Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma

Abstract

Importance Although patients with resected pancreatic adenocarcinoma are at high risk for disease recurrence, few markers are available to inform patient outcomes. Objective To evaluate alterations of the four main driver genes for pancreatic adenocarcinoma and patient outcomes after cancer resection. Design, Setting, and Participants We analyzed protein expression and DNA alterations for KRAS, CDKN2A, SMAD4, and TP53 by immunohistochemistry and next-generation sequencing in formalin-fixed, paraffin-embedded tumors from 356 patients with resected pancreatic adenocarcinoma evaluated at three U.S. centers. Associations of driver gene alterations with disease-free survival (DFS) and overall survival (OS) were evaluated using Cox proportional hazards regression with estimation of hazard ratios (HR) and 95% confidence intervals (CI) and adjustment for age, sex, tumor characteristics, institution, and peri-operative treatment. Main Outcomes DFS and OS among patients with resected pancreatic adenocarcinoma Results Patients with KRAS mutant tumors had worse DFS and OS compared to patients with KRAS wild-type tumors, with median OS of 20.3 versus 38.6 months and 5-year OS of 13.0% versus 30.2%, respectively. Particularly poor outcomes were identified in patients with KRAS G12D-mutant tumors, who had median OS of 15.3 months. Patients whose tumors lacked CDKN2A expression had worse DFS and OS compared to patients whose tumors retained CDKN2A, with median OS of 19.7 versus 24.6 months and 5-year OS of 11.9% versus 19.5%, respectively. SMAD4 status was not associated with DFS or OS, while TP53 status was associated only with DFS (P=0.04). Patients had worse DFS and OS with greater number of altered driver genes. Compared to patients with 0-2 altered genes, those with 4 altered genes had HR for DFS of 1.79 (1.24-2.59; P<0.01) and OS of 1.38 (0.98-1.94; P=0.06). Five-year OS was 18.4% for patients with 0-2 gene alterations, 14.1% for 3 alterations and 8.2% for 4 alterations. Alterations in the four driver genes were not significantly associated with local recurrence as the first site of disease recurrence. Conclusions and Relevance Patient outcomes are associated with alterations of the four main driver genes in resected pancreatic adenocarcinoma.

Endocrine-exocrine signaling drives obesity-associated pancreatic ductal adenocarcinoma

“…To determine if a similar phenomenon is evident in human tumors, we performed targeted exome sequencing and IHC to evaluate alterations of KRAS, TP53, CDKN2A/p16, and SMAD4 in 184 human tumors with known patient BMI at diagnosis (Table S4). Although we observed a significant increase in SMAD4 loss with elevated BMI (odds ratio 3.82 for BMI>30 kg/m 2 compared to BMI<25 kg/m 2 ), the total number of driver gene alterations per tumor, which we have previously shown predicts worse PDAC outcome (Qian et al, 2018), did not significantly differ across categories of BMI (Table S5). Together, these data suggest that obesity may function independently of driver gene alterations in both mice and humans to promote pancreatic tumorigenesis.…”

“…Acquisition of resected PDAC biospecimens including institutional review board approval and informed consent procedures were previously described (Qian et al, 2018). Preoperative body-mass index (BMI) and molecular data on the main PDAC driver genes was available for 184 of 356 patients from this prior study.…”

“…This suggests that although weight may decrease in months preceding diagnosis, the rank order of 2 measurements is likely to be highly consistent. Targeted exome sequencing and immunohistochemistry (IHC) have been previously described (Qian et al, 2018). We used World Health Organization categories to classify patients as normal weight (<25 kg/m 2 ), overweight (25-30 kg/m 2 ), or obese (>30 kg/m 2 ).…”

“…IHC for detection of CCK expression in human PDAC samples was performed on 4 µm sections of formalin-fixed paraffin-embedded tissue blocks containing neoplastic and nonneoplastic pancreatic parenchyma that were obtained as part of specimens resected for pancreatic adenocarcinoma treatment, as previously described (Qian et al, 2018). Antigen retrieval was performed using citrate buffer (pH 6.0, Dako) in a 2100 Antigen Retriever system (Electron 108 human islets of northern European descent were isolated at the Oxford Consortium for Islet Transplantation (OXCIT, Oxford, UK) as previously described (Cross et al, 2012).…”

Novel Targets in Pancreatic Cancer Therapy - Current Status and Ongoing Translational Efforts

“…The SMAD4 mutation status has been described as predictive biomarker for treatment failure and has been linked to response to irinotecan-based chemotherapy [59,60,61]. More recently, the specific subtype of oncogenic KRAS mutations and the mutation status of SMAD4 , p53 and CDKN2A have been found to be good predictors of outcome and overall survival [62,63]. Taken together, these data open up avenues for an individualized choice of specific chemotherapy regimens to date; with the ever growing wealth of cancer genomic data, these considerations are likely to quickly gain increasing importance in routine clinical practice.…”