ERBB2 gene as a potential therapeutic target in small bowel adenocarcinoma.

Abstract

205 Background: Small bowel adenocarcinoma (SBA) is an aggressive tumor responsible for poor outcomes with an expected median OS at 5 years inferior to 30%. Because of its low incidence, few prospective studies have been performed leading to insufficient knowledge and absence of standard of care. Aiming to better understand the small bowel carcinogenesis process we screened for somatic mutations a large data set of patients in more than 740 mutational hotspots among 46 genes. Methods: In total, 83 SBA cases were selected from 2 European databases. The sequencing was performed using the Ion 316 Chip. We additionally looked into MSI status and ERBB2 expression (immunochemistry and FISH). Results: Tumors were mostly located in the duodenum (47%) and stage ≥ 3 (63%). Among the 46 genes investigated, 8 were mutated in more than 5% of the cases: KRAS, TP53, APC, SMAD4, PIK3CA, ERBB2, BRAF, and FBXW7. Compelling mutations (7 cases) and amplifications (3 cases) 12% of the patients had an ERBB2 alteration. In this group, ERBB2 alterations were positively associated with dMMR status (p=0.006) and APC mutations (p=0.02) but negatively associated with p53 mutations (p=0.038). Interestingly, ERBB2 mutations were mainly detected within tumors derived from the foregut while ERBB2 amplifications were limited those derived from the midgut. Conclusions: This study describes the first large screening of somatic mutations in SBA using next generation sequencing. ERBB2 mutation was revealed to be one of the most frequent alterations in SBA with a distribution dependent on tumor location. In most cases patients harbored the same p.L755S-ERBB2 mutation. In clinical practice, this study may suggest that more than 10% of the patients with SBA could be treated using anti-ERBB2-targeted agents.[Table: see text]

Clinicopathologic and prognostic associations of KRAS and BRAF mutations in small intestinal adenocarcinoma

“…Although a few previous studies of small intestinal adenocarcinomas have examined KRAS and/or BRAF mutations, which are well-known oncogenes in colorectal cancer, most of these analyses were performed on small numbers of patients (Table 9). 1,3,[10][11][12][13][14][15][16][17][18][19][20] The frequency of KRAS mutations among small intestinal adenocarcinomas ranged from 9 to 83% in the previous studies. Previous studies from Japan with homogeneous ethnic groups showed a wide range of frequencies of KRAS mutation (9-71%), [13][14][15]19 and other studies with heterogeneous ethnic groups, such as studies from USA, also reported various frequencies of KRAS mutation (14-83%).…”

“…Several different techniques for detecting KRAS and/or BRAF mutation were used, including restriction fragment length polymorphism, allele-specific oligonucleotide hybridization, PCR-single-strand conformation polymorphism, allele discrimination assay and Sanger sequencing. 1,3,[10][11][12][13][14][15][16][17][18][19][20] In addition to different detection techniques, differences in sample size may contribute to the wide range of KRAS mutation frequencies observed. The overall prevalence of KRAS mutations in the previous studies was 38% (150/400).…”

“…Modern Pathology (2016) 29, 402-415; doi:10.1038/modpathol.2016.40; published online 19 February 2016 Although the small intestine accounts for 90% of the mucosal surface area of the gastrointestinal tract, small intestinal adenocarcinoma is rare and accounts for only approximately 2% of gastrointestinal malignancies. 1 Epidemiologic observations have shown an increasing incidence of small intestinal adenocarcinoma in recent years, with an estimated 9160 new cases in 2014 in the United States. 2 Small intestinal adenocarcinoma has a poor prognosis at all stages, which appears to be intermediate between that of colon and gastric cancer.…”

“…5 Unfortunately, there is no standard treatment and the place of new targeted therapies has still to be defined. 1 Moreover, the number of tumor samples collected remains limited because of the low incidence of the disease, which explains the lack of information regarding somatic genetic alterations that occur during small intestinal carcinogenesis.…”

“…1,3,[10][11][12][13][14][15][16][17][18][19][20] In addition, because most of these few analyses were performed on only small numbers of small intestinal adenocarcinoma patients, they need to be validated.…”