Imaging-Based Subtypes of Pancreatic Ductal Adenocarcinoma Exhibit Differential Growth and Metabolic Patterns in the Pre-Diagnostic Period: Implications for Early Detection

Frontiers in Oncology

Natalia Khalaf¹  Ajay Goel²  Daniel D. Von Hoff³  Eric P. Tamm⁴  Anirban Maitra⁵  Brian M. Wolpin⁶  Walter G. Park⁷  Randall E. Brand⁸  Aatur D. Singhi⁹  Pearl Fernandes^1,10  Lauren Widmann^1,10  Annie Dai^1,10  Mohamed Zaid^1,10  Eugene J. Koay^1,10  Dalia Elganainy^1,10  Syed Rahmanuddin^1,11  Michael H. Rosenthal^1,12  Anil K. Dasyam^1,13  Prashant Dogra^1,14  Javier R. Ramirez^1,14  Maria J. Pelaez^1,14  Vittorio Cristini^1,14  Zhihui Wang^1,14 

[1] 0Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX, United States;1Department of Molecular Diagnostics and Experimental Therapeutics, City of Hope, Duarte, CA, United States;2Molecular Medicine, Translational Genomics Research Institute, Phoenix, AZ, United States;3Department of Abdominal Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;4Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, United States;Department of Medicine, Stanford University, Stanford, CA, United States;Department of Medicine, University of Pittsburgh, Pittsburgh, PA, United States;Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, United States;Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States;Department of Radiology, City of Hope, Duarte, CA, United States;Department of Radiology, Dana Farber Cancer Institute, Boston, MA, United States;Department of Radiology, University of Pittsburgh, Pittsburgh, PA, United States;Mathematics in Medicine Program, Houston Methodist Research Institute, Houston, TX, United States;

关键词: pancreatic cancer;    early detection;    computed tomography;    mathematical modeling;    tumor metabolism;   

DOI  :  10.3389/fonc.2020.596931

来源: DOAJ

【 摘 要 】

BackgroundPreviously, we characterized subtypes of pancreatic ductal adenocarcinoma (PDAC) on computed-tomography (CT) scans, whereby conspicuous (high delta) PDAC tumors are more likely to have aggressive biology and poorer clinical outcomes compared to inconspicuous (low delta) tumors. Here, we hypothesized that these imaging-based subtypes would exhibit different growth-rates and distinctive metabolic effects in the period prior to PDAC diagnosis.Materials and methodsRetrospectively, we evaluated 55 patients who developed PDAC as a second primary cancer and underwent serial pre-diagnostic (T0) and diagnostic (T1) CT-scans. We scored the PDAC tumors into high and low delta on T1 and, serially, obtained the biaxial measurements of the pancreatic lesions (T0-T1). We used the Gompertz-function to model the growth-kinetics and estimate the tumor growth-rate constant (α) which was used for tumor binary classification, followed by cross-validation of the classifier accuracy. We used maximum-likelihood estimation to estimate initiation-time from a single cell (10-6 mm3) to a 10 mm3 tumor mass. Finally, we serially quantified the subcutaneous-abdominal-fat (SAF), visceral-abdominal-fat (VAF), and muscles volumes (cm3) on CT-scans, and recorded the change in blood glucose (BG) levels. T-test, likelihood-ratio, Cox proportional-hazards, and Kaplan-Meier were used for statistical analysis and p-value <0.05 was considered significant.ResultsCompared to high delta tumors, low delta tumors had significantly slower average growth-rate constants (0.024 month−1 vs. 0.088 month−1, p<0.0001) and longer average initiation-times (14 years vs. 5 years, p<0.0001). α demonstrated high accuracy (area under the curve (AUC)=0.85) in classifying the tumors into high and low delta, with an optimal cut-off of 0.034 month−1. Leave-one-out-cross-validation showed 80% accuracy in predicting the delta-class (AUC=0.84). High delta tumors exhibited accelerated SAF, VAF, and muscle wasting (p <0.001), and BG disturbance (p<0.01) compared to low delta tumors. Patients with low delta tumors had better PDAC-specific progression-free survival (log-rank, p<0.0001), earlier stage tumors (p=0.005), and higher likelihood to receive resection after PDAC diagnosis (p=0.008), compared to those with high delta tumors.ConclusionImaging-based subtypes of PDAC exhibit distinct growth, metabolic, and clinical profiles during the pre-diagnostic period. Our results suggest that heterogeneous disease biology may be an important consideration in early detection strategies for PDAC.

【 授权许可】

Unknown