Abstract 2183: Genomic profiling of small bowl adenocarcinoma reveals targetable mutations in multiple signaling pathways

Abstract

Abstract Background: Small bowel adenocarcinoma (SBA) is a rare malignancy of the gastrointestinal (GI) tract without approved targeted therapy. Because the treatment approaches for colorectal cancer showed limited efficacy in SBA, the NCCN guide strongly encourages SBA patients to participate in clinical trials. The identification of targetable mutations through genomic profiling will gain new insights into the etiology of SBA and enable physicians to select the matched trials for patients. Methods: To characterize actionable targets in 50 Chinese SBA patients, a 830-gene next-generation sequencing panel was applied to assess the mutational status of their tumor tissues, including SNV, insertions/deletions, CNV and re-arrangements. Also, paired genomic DNA sample was extracted and analyzed by a 139-gene NGS panel to identify pathogenic germline variants. Results: The most frequently mutated genes in this SBA cohort were TP53 (68%), KRAS (56%), APC (38%), SMAD4 (20%), CTNNB1 (16%), ARID2 (14%), FAT3 (12%), FBXW7 (12%), KMT2C (12%) and PIK3CA (12%). Potentially targetable alterations include BRAF (10%), MDM2 (10%), ERBB2/HER2 (8%), PIK3CA (4%) and MAP2K1 (4%). Except one V600E mutation, all mutations in BRAF are either type 2 (L597R) or type 3 (N581S and D594N) which were sensitive to MEK inhibitor trametinib. We also found two MAP2K1 activating mutations (K57E and K57N) which can be targeted by trametinib. ERBB2/HER2 was highly amplified in one patient (copy number 25) and ERBB2/HER2 driver mutations were seen in 3 (6%) patients including V842I (n =2) and V777L (n =1). These four patients were good candidates for HER2-targeted therapy clinical trials. We also observed two activating PIK3CA mutations (R108H and G364R) which may be sensitive to PIK3CA inhibitor alpelisib. In addition, we observed targetable gene amplification of MDM2 (n =1) and FGF3/4/19 (n =2). Interestingly, one patient carried an activating ZKSCAN1-MET fusion gene which can be targeted by FDA-approved MET inhibitor carbozantinib. Among 46 patients with available MSI status, two were designated as microsatellite instability. The median TMB of microsatellite stable patients was 3.7 mutations/Mb. Lastly, we observed five deleterious germline mutations, two for SBDS, one each for APC, ERCC5 and MLH1. Overall, at least 18 (36%) patients harbored potentially actionable genetic mutations. Conclusions: The mutational landscape of our SBA cohort provided compelling evidence that multiple signaling pathways play a role in the pathogenesis of SBA and many driver mutations in these pathways are targetable. Our findings indicated that SBA patients should participate in matched clinical trials for better management of this disease. Citation Format: Rong Liu, Xiaomo Li, Zhiming Zhao, Tonghui Ma, Fei Wang, Si Liu. Genomic profiling of small bowl adenocarcinoma reveals targetable mutations in multiple signaling pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2183.