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

IF 5.3 2区医学 Q1 ONCOLOGY JCO precision oncology Pub Date : 2024-08-01 DOI:10.1200/PO.24.00138

Thejus Jayakrishnan, Yasmine Baca, Joanne Xiu, Mehrie Patel, Benjamin A Weinberg, Emil Lou, Jashodeep Datta, Moh'd Khushman, Pat Gulhati, Sanjay Goel, Tiago Biachi de Castria, Vaia Florou, Kanika G Nair, Suneel D Kamath, Alok A Khorana

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Abstract

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.

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早发胆道癌与一般发病胆道癌的分子差异及其治疗意义

目的：早发胆道癌（eoBTC）是快速增长的早发癌亚群之一，但人们对其生物学特性知之甚少。我们试图利用真实世界的多组学数据集确定 eoBTC 与平均发病胆道癌（aoBTC）的新分子特征：研究对象包括BTC患者，他们的肿瘤在Caris生命科学公司进行了分子分析，并按年龄进行了分类（P值经多重检验调整，在Q＜0.05（分子比较）或Q＜0.25（基因组富集分析[GSEA]）时具有显著性）。保险理赔数据用于生存分析：研究共纳入 5587 例 BTC 患者（453 例 eoBTC，中位年龄 = 44 岁；5134 例 aoBTC，中位年龄 = 68 岁）。表皮生长因子受体 2 融合（eoBTC 为 15.7%，aoBTC 为 5.9%）和 NIPBL 融合（eoBTC 为 1.1%，aoBTC 为 0%）在 eoBTC 中的发生率明显更高（两者的 Q 值均小于 0.001）。干扰素γ-IFG评分（折叠变化[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 中，血管生成在 eoBTC 中富集（归一化富集得分 [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）在 aoBTC 中富集。中位总生存期（OS）为16.5个月（eoBTC）对13.3个月（aoBTC），危险比=0.86，P=0.004。FGFR2融合（融合与未融合）的中位OS：eoBTC为21.7个月对15.0个月（P = .47），aoBTC为18.6个月对12.2个月（P < .001）：我们发现了一些关键的差异，包括 eoBTC 中 FGFR2 融合的发生率更高，以及免疫疗法相关标志物的变化。FGFR2融合状态会影响eoBTC更好的预后。我们的研究结果强调了确保获得新一代测序检测的必要性，包括及时发现可采取行动的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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