Genomics-Driven Precision Medicine for Advanced Pancreatic Cancer: Early Results from the COMPASS Trial

Kyaw L. Aung, Sandra E. Fischer, Robert E. Denroche, Gun-Ho Jang, Anna Dodd, Sean Creighton, Bernadette Southwood, Sheng-Ben Liang, Dianne Chadwick, Amy Zhang, Grainne M. O'Kane, Hamzeh Albaba, Shari Moura, Robert C. Grant, Jessica K. Miller, Faridah Mbabaali, Danielle Pasternack, Ilinca M. Lungu, John M.S. Bartlett, Sangeet Ghai, Mathieu Lemire, Spring Holter, Ashton A. Connor, Richard A. Moffitt, Jen Jen Yeh, Lee Timms, Paul M. Krzyzanowski, Neesha Dhani, David Hedley, Faiyaz Notta, Julie M. Wilson, Malcolm J. Moore, Steven Gallinger, Jennifer J. Knox

To perform real time whole genome sequencing (WGS) and RNA sequencing (RNASeq) of advanced pancreatic ductal adenocarcinoma (PDAC) to identify predictive mutational and transcriptional features for better treatment selection.  Experimental Design: Patients with advanced PDAC were prospectively recruited prior to first-line combination chemotherapy. Fresh tumor tissue was acquired by image guided percutaneous core biopsy for WGS and RNASeq. Laser capture microdissection was performed for all cases. Primary endpoint was feasibility to report WGS results prior to first disease assessment CT scan at 8 weeks. The main secondary endpoint was discovery of patient subsets with predictive mutational and transcriptional signatures. Sixty three patients underwent a tumor biopsy between December 2015 and June 2017. WGS and RNASeq were successful in 62 (98%) and 60 (95%), respectively. Genomic results were reported at a median of 35 days (range 19-52 days) from biopsy, meeting the primary feasibility endpoint. Objective responses to first line chemotherapy were significantly better in patients with the classical PDAC RNA subtype compared to those with the basal-like subtype (P=0.004). The best progression free survival was observed in those with classical subtype treated with m-FOLFIRINOX. GATA6 expression in tumor measured by RNA in situ hybridization was found to be a robust surrogate biomarker for differentiating classical and basal-like PDAC subtypes. Potentially actionable genetic alterations were found in 30% of patients. Prospective genomic profiling of advanced PDAC is feasible and our early data indicate that chemotherapy response differs among patients with different genomic/transcriptomic subtypes.