A novel classification of small bowel adenocarcinoma based on a hidden genome classifier: A multi-institutional study.

Abstract

724 Background: Small bowel adenocarcinoma (SBA) is a rare malignancy with poor prognosis. Data describing the clinical and pathologic characteristics of this disease are sparse, and few studies examine the genetic footprint of SBAs within the continuum of the gastrointestinal tract. Methods: All patients with small bowel adenocarcinoma for whom primary tumor tissue was available from 1993 to 2021 at six institutions were included. A hidden genome classifier (HGC) was developed based on genomic features from 286 gastroesophageal cancers (foregut) and 286 colorectal cancers (hindgut) using targeted tumor sequencing. The SBA samples were run through the HGC to obtain the predicted probability of either foregut or hindgut lineage. For patients submitted to curative intent resection, overall survival (OS) was calculated from 90 days post resection until date of last follow up. Cox regression was used to examine factors associated with OS and to construct the multivariable model. Results: Of a total of 243 patients with SBA, 60% were male. The most common anatomic locations were duodenum (53%), jejunum (28%), and ileum (12%). HGC prediction of foregut lineage was higher for duodenal (55%) and intestinal-type periampullary (64%) tumors, while prediction of hindgut lineage was higher for ileal (68%) and jejunal (54%) tumors. Patients were then divided into three HGC prediction groups based on the lowest-, highest-, and inter-quartile ranges: foregut (n=61), characterized by gene amplification of CDK12, CD3, EGFR, and KRAS and cytoband segmentation of chromosomes 8-p21.1 and 15-q26.3; hindgut (n=61), characterized by APC and KRAS mutations; and mixed-type (n=121) with elements of both. Among those undergoing curative-intent surgery (n=160), median OS was 73 months. On multivariable analysis, HGC prediction group (hindgut vs mixed-type, HR 3.22, 95%CI 1.54-6.73), age (HR 1.03, 95%CI 1.01-1.05) and positive lymph node status (HR 1.96, 95%CI 1.02-3.76) were associated with decreased survival (Table). Neither anatomic site nor the presence of other driver mutations was associated with survival. Conclusions: Small bowel adenocarcinomas display genomic heterogeneity. A novel hidden genome classifier that stratifies SBAs based on homology to foregut or hindgut genomic alterations may be superior to anatomic location for characterizing disease biology. Additional studies are needed to validate and further explore these findings. [Table: see text]