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Small bowel adenocarcinoma phenotyping, a clinicobiological prognostic study.

ABSTRACT: BACKGROUND: Small bowel adenocarcinoma (SBA) is a rare tumour with a poor prognosis. Molecular biology data on SBA carcinogenesis are lacking. METHODS: Expression of HER2, β-catenin, p53 and mismatch repair (MMR) protein was assessed by immunohistochemistry. KRAS, V600E BRAF mutations and microsatellite instability were investigated. RESULTS: We obtained samples from 63 SBA patients (tumour stages: I-II: 30%; III: 35%; IV: 32%; locally advanced: 3%). HER2 overexpression (3+) was observed in 2 out of 62 patients, overexpression of p53 in 26 out of 62, abnormal expression of β-catenin in 12 out of 61, KRAS mutation in 21 out of 49, BRAF V600E mutation in 1 out of 40 patients, MMR deficiency (dMMR) in 14 out of 61 and was consistent with Lynch syndrome in 9 out of 14 patients. All of the dMMR tumours were in the duodenum or jejunum and only one was stage IV. Median overall survival (OS) was 36.6 months (95% CI, 26.9-72.2). For all patients, in univariate analysis, stages I-II (P<0.001), WHO PS 0-1 (P=0.01) and dMMR phenotype (P=0.02) were significantly associated with longer OS. In multivariate analysis, disease stage (P=0.01) and WHO PS 0-1 (P=0.001) independently predicted longer OS. For stage IV patients, median OS was 20.5 months (95% CI: 14.6; 36.6 months). In multivariate analysis, WHO PS 0-1 (P=0.0001) and mutated KRAS status (P=0.02) independently predicted longer OS. CONCLUSION: This large study suggests that molecular alterations in SBA are closer to those in colorectal cancer (CRC) than those in gastric cancer, with low levels of HER 2 overexpression and high frequencies of KRAS mutations. The seemingly higher frequency of dMMR than in CRC may be explained by the higher frequency of Lynch syndrome in SBA patients. A dMMR phenotype was significantly associated with a non-metastatic tumour (P=0.02). A trend for a good prognosis and a duodenum or jejunum primary site was associated with dMMR.

SUBMITTER: Aparicio T

PROVIDER: S-EPMC3859950 | biostudies-other | 2013 Dec

REPOSITORIES: biostudies-other

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Project description:ImportanceSmall-bowel adenocarcinomas (SBAs) are rare cancers with a significantly lower incidence, later stage at diagnosis, and worse overall survival than other intestinal-derived cancers. To date, comprehensive genomic analysis of SBA is lacking.ObjectiveTo perform in-depth genomic characterization of a large series of SBAs and other gastrointestinal tumors to draw comparisons and identify potentially clinically actionable alterations.Design, setting, and participantsProspective analysis was performed of clinical samples from patients with SBA (n?=?317), colorectal cancer (n?=?6353), and gastric carcinoma (n?=?889) collected between August 24, 2012, and February 3, 2016, using hybrid-capture-based genomic profiling, at the request of the individual treating physicians in the course of clinical care for the purpose of making therapy decisions.ResultsOf the 7559 patients included in analysis, 4138 (54.7%) were male; the median age was 56 (range, 12-101) years. The frequency of genomic alterations seen in SBA demonstrated distinct differences in comparison with either colorectal cancer (APC: 26.8% [85 of 317] vs 75.9% [4823 of 6353], P?<?.001; and CDKN2A: 14.5% [46 of 317] vs 2.6% [165 of 6353], P?<?.001) or gastric carcinoma (KRAS: 53.6% [170 of 317] vs 14.2% [126 of 889], P?<?.001; APC: 26.8% [85 of 317] vs 7.8% [69 of 889], P?<?.001; and SMAD4: 17.4% [55 of 317] vs 5.2% [46 of 889], P?<?.001). BRAF was mutated in 7.6% (484 of 6353) of colorectal cancer and 9.1% (29 of 317) of SBA samples, but V600E mutations were much less common in SBA, representing only 10.3% (3 of 29) of BRAF-mutated cases. The ERBB2/HER2 point mutations (8.2% [26 of 317]), microsatellite instability (7.6% [13 of 170]), and high tumor mutational burden (9.5% [30 of 317]) were all enriched in SBA. Significant differences were noted in the molecular profile of unspecified SBA compared with duodenal adenocarcinoma, as well as in inflammatory bowel disease-associated SBAs. Targetable alterations in several additional genes, including PIK3CA and MEK1, and receptor tyrosine kinase fusions, were also identified in all 3 series.Conclusions and relevanceThis study presents to our knowledge the first large-scale genomic comparison of SBA with colorectal cancer and gastric carcinoma. The distinct genomic differences establish SBA as a molecularly unique intestinal cancer. In addition, genomic profiling can identify potentially targetable genomic alterations in the majority of SBA cases (91%), and the higher incidence of microsatellite instability and tumor mutational burden in SBA suggests a potential role for immunotherapy.

Project description:Background: Small bowel adenocarcinoma (SBA) is a rare gastrointestinal tumor with high malignancy. The aim of this study was to comprehensively evaluate the distant metastasis pattern and establish nomograms predicting survival for SBA. Methods: From 2010 to 2015, patients diagnosed with SBA were identified based on the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier survival analysis was applied to compare survival differences between metastasis patterns. Then, univariate and multivariate cox analyses were applied to screened out independent prognostic factors of cancer-specific survival (CSS) and overall survival (OS), and identify the risk factors for metastasis of SBA. To assess the discrimination and calibration of nomograms, the concordance index (C-index), calibration curves, receiver-operating characteristic curve (ROC), and decision curve analysis (DCA) were calculated. Results: Kaplan-Meier curves revealed that metastasis patterns were significantly correlated with CSS (p < 0.001) and OS (p < 0.001). Then, the metastasis pattern was showed to be an independent prognostic factor of OS and CSS in patients with SBA, as well as age, grade, T stage, N stage, surgery, retrieval of regional lymph nodes, and chemotherapy. Combining these factors, we constructed prognostic nomograms, which suggested that the metastasis pattern made the greatest contribution to the survival of patients with SBA. Nomograms for OS and CSS had a C-index of 0.787 and 0.793, respectively. Calibration curves showed an excellent agreement between probability and actual observation in the training and validation cohort. Decision curve analysis also exhibited its clinical value with an improved net benefit. In addition, the models we constructed had better prognostic accuracy and clinical utility than traditional TNM staging based on C-index and ROC. Further, Cox regression analysis showed that old age, poor differentiation, N2, and not receiving chemotherapy were the risk factors for prognosis in patients with metastatic SBA. Conclusion: As an independent prognostic factor, the metastasis pattern exhibited the greatest predictive effect on OS and CSS for patients with SBA. Adjuvant chemotherapy had a positive effect on the survival of patients with SBA. Nomograms for predicting 3-and 5-year OS and CSS of patients with SBA were constructed, which could identify patients with higher risk and might be superior in predicting the survival of patients with SBA than TNM staging.

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Small bowel adenocarcinoma phenotyping, a clinicobiological prognostic study.

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