameter alone in tissue characterization of the pancreas.

Redefining the Positive Margin in Pancreatic Cancer: Impact on Patterns of Failure, Long-Term Survival and Adjuvant Therapy.

PURPOSE: There is debate regarding the definition and clinical significance of margin clearance in pancreatic ductal adenocarcinoma (PDA). A comprehensive archival analysis of surgical resection margins was performed to determine the effect on locoregional recurrence and survival, and the impact of adjuvant therapy in PDA. METHODS: We identified 105 patients with resected PDA. Pancreatic, anterior, bile duct, and posterior surgical resection margins (PM; posterior surface, uncinate and vascular groove) were identified. Three pathologists reviewed all archival surgical specimens and recategorized each margin as tumor at ink/transected, <0.5, 0.5-1, >1-2, or >2 mm from the inked surface. The impact of these and other clinical variables was assessed on local control, disease-free survival (DFS), and overall survival (OS). RESULTS: Among all margins, PM clearance up to 2 mm was prognostic of DFS (p = 0.01) and OS (p = 0.01). Dichotomizing the PM at 2 mm revealed it to be an independent predictor of local recurrence-free survival [hazard ratio HR] 0.20, 95% confidence interval [CI] 0.048-0.881, p = 0.033), DFS (HR 0.46, 95% CI 0.22-0.96, p = 0.03), and OS (HR 0.31, 95% CI 0.14-0.74, p = 0.008). A margin status of >2 mm was also prognostic of OS in patients who received adjuvant chemotherapy (HR 0.31, 95% CI 0.11-0.89, p = 0.03), however this difference was mitigated in patients receiving adjuvant chemoradiotherapy (HR 0.40, 95% CI 0.10-1.58, p = 0.19). CONCLUSION: These data highlight the clinical significance of the PM and the lack of significance of other resection margins. Clearance in excess of 2 mm should be considered to improve long-term clinical outcomes. The use of adjuvant radiotherapy should be strongly considered in patients with PMs <2 mm.

Targeting mTOR in Pancreatic Ductal Adenocarcinoma.

Treatment options for advanced pancreatic ductal adenocarcinoma (PDAC) are limited; however, new therapies targeting specific tumor-related molecular characteristics may help certain patient cohorts. Emerging preclinical data have shown that inhibition of mammalian target of rapamycin (mTOR) in specific KRAS-dependent PDAC subtypes leads to inhibition of tumorigenesis in vitro and in vivo. Early phase II studies of mono-mTOR inhibition have not shown promise. However, studies have shown that combined inhibition of multiple steps along the mTOR signaling pathway may lead to sustained responses by targeting mechanisms of tumor resistance. Coordinated inhibition of mTOR along with specific KRAS-dependent mutations in molecularly defined PDAC subpopulations may offer a viable alternative for treatment in the future.