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

Area of Science:

• Oncology
• Genomics
• Cancer Biology

Background:

• Early-onset cancers, including biliary tract cancer (BTC), are a growing concern with limited understanding of their underlying biology.
• Distinguishing molecular characteristics between early-onset BTC (eoBTC) and average-onset BTC (aoBTC) is crucial for targeted therapies.

Purpose of the Study:

• To identify novel molecular differences between eoBTC and aoBTC using a comprehensive multiomics dataset.
• To investigate the impact of these molecular differences on patient outcomes.

Main Methods:

• Retrospective analysis of 5,587 BTC patients (453 eoBTC, 5,134 aoBTC) with molecular profiling data.
• Comparison of molecular alterations, including gene fusions and immune scores, between eoBTC and aoBTC groups.
• Survival analysis using insurance claims data to correlate molecular features with overall survival (OS).

Main Results:

• Significantly higher prevalence of FGFR2 fusions (15.7% vs 5.9%) and NIPBL fusions (1.1% vs 0%) in eoBTC compared to aoBTC.
• eoBTC demonstrated enrichment in angiogenesis pathways, while aoBTC showed enrichment in interferon gamma and inflammatory response pathways.
• Overall survival was longer in eoBTC (16.5 months) versus aoBTC (13.3 months), with FGFR2 fusion status influencing outcomes in both groups.

Conclusions:

• Significant molecular disparities exist between eoBTC and aoBTC, notably the increased frequency of FGFR2 fusions in younger patients.
• FGFR2 fusion status is a key determinant of outcomes in eoBTC, underscoring its importance as a therapeutic target.
• The findings emphasize the critical need for widespread access to next-generation sequencing for early identification of actionable targets in BTC.