Comprehensive genomic and transcriptomic characterization of small bowel adenocarcinoma.
Authors: Pandya Karan , Xiu Joanne , Farrell Alex , Overman Michael J. , Seeber Andreas , Abraham Jim , Shields Anthony Frank , Lou Emil , Marshall John , Abbruzzese James L. , Lenz Heinz-Josef , Korn Wolfgang Michael , Gulhati Pat 
Published: June 2022

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Background: Small bowel adenocarcinoma (SBA) is a rare cancer with rising incidence and worse overall survival (OS) compared to other intestinal cancers. Clinical management of SBA is primarily extrapolated from colorectal cancer (CRC). Comprehensive genomic and transcriptomic profiling of SBA will facilitate development of disease-specific therapeutic strategies. We investigated molecular alterations and association with clinical outcomes in a large cohort of SBA pts. Methods: Tumors were analyzed using 592 gene next-generation sequencing of DNA (592 genes or WES), RNA (WTS) and IHC (Caris). Immune infiltration was calculated by QuantiSeq. OS was calculated from treatment start/tissue collection to last contact from insurance claims. Results: We analyzed 823 SBA tumors: 448 primary/312 metastases, 586 duodenal (DA)/95 jejunal (JA)/38 ileal (IA). Median age of JA pts was lower (57yo) than DA (67yo) and IA (68yo). Upon subsite comparison, HER2 overexpression (2.5%) and amplification (3.6%) was only seen in DA, while HER2 mutations (mts) were most common in JA (10%) and absent in IA. IA had the lowest rate of KRAS (30%) and APC (11%) mts and highest rate of DDR mts (37%). JAs were enriched in RSPO3 fusion (19%) and BRAF mts (21%). Among BRAF mts in SBA, class 3 comprised 53%, class 2 37% and class 1 10%. MSI/dMMR was seen in 8% SBA and TMB-H in 11% with no difference among subsites. Compared to 14000 CRC tumors, SBA had significantly higher immune infiltrates regardless of MSI status (p<0.001), with highest fold change in myeloid dendritic cells (15.5), Tregs (9.4), neutrophils (3.6) and M2 Macrophages (3.5). When investigating clinical outcome of SBA pts (n=751), favorable prognostic markers included TMB³8 mts/Mb (HR: 0.65, 95%CI: 0.50-0.85), mts in APC (HR: 0.76, 95% CI: 0.62-0.93), MSH6 (HR: 0.45, 95% CI: 0.20-0.99), HNF1A (HR: 0.268, 95% CI: 0.11-0.65), PRKDC (HR: 0.45, 95% CI: 0.20-1.01) and ERBB3 (HR: 0.46, 95% CI: 0.26-0.82), while TP53 (HR: 1.32, 95% CI: 1.10-1.59) and CDKN2A (HR: 1.7, 95% CI: 1.25-2.3) mts and positive PD-L1 (HR: 1.44, 95% CI: 1.09-1.90) predicted worse OS. Among SBA pts treated with chemotherapy (n=258), DA had worse OS than IA/JA (HR: 1.44, 95% CI: 1.05-1.98), which had worse OS than left-sided [LS] (HR: 1.86, 95% CI: 1.39-2.46) and right-sided [RS] CRC pts (HR: 1.35, 95% CI: 1.01-1.79). DA pts had significantly worse OS compared to LS (HR=2.97, 95% CI: 1.73-5.08) and RS (HR=1.88, 95% CI: 1.08-3.24) CRC pts. Conclusions: This study represents the largest SBA cohort with comprehensive genomic and transcriptomic profiling. We identified subsite-specific enrichment in targetable alterations, including HER2 overexpression/amplification in DA, BRAF/HER2 mts and RSPO3 fusions in JA, and DDR mts in IA. SBAs harbor higher immune infiltrates than CRC, suggesting active immune modulation. DA is characterized by poor overall outcomes and decreased therapeutic benefit from chemotherapy compared to LS- and RS- CRCs.