Abstract PR04: Therapeutic development platform for pancreatic cancer in the UK national health service: Lessons learned and initial results from Precision-Panc
Authors: Froeling Fieke E.M. , Valle Juan , Upstill-Goddard Rosie , Grimwood Paul , Westwood Paul , Dreyer Stephan B. , Kelly Caroline , Duthie Fraser , Dixon Judith , Bradley Sarah , Evans T.R. Jeffry , Sansom Owen J. , Biankin Andrew V. , Chang David K. 
Published: January 2024

Abstract
Introduction Pancreatic Cancer (PC) remains almost universally lethal. Precision-Panc UK therapeutic development platform was established to overcome challenges of delivering precision medicine and accelerate drug development for PC. Methods A Master Protocol (MP) was established to screen, biopsy, and molecularly profile patients for subsequent enrolment into multiple PRIMUS clinical trials. Research patient and tissue pathways were incorporated into routine clinical practice for molecular profiling using a bespoke Clinical Cancer Genome assay utilising targeted capture next generation sequencing technology. Whole transcriptome is performed using BioClavis Temp-O-Seq technology. In addition, tumor NGS of selected cases are discussed in the virtual Precision-Panc Molecular Tumor Board for collective interpretation of results, and to support of clinical decision making, trial enrolment and precision medicine. Results (updated data to be presented if selected for presentation) To date, 670 patients have been screened for Precision-Panc, 567 patients were registered on the MP, and 336 enrolled in PRIMUS trials. Main reasons for attrition were decline in performance status, death, alternative diagnosis, or patient declined active treatment or PRIMUS trials. Tissue biopsies were obtained either by endoscopic ultrasound or interventional radiology as part of diagnostic pathway. Sixty five of the 483 samples submitted to the sequencing laboratory contained insufficient material (13% upstream sample fail). Of the 418 samples sequenced, a clinical grade report could be issued for 393 (94%) samples (6% failed sequencing/analysis QC matrix). Most patients carried KRAS G12D mutations (48%), followed by G12V (30%), G12R (12%), Q61H (6%) and G12C (1%), leading to different downstream signalling on transcriptomic pathway analysis. KRAS wildtype was seen in 35 cases (8.9%). Homologous recombination deficiency genomic scar was seen in ~10% (biomarker for the PRIMUS-001 and -002 trials, evaluating FOLFOX-A versus AG as first-line treatment for metastatic PC or in the neoadjuvant setting). Somatic driver variants in RNF43 were detected in 25 patients (7%) (PRIMUS-007, 2nd line trial of porcupine inhibitor RXC004 in RNF43 mutated advanced PC). Four patients (1.2%) were found to be MSI high and 32 (9.3%) had a TMB≥4mutations/Mb (eligible for PRIMUS-008; Pembrolizumab/Olaparib in patients with high TMB). Transcriptomic profiling confirmed previously described molecular subtypes with a relatively higher percentage of squamous/basal-like cancers in patients who rapidly deteriorated and dropped off the treatment pathway. Conclusion We present the initial experience and real-world challenges in longitudinal fashion in delivering precision medicine for PC, with attrition in both patient and tissue pathways. The majority of samples were successfully sequenced, and research activities were embedded in routine clinical practice, enabling easier trial enrolment, therapeutic and biomarker development for PC.
Citation Format: Fieke E.M. Froeling, Juan Valle, Rosie Upstill-Goddard, Paul Grimwood, Paul Westwood, Stephan B. Dreyer, Caroline Kelly, Fraser Duthie, Judith Dixon, Sarah Bradley, T.R. Jeffry Evans, Owen J. Sansom, Andrew V. Biankin, David K. Chang. Therapeutic development platform for pancreatic cancer in the UK national health service: Lessons learned and initial results from Precision-Panc [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr PR04.