Abstract：
OBJECTIVE: 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.
CONCLUSIONS: 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.
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.
CONCLUSIONS: 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.
摘要：
目的：早发性胆道癌（eoBTC）是快速增长的早发性癌症子集，然而对它的生物学知之甚少。我们试图使用真实世界的多组学数据集确定eoBTC与平均起效BTC（aoBTC）的新分子特征。
方法：该研究包括BTC患者，其肿瘤在CarisLifeSciences进行了分子分析，并按年龄分类（eoBTC<50岁，aoBTC≥50年)。针对多次测试调整P值,并且认为在Q<0.05(分子比较)或Q<0.25(基因集富集分析[GSEA])时是显著的。保险索赔数据用于生存分析。
结果：该研究包括5,587例BTC患者（453eoBTC，中位年龄=44岁和5,134aoBTC，中位年龄=68岁)。FGFR2融合（eoBTC中的15.7％vaoBTC中的5.9％）和NIPBL融合（1.1％v0％）在eoBTC中明显更普遍（均Q<0.001）。干扰素γ-IFG评分(倍数变化[FC]，1.1；Q=0.01）和T细胞炎症评分（FC，17.3；Q=0.03）在aoBTC中明显更高。在GSEA,血管生成在eoBTC中富集(归一化富集评分[NES]=1.51;Q=0.16),而IFG(NES=-1.58;Q=0.06)和炎症反应(NES=-1.46;Q=0.18)富含aobTC。中位总生存期（OS）为16.5（eoBTC）和13.3个月（aoBTC），危险比=0.86，P=.004。eoBTCFGFR2融合（无融合）的中位OS为21.7和15.0个月（P=0.47），aoBTC为18.6和12.2个月（P<.001）。
结论：我们发现了重要的差异，包括eoBTC中FGFR2融合的患病率较高，以及免疫治疗相关标志物的变异。eoBTC更好的结果受FGFR2融合状态的影响。我们的发现强调了确保获得下一代测序测试的必要性，包括迅速识别可采取行动的目标。
方法：该研究包括BTC患者，其肿瘤在CarisLifeSciences进行了分子分析，并按年龄分类（eoBTC<50岁，aoBTC≥50年)。针对多次测试调整P值,并且认为在Q<0.05(分子比较)或Q<0.25(基因集富集分析[GSEA])时是显著的。保险索赔数据用于生存分析。
结果：该研究包括5,587例BTC患者（453eoBTC，中位年龄=44岁和5,134aoBTC，中位年龄=68岁)。FGFR2融合（eoBTC中的15.7％vaoBTC中的5.9％）和NIPBL融合（1.1％v0％）在eoBTC中明显更普遍（均Q<0.001）。干扰素γ-IFG评分(倍数变化[FC]，1.1；Q=0.01）和T细胞炎症评分（FC，17.3；Q=0.03）在aoBTC中明显更高。在GSEA,血管生成在eoBTC中富集(归一化富集评分[NES]=1.51;Q=0.16),而IFG(NES=-1.58;Q=0.06)和炎症反应(NES=-1.46;Q=0.18)富含aobTC。中位总生存期（OS）为16.5（eoBTC）和13.3个月（aoBTC），危险比=0.86，P=.004。eoBTCFGFR2融合（无融合）的中位OS为21.7和15.0个月（P=0.47），aoBTC为18.6和12.2个月（P<.001）。
结论：我们发现了重要的差异，包括eoBTC中FGFR2融合的患病率较高，以及免疫治疗相关标志物的变异。eoBTC更好的结果受FGFR2融合状态的影响。我们的发现强调了确保获得下一代测序测试的必要性，包括迅速识别可采取行动的目标。
