Molecular Differences With Therapeutic Implications in Early-Onset Compared With Average-Onset Biliary Tract Cancers.

Abstract

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. 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). <i>P</i> values were adjusted for multiple testing and considered significant at <i>Q</i> < 0.05 (molecular comparisons) or <i>Q</i> < 0.25 (Gene Set Enrichment Analysis [GSEA]). Insurance claims data were used for survival analysis. The study included 5,587 patients with BTC (453 eoBTC, median age = 44 years and 5,134 aoBTC, median age = 68 years). <i>FGFR2</i> fusion (15.7% in eoBTC <i>v</i> 5.9% in aoBTC) and <i>NIPBL</i> fusion (1.1% <i>v</i> 0%) were significantly more prevalent in eoBTC (both <i>Q</i> < 0.001). The interferon gamma-IFG score (fold change [FC], 1.1; <i>Q</i> = 0.01) and T-cell inflammation score (FC, 17.3; <i>Q</i> = 0.03) were significantly higher in aoBTC. On GSEA, angiogenesis was enriched in eoBTC (normalized enrichment score [NES] = 1.51; <i>Q</i> = 0.16), whereas IFG (NES = -1.58; <i>Q</i> = 0.06) and inflammatory response (NES = -1.46; <i>Q</i> = 0.18) were enriched in aoBTC. The median overall survival (OS) was 16.5 (eoBTC) versus 13.3 months (aoBTC), hazard ratio = 0.86, <i>P</i> = .004. The median OS by FGFR2 fusion (with fusion <i>v</i> without) was 21.7 versus 15.0 months (<i>P</i> = .47) for eoBTC and 18.6 versus 12.2 months (<i>P</i> < .001) for aoBTC. We identified crucial differences including higher prevalence of <i>FGFR2</i> fusions in eoBTC and variations in immunotherapy-related markers. Better outcomes in eoBTC were affected by the <i>FGFR2</i> fusion status. Our findings underscore the need for ensuring access to next-generation sequencing testing, including prompt identification of actionable targets.