title: Personalized Management of Pancreatic Ductal Adenocarcinoma Patients through Computational Modeling.
abstract: Phenotypic diversity in pancreatic ductal adenocarcinoma (PDAC) results in a variety of treatment responses. Rapid autopsy studies have revealed a subgroup of PDAC patients with a lower propensity to develop metastatic disease, challenging the common perception that all patients die of widely metastatic disease, but questions remain about root causes of this difference and the potential impact on treatment strategies. In this study, we addressed these questions through the development of a mathematical model of PDAC progression that incorporates the major alteration status of specific genes with predictive utility. The model successfully reproduced clinical outcomes regarding metastatic patterns and the genetic alteration status of patients from two independent cohorts from the United States and Japan. Using this model, we defined a candidate predictive signature in patients with low metastatic propensity. If a primary tumor contained a small fraction of cells withKRASand additional alterations toCDKN2A, TP53, orSMAD4genes, the patient was likely to exhibit low metastatic propensity. By using this predictive signature, we computationally simulated a set of clinical trials to model whether this subgroup would benefit from locally intensive therapies such as surgery or radiation therapy. The largest overall survival benefit resulted from complete resection, followed by adjuvant chemoradiation therapy and salvage therapies for isolated recurrence. While requiring prospective validation in a clinical trial, our results suggest a new tool to help personalize care in PDAC patients in seeking the most effective therapeutic modality for each individual.Cancer Res; 77(12); 3325-35. ©2017 AACR.
authors.affiliation: Department of Biology, Kyushu University, Fukuoka, Japan. kimiyo@jimmy.harvard.edu kyamamoto@kyushu-u.org haeno@kyushu-u.org.|Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.|Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.|Departments of General and Gastroenterological Surgery, Osaka Medical College Hospital, Osaka, Japan.
authors.forename: Kimiyo N
authors.initials: KN
authors.lastname: Yamamoto
authors.affiliation: Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Yachida
authors.affiliation: Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Akira
authors.initials: A
authors.lastname: Nakamura
authors.affiliation: Division of Health Medical Computational Science, Health Intelligence Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Niida
authors.affiliation: Department of Gastroenterological Surgery, Kagawa University, Kagawa, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Oshima
authors.affiliation: Department of Biostatistics and Informatics, University of Colorado School of Medicine, Colorado.
authors.forename: Subhajyoti
authors.initials: S
authors.lastname: De
authors.affiliation: Department of Radiation Oncology & Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Rosati
authors.affiliation: Department of Radiation Oncology & Molecular Radiation Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Herman
authors.affiliation: Department of Pathology, David M. Rubenstein Center for Pancreatic Cancer Research, and the Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Iacobuzio-Donahue
authors.affiliation: Department of Biology, Kyushu University, Fukuoka, Japan. kimiyo@jimmy.harvard.edu kyamamoto@kyushu-u.org haeno@kyushu-u.org.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Haeno
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D006801:Humans; D053208:Kaplan-Meier Estimate; D008962:Models, Theoretical; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy; D057285:Precision Medicine / Q000379:methods*; D059467:Transcriptome
chemical_list: D014408:Biomarkers, Tumor