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Purpose: Early-onset biliary tract cancer (eoBTC) is among the fast-growing subset of early-onset cancers, yet little is known about its biology. We sought to identify novel molecular characteristics of eoBTC in relation to average-onset BTC (aoBTC) using a real-world multiomics data set., Methods: The study comprised patients with BTC whose tumors underwent molecular analyses at Caris Life Sciences and were categorized by age (<50 years for eoBTC, ≥50 years for aoBTC). P values were adjusted for multiple testing and considered significant at Q < 0.05 (molecular comparisons) or Q < 0.25 (Gene Set Enrichment Analysis [GSEA]). Insurance claims data were used for survival analysis., Results: The study included 5,587 patients with BTC (453 eoBTC, median age = 44 years and 5,134 aoBTC, median age = 68 years). FGFR2 fusion (15.7% in eoBTC v 5.9% in aoBTC) and NIPBL fusion (1.1% v 0%) were significantly more prevalent in eoBTC (both Q < 0.001). The interferon gamma-IFG score (fold change [FC], 1.1; Q = 0.01) and T-cell inflammation score (FC, 17.3; Q = 0.03) were significantly higher in aoBTC. On GSEA, angiogenesis was enriched in eoBTC (normalized enrichment score [NES] = 1.51; Q = 0.16), whereas IFG (NES = -1.58; Q = 0.06) and inflammatory response (NES = -1.46; Q = 0.18) were enriched in aoBTC. The median overall survival (OS) was 16.5 (eoBTC) versus 13.3 months (aoBTC), hazard ratio = 0.86, P = .004. The median OS by FGFR2 fusion (with fusion v without) was 21.7 versus 15.0 months ( P = .47) for eoBTC and 18.6 versus 12.2 months ( P < .001) for aoBTC., Conclusion: We identified crucial differences including higher prevalence of FGFR2 fusions in eoBTC and variations in immunotherapy-related markers. Better outcomes in eoBTC were affected by the FGFR2 fusion status. Our findings underscore the need for ensuring access to next-generation sequencing testing, including prompt identification of actionable targets.

Introduction: Prognosis of biliary tract cancers (BTC) remains dismal and novel treatment strategies are needed to improve survival. BRCA mutations are known to occur in BTC but their frequency and the molecular landscape in which they are observed in distinct sites of BTC remain unknown., Material and Methods: Tumour samples from 1292 patients with BTC, comprising intrahepatic cholangiocarcinoma (IHC, n=746), extrahepatic cholangiocarcinoma (EHC, n=189) and gallbladder cancer (GBC, n=353), were analysed using next-generation sequencing (NGS). Tumour mutational burden (TMB) was calculated based on somatic non-synonymous missense mutations. Determination of tumour mismatch repair (MMR) or microsatellite instability (MSI) status was done by fragment analysis, immunohistochemistry and the evaluation of known microsatellite loci by NGS. Programmed death ligand 1 expression was analysed using immunohistochemistry., Results: Overall, BRCA mutations were detected in 3.6% (n=46) of samples ( BRCA1: 0.6%, BRCA2: 3%) with no significant difference in frequency observed based on tumour site. In GBC and IHC, BRCA2 mutations (4.0% and 2.7%) were more frequent than BRCA1 (0.3% and 0.4%, p<0.05) while in EHC, similar frequency was observed (2.6% for BRCA2 vs 2.1% for BRCA1 ). BRCA mutations were associated with a higher rate in subjects with MSI-H/deficient mismatch repair (19.5% vs 1.7%, p<0.0001) and tumours with higher TMB, regardless of the MMR or MSI status (p<0.05)., Conclusions: BRCA mutations are found in a subgroup of patients with BTC and are characterised by a distinct molecular profile. These data provide a rationale testing poly(ADP-ribose)polymeraseinhibitors and other targeted therapies in patients with BRCA -mutant BTC., Competing Interests: Competing interests: JX, YB and WMK are employers of Caris Life Sciences. JLM and AS are consultants for Caris Life Sciences. RMG received research and travel support from Caris Life Sciences. AFS received research, travel, and speaking fees from Caris Life Sciences. MES, AG, HL and AS received travel support from Caris Life Sciences., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)