Dataset Information

Multiparametric Modelling of Survival in Pancreatic Ductal Adenocarcinoma Using Clinical, Histomorphological, Genetic and Image-Derived Parameters.

ABSTRACT: RATIONALE:Pancreatic ductal adenocarcinoma (PDAC) remains a tumor entity of exceptionally poor prognosis, and several biomarkers are under current investigation for the prediction of patient prognosis. Many studies focus on promoting newly developed imaging biomarkers without a rigorous comparison to other established parameters. To assess the true value and leverage the potential of all efforts in this field, a multi-parametric evaluation of the available biomarkers for PDAC survival prediction is warranted. Here we present a multiparametric analysis to assess the predictive value of established parameters and the added contribution of newly developed imaging features such as biomarkers for overall PDAC patient survival. METHODS:103 patients with resectable PDAC were retrospectively enrolled. Clinical and histopathological data (age, sex, chemotherapy regimens, tumor size, lymph node status, grading and resection status), morpho-molecular and genetic data (tumor morphology, molecular subtype, tp53, kras, smad4 and p16 genetics), image-derived features and the combination of all parameters were tested for their prognostic strength based on the concordance index (CI) of multivariate Cox proportional hazards survival modelling after unsupervised machine learning preprocessing. RESULTS:The average CIs of the out-of-sample data were: 0.63 for the clinical and histopathological features, 0.53 for the morpho-molecular and genetic features, 0.65 for the imaging features and 0.65 for the combined model including all parameters. CONCLUSIONS:Imaging-derived features represent an independent survival predictor in PDAC and enable the multiparametric, machine learning-assisted modelling of postoperative overall survival with a high performance compared to clinical and morpho-molecular/genetic parameters. We propose that future studies systematically include imaging-derived features to benchmark their additive value when evaluating biomarker-based model performance.

SUBMITTER: Kaissis GA

PROVIDER: S-EPMC7287805 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Multiparametric Modelling of Survival in Pancreatic Ductal Adenocarcinoma Using Clinical, Histomorphological, Genetic and Image-Derived Parameters.

Kaissis Georgios A GA Jungmann Friederike F Ziegelmayer Sebastian S Lohöfer Fabian K FK Harder Felix N FN Schlitter Anna Melissa AM Muckenhuber Alexander A Steiger Katja K Schirren Rebekka R Friess Helmut H Schmid Roland R Weichert Wilko W Makowski Marcus R MR Braren Rickmer F RF

Journal of clinical medicine 20200425 5

<h4>Rationale</h4>Pancreatic ductal adenocarcinoma (PDAC) remains a tumor entity of exceptionally poor prognosis, and several biomarkers are under current investigation for the prediction of patient prognosis. Many studies focus on promoting newly developed imaging biomarkers without a rigorous comparison to other established parameters. To assess the true value and leverage the potential of all efforts in this field, a multi-parametric evaluation of the available biomarkers for PDAC survival pr ...[more]

PMID: 32344944

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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with a dismal prognosis. However, while most patients die within the first year of diagnosis, very rarely, a few patients can survive for >10 years. Better understanding the molecular characteristics of the pancreatic adenocarcinomas from these very-long-term survivors (VLTS) may provide clues for personalized medicine and improve current pancreatic cancer treatment. To extend our previous investigation, we examined the proteomes of individual pancreas tumor tissues from a group of VLTS patients (survival ?10 years) and short-term survival patients (STS, survival <14 months). With a given analytical sensitivity, the protein profile of each pancreatic tumor tissue was compared to reveal the proteome alterations that may be associated with pancreatic cancer survival. Pathway analysis of the differential proteins identified suggested that MYC, IGF1R and p53 were the top three upstream regulators for the STS-associated proteins, and VEGFA, APOE and TGF?-1 were the top three upstream regulators for the VLTS-associated proteins. Immunohistochemistry analysis using an independent cohort of 145 PDAC confirmed that the higher abundance of ribosomal protein S8 (RPS8) and prolargin (PRELP) were correlated with STS and VLTS, respectively. Multivariate Cox analysis indicated that 'High-RPS8 and Low-PRELP' was significantly associated with shorter survival time (HR=2.69, 95% CI 1.46-4.92, P=0.001). In addition, galectin-1, a previously identified protein with its abundance aversely associated with pancreatic cancer survival, was further evaluated for its significance in cancer-associated fibroblasts. Knockdown of galectin-1 in pancreatic cancer-associated fibroblasts dramatically reduced cell migration and invasion. The results from our study suggested that PRELP, LGALS1 and RPS8 might be significant prognostic factors, and RPS8 and LGALS1 could be potential therapeutic targets to improve pancreatic cancer survival if further validated.

Project description:Importance:Pancreatic ductal adenocarcinoma (PDAC) has a higher incidence and worse outcomes among black patients than white patients, potentially owing to a combination of socioeconomic, biological, and treatment differences. The role that these differences play remains unknown. Objectives:To determine the level of survival disparity between black and white patients in a modern PDAC cohort and whether treatment inequity is associated with such a disparity. Design, Setting, and Participants:This cohort study used data on 278?936 patients with PDAC with database-defined race from the National Cancer Database from January 1, 2004, to December 31, 2015. The median follow-up for censored patients was 24 months. The National Cancer Database, comprising academic and community facilities, includes about 70% of new cancer diagnoses in the United States. Race-stratified receipt of therapy was the primary variable of interest. Multivariable analyses included additional demographic and clinical parameters. Data analysis was initially completed on November 30, 2018, and revised data analysis was completed on June 27, 2019. Main Outcomes and Measures:Overall survival was the primary outcome, analyzed with Kaplan-Meier and multivariable Cox proportional hazards regression modeling. Results:The cohort included 278?936 patients (137?121 women and 141?815 men; mean [SD] age, 68.72 [11.57] years); after excluding patients from other racial categories, 243?820 of the 278?936 patients (87.4%) were white and 35?116 of the 278?936 patients (12.6%) were black. Unadjusted median overall survival was longer for white patients than for black patients (6.6 vs 6.0 months; P?<?.001). Black patients presented at younger ages than white patients (15?819 of 35?116 [45.0%] vs 83?846 of 243?820 [34.4%] younger than 65 years; P?<?.001) and with more advanced disease (20?853 of 31?600 [66.0%] vs 135?317 of 220?224 [61.4%] with stage III or IV disease; P?<?.001). Black patients received fewer surgical procedures than white patients for potentially resectable stage II disease (4226 of 8097 [52.2%] vs 39?214 of 65?124 [60.2%]; P?<?.001) and slightly less chemotherapy for advanced disease (2756 of 4067 [67.8%] vs 17?296 of 25?227 [68.6%] for stage III disease [P?=?.001]; 8208 of 16?104 [51.0%] vs 58?603 of 105?616 [55.5%] for stage IV disease [P?<?.001]). Decreased survival for black patients persisted in multivariable modeling controlled for sociodemographic parameters (hazard ratio, 1.04 [95% CI, 1.02-1.05]). Conversely, modeling that controlled specifically for clinical parameters such as disease stage and treatment revealed a modest survival advantage (hazard ratio, 0.94 [95% CI, 0.93-0.96]) among black patients. Resection was the factor most strongly associated with overall survival (hazard ratio, 0.39 [95% CI, 0.38-0.39]). Conclusions and Relevance:Black patients with PDAC present at younger ages and with more advanced disease than white patients, suggesting that differences in tumor biology may exist. Black patients receive less treatment stage for stage and fewer surgical procedures for resectable cancers than white patients; these findings may be only partly associated with socioeconomic differences. When disease stage and treatment were controlled for, black patients had no decrease in survival.

Project description:The prognosis for pancreatic ductal adenocarcinoma (PDAC) remains poor despite decades of effort. The abundant extracellular matrix (ECM) in PDAC comprises a major fraction of the tumor mass and plays various roles in promoting resistance to therapies. However, nonselective depletion of ECM has led to poor patient outcomes. Consistent with that observation, we previously showed that individual matrisome proteins derived from stromal cells correlate with either long or short patient survival. In marked contrast, those derived from cancer cells correlate strongly with poor survival. Here, we studied three cancer cell-derived matrisome proteins that are significantly overrepresented during PDAC progression, AGRN (agrin), SERPINB5 (serine protease inhibitor B5), and CSTB (cystatin B). Using both overexpression and knockdown experiments, we demonstrate that all three are promoters of PDAC metastasis. Furthermore, these proteins operate at different metastatic steps. AGRN promoted epithelial-to-mesenchymal transition in primary tumors, whereas SERPINB5 and CSTB enhanced late steps in the metastatic cascade by elevating invadopodia formation and in vivo extravasation. All three genes were associated with a poor prognosis in human patients and high levels of SERPINB5, secreted by cancer cells and deposited in the ECM, correlated with poor patient prognosis. This study provides strong evidence that cancer cell-derived matrisome proteins can be causal in promoting tumorigenesis and metastasis and lead to poor patient survival. Therefore, compared with the bulk matrix, mostly made by stromal cells, precise interventions targeting cancer cell-derived matrisome proteins, such as AGRN, SERPINB5, and CSTB, may represent preferred potential therapeutic targets. SIGNIFICANCE: This study provides insights into the biological roles of cancer cell-derived matrisome proteins in PDAC and supports the notion that these proteins are protumorigenic and better therapeutic targets.

Dataset Information

Multiparametric Modelling of Survival in Pancreatic Ductal Adenocarcinoma Using Clinical, Histomorphological, Genetic and Image-Derived Parameters.

Publications

Multiparametric Modelling of Survival in Pancreatic Ductal Adenocarcinoma Using Clinical, Histomorphological, Genetic and Image-Derived Parameters.

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