# Rare, Yet Targetable: New Perspectives on Ampullary Carcinomas

## TL;DR

This review proposes a precision care strategy for ampullary carcinoma, a rare cancer, by combining histology and genetic profiling to guide treatment decisions.

## Contribution

The paper introduces a 'lineage-first, mutation-fast' approach to optimize diagnosis and treatment of ampullary carcinomas using multi-omic data.

## Key findings

- Histology-based classification guides treatment, with intestinal subtypes responding to colorectal regimens and pancreatobiliary subtypes to pancreaticobiliary therapy.
- Next-generation sequencing identifies actionable mutations such as ERBB2/HER2 amplifications, MSI-high/dMMR, and BRAF V600E in ampullary carcinomas.
- Rapid-core panels and comprehensive profiling at progression improve precision in treatment selection for ampullary carcinoma patients.

## Abstract

Ampullary carcinoma (AC) is a rare gastrointestinal malignancy with dual intestinal and pancreatobiliary differentiation, complicating diagnosis, staging, and treatment. This review synthesizes current epidemiology, pathology, and multi-omic data to outline a pragmatic care pathway: lineage-first at presentation, mutation-fast at progression. Histology remains the primary classifier: the intestinal subtype generally aligns with colorectal regimens, whereas pancreatobiliary and mixed subtypes favor pancreaticobiliary therapy. In selected fit patients, modified FOLFIRINOX may address mixed phenotypes. Next-generation sequencing adds precision by identifying therapeutically relevant alterations, including ERBB2/HER2 amplifications, MSI-high/dMMR, BRAF V600E, and rare NTRK or RET fusions, while KRAS mutations are enriched in pancreatobiliary tumors. We recommend early application of a rapid-core panel (KRAS/BRAF, MSI/dMMR, ERBB2/HER2, RNA-based fusions) to capture high-impact targets, followed by comprehensive profiling at first progression. Liquid biopsy, plasma circulating tumor DNA (ctDNA), or bile-derived DNA may complement tissue and help identify the dominant lineage. Research priorities include ampulla-enriched umbrella trials, explicit AC subcohorts in tissue-agnostic studies, and ctDNA-informed endpoints. This lineage-first, mutation-fast paradigm supports precision care and evidence generation in AC.