Genome-Derived Ampullary Adenocarcinoma Classifier and Postresection Prognostication.

Area of Science:

• Oncology
• Genomics
• Molecular Pathology

Background:

• Ampullary adenocarcinoma (AA) exhibits significant clinical and genomic heterogeneity.
• A prior genomic classifier demonstrated superior accuracy in defining biologically distinct phenotypes compared to standard histology.
• External validation is crucial for the clinical integration of this genomic classifier.

Purpose of the Study:

• To externally validate the prognostic capability of a previously developed genomic classifier for ampullary adenocarcinoma.
• To assess the classifier's ability to stratify patients based on survival outcomes.

Main Methods:

• A retrospective international cohort study included 192 patients with histologically confirmed AA undergoing curative-intent resection.
• A multilevel meta-feature regression model, trained on a large cohort of adenocarcinomas, was applied to AA sequencing data.
• Genomic classification was correlated with immunohistologic subtypes (intestinal and pancreatobiliary) and overall survival using statistical models.

Main Results:

• Concordance between immunohistologic and genomic subtypes was 55%.
• While standard immunohistologic subtypes did not correlate with survival (P=.26), genomic probabilities showed significant prognostic value.
• Higher colorectal genomic probability correlated with improved survival, whereas higher pancreatic and distal bile duct probabilities were associated with poorer survival.

Conclusions:

• The ampullary adenocarcinoma genomic classifier is reproducible and enhances survival stratification beyond standard immunohistologic classification.
• This molecular classification provides a robust tool for stratifying clinical outcomes.
• Further prospective validation in clinical trials is warranted for potential integration into patient care.