Clinicogenomic Characterization of Primary Sclerosing Cholangitis-Associated Biliary Tract Cancers

Abstract Purpose: Biliary tract cancer (BTC) is the leading cause of death in patients with primary sclerosing cholangitis (PSC). PSC-related BTC is poorly understood, and the risks and benefits of conventional and immunotherapy treatments are unknown. We aimed to characterize clinical outcomes and genomes of PSC-related BTCs. Experimental Design: This was a retrospective cohort study of BTC patients with underlying PSC treated at MD Anderson Cancer Center (N=46) and Princess Margaret Cancer Centre (N=16), which were contrasted to non-PSC-related BTC patients (N=146). We compared outcomes between PSC and non-PSC, and PSC treated with and without immunotherapy. A combination of targeted sequencing (N=139), whole genome sequencing (N=27), and whole genome with paired RNA-seq (N=33), delineated the genomic and transcriptomic landscape of PSC-associated BTCs. Results: In PSC-related BTC, the addition of immunotherapy to chemotherapy was associated with improved first-line progression-free survival (N=22 versus 11, median PFS 12.2 versus 4.7 months, p=0.01). Immune-related adverse events were rare (N=2, 12.5%) and improved after treatment discontinuation. Classic actionable genomic alterations, including IDH1 mutations and FGFR2 fusions, were absent in PSC-related BTCs. PSC tumors had a 2.6-fold higher tumor mutational burden (p=3.28e-05) compared to non-PSC tumors. Transcriptomic profiling revealed a subset of PSC tumors displaying RNA signatures of immunotherapy response. Conclusions: Immunotherapy in PSC-associated BTCs appeared safe, with a potential signal of effectiveness. Given the sample size and retrospective design, these results are hypothesis-generating. Together, these results demonstrate the unique biology underlying PSC-associated BTCs, highlighting the need for prospective trials and the development of specialized treatment strategies.