Real-world data validation of the PurIST pancreatic ductal adenocarcinoma gene expression classifier and its prognostic implications

Background Pancreatic ductal adenocarcinoma (PDAC) is amongst the deadliest cancers, with few modern tools to inform patient prognosis and help guide treatment options. Transcriptome-based molecular subtyping is one emerging technology that has been employed to help patients optimize available therapeutic approaches. Here we retrospectively demonstrate the clinical validity of PurIST (Purity Independent Subtyping of Tumors), an RNA-based classifier that divides PDAC patients into two subtypes with differential prognoses, as a validated laboratory-developed test (LDT) on the Tempus Labs sequencing platform. Methods A cohort comprising 258 late-stage PDAC patients with available transcriptomic and outcomes data was drawn from the Tempus clinicogenomic database and classified using PurIST into one of two subtypes (“Basal” or “Classical”). Differences in patient survival from the date of diagnosis were compared between subtypes, and between two common first-line treatment regimens, FOLFIRINOX, and gemcitabine + nab-paclitaxel. Results Of the 258 PDAC patients in the validation cohort, PurIST classified 173 as classical subtype, 59 as basal subtype, and 26 as no-calls. Reinforcing previous findings, patients of the basal subtype had significantly lower overall survival than those of the classical subtype. Notably, differential survival by subtype was significant among the subset of patients on FOLFIRINOX, but not those on gemcitabine + nab-paclitaxel. Conclusions The implementation of PurIST on a high-throughput clinical laboratory RNA-Seq platform and the demonstration of the model’s clinical utility in a real-world cohort together show that PurIST can be used at scale to refine PDAC prognosis and thereby inform treatment selection to improve outcomes for advanced-stage PDAC patients. ### Competing Interest Statement Stephane Wenric, John Guittar, Yun E. Wang, Amrita A. Iyer, Hyunseok P. Kang were employed by Tempus Labs at the time of their contribution to the manuscript. James M. Davison, Gregory M. Mayhew, Kirk D. Beebe, Michael V. Milburn were employed by GeneCentric at the time of their contribution to the manuscript. Dr. Charles Perou is a board of directors member, equity stock holder, and consultant for GeneCentric. ### Funding Statement This study did not receive any funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was performed using de-identified data and covered by an exempt determination from Advarra, Inc Institutional Review Board (IRB), Pro00042950 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript.