Molecular Landscape of Small Bowel Adenocarcinoma

Simple Summary: Small bowel adenocarcinoma (SBA) is a rare malignancy with worse prognosis compared to other cancers of the gastrointestinal tract. Over 90% of SBA tumors harbor targetable genetic alterations. Molecular analysis to identify these alterations, using tissue- or blood-based next generation sequencing, is critical and may impact treatment decisions. The aim of our review is to highlight molecular drivers of SBA tumorigenesis. We highlight key mutational and transcriptomic differences between SBA and colorectal cancer, from which much of the clinical management of SBA is currently extrapolated. We provide evidence that SBA is a molecularly unique intestinal malignancy, with distinct genomic alterations predictive of response to targeted therapy and immunotherapy. Abstract: Small bowel adenocarcinoma (SBA) is a rare malignancy, with lower incidence, later stage at diagnosis, and poor overall prognosis compared to other cancers of the gastrointestinal tract. Owing to the rarity of the disease along with the paucity of high-quality tissue samples and preclinical models, little is known about the molecular alterations characteristic of SBA. This is reflected by the fact that the clinical management of SBA is primarily extrapolated from colorectal cancer (CRC). Recent advances in genomic profiling have highlighted key differences between these tumors, establishing SBA as a molecularly unique intestinal cancer. Moreover, comprehensive molecular analysis has identified a relatively high incidence of potentially targetable genomic alterations in SBA, predictive of response to targeted and immunotherapies. Further advances in our knowledge of the mutational and transcriptomic landscape of SBA, guided by an increased understanding of the molecular drivers of SBA, will provide opportunities to develop novel diagnostic tools and personalized therapeutic strategies.