Small Bowel Adenocarcinoma Patients Research Articles

Small bowel neuroendocrine tumors: Unique features and low lethality compared with small bowel adenocarcinoma.

Population-based studies comparing clinical characteristics and survival disparities between patients with small bowel adenocarcinoma (SBA) and small bowel neuroendocrine tumors (SBNETs) in the United States are limited. Data for patients with SBA or SBNETs, obtained from the Surveillance, Epidemiology, and End Results database for the years between 2000 and 2018 were analyzed. Between 2000 and 2018, the age-adjusted incidence of SBA experienced a marginal increase whereas SBNETs demonstrated a significant increase, emerging as the predominant subtype of small bowel cancer (SBC). Diagnoses peaked at ages 65-69years for SBA and 60-64years for SBNETs, with the latter exhibiting a heightened age-specific incidence and maintaining equilibrium in gender distribution. Clinicopathologic disparities revealed SBA's duodenal predilection, larger tumor size, and advanced stages, contrasting with SBNETs' ileal predilection, early-stage presentation, and superior outcomes. SBNETs patients underwent surgery more frequently but received less chemotherapy and radiation than SBA patients. Factors intricately correlated with a diagnosis of SBNETs included female gender, White race, advanced age, marital status, recent diagnoses, superior tumor differentiation, smaller size, distal location, and early-stage presentation. Survival analysis unveiled a remarkable 79% reduction in the mortality risk for SBNETs compared with SBA. Subgroup analysis further confirmed the consistently favorable survival advantages of SBNETs, highlighting the clinical relevance of histological classification in prognostication. Compared with SBA, SBNETs exhibited distinctive clinicopathological features characterized by a higher inclination toward low-grade and early-stage manifestations, thereby contributing to superior survival outcomes.

Development and validation of a nomogram for predicting cancer-specific survival in small-bowel adenocarcinoma patients using the SEER database

BackgroundSmall bowel adenocarcinoma (SBA) is a rare gastrointestinal malignancy forwhich survival is hampered by late diagnosis, complex responses to treatment, and poor prognosis. Accurate prognostic tools are crucial for optimizing treatment strategies and improving patient outcomes. This study aimed to develop and validate a nomogram based on the Surveillance, Epidemiology, and End Results (SEER) database to predict cancer-specific survival (CSS) in patients with SBA and compare it to traditional American Joint Committee on Cancer (AJCC) staging.MethodsWe analyzed data from 2,064 patients diagnosed with SBA between 2010 and 2020 from the SEER database. Patients were randomly assigned to training and validation cohorts (7:3 ratio). Kaplan‒Meier survival analysis, Cox multivariate regression, and nomograms were constructed for analysis of 3-year and 5-year CSS. The performance of the nomograms was evaluated using Harrell’s concordance index (C-index), the area under the receiver operating characteristic (ROC) curve, calibration curves, decision curve analysis (DCA), net reclassification improvement (NRI), and integrated discrimination improvement (IDI).ResultsMultivariate Cox regression identified sex, age at diagnosis, marital status, tumor site, pathological grade, T stage, N stage, M stage, surgery, retrieval of regional lymph nodes (RORLN), and chemotherapy as independent covariates associated with CSS. In both the training and validation cohorts, the developed nomograms demonstrated superior performance to that of the AJCC staging system, with C-indices of 0.764 and 0.759, respectively. The area under the curve (AUC) values obtained by ROC analysis for 3-year and 5-year CSS prediction significantly surpassed those of the AJCC model. The nomograms were validated using calibration and decision curves, confirming their clinical utility and superior predictive accuracy. The NRI and IDI indicated the enhanced predictive capability of the nomogram model.ConclusionThe SEER-based nomogram offers a significantly superior ability to predict CSS in SBA patients, supporting its potential application in clinical decision-making and personalized approaches to managing SBA to improve survival outcomes.

Molecular characterization of Chinese patients with small bowel adenocarcinoma.

Small bowel adenocarcinoma (SBA) is a rare malignancy of the gastrointestinal tract, and its unique location within the small intestine presents difficulties in obtaining tissue samples from the lesions. This limitation hinders the research and development of effective clinical treatment methods. Circulating tumor DNA (ctDNA) analysis holds promise as an alternative approach for investigating SBA and guiding treatment decisions, thereby improving the prognosis of SBA. Between January 2017 and August 2021, a total of 336 tissue or plasma samples were obtained and the corresponding mutation status in tissue or blood was evaluated with NGS. The study found that in SBA tissues, the most commonly alternated genes were TP53, KRAS, and APC, and the most frequently affected pathways were RTK-RAS-MAPK, TP53, and WNT. Notably, the RTK-RAS-MAPK pathway was identified as a potential biomarker that could be targeted for treatment. Then, we validated the gene mutation profiling of ctDNA extracted from SBA patients exhibited the same characteristics as tissue samples for the first time. Subsequently, we applied ctDNA analysis on a terminal-stage patient who had shown no response to previous chemotherapy. After detecting alterations in the RTK-RAS-MAPK pathway in the ctDNA, the patient was treated with MEK + EGFR inhibitors and achieved a tumor shrinkage rate of 76.33%. Our study utilized the largest Chinese SBA cohort to uncover the molecular characteristics of this disease, which might facilitate clinical decision making for SBA patients.

Identifying risk and prognostic factors for synchronous liver metastasis in small bowel adenocarcinoma: a predictive analysis using the SEER database.

Small bowel adenocarcinoma (SBA) is a rare gastrointestinal malignancy with an increasing incidence and a high propensity for liver metastasis (LM). This study aimed to investigate the risk factors for synchronous LM and prognostic factors in patients with LM. Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, this study analyzed data from 2,064 patients diagnosed with SBA between 2010 and 2020. Logistic regression was used to determine risk factors for synchronous LM. A nomogram was developed to predict the risk of LM in SBA patients, and its predictive performance was assessed through receiver operating characteristic (ROC) curves and calibration curves. Kaplan-Meier and Cox regression analyses were conducted to evaluate survival outcomes for SBA patients with LM. Synchronous LM was present in 13.4% of SBA patients (n = 276). Six independent predictive factors for LM were identified, including tumor location, T stage, N stage, surgical intervention, retrieval of regional lymph nodes (RORLN), and chemotherapy. The nomogram demonstrated good discriminative ability, with an area under the curve (AUC) of 83.8%. Patients with LM had significantly lower survival rates than those without LM (P < 0.001). Survival analysis revealed that advanced age, tumor location in the duodenum, surgery, RORLN and chemotherapy were associated with cancer-specific survival (CSS) in patients with LM originating from SBA. This study highlights the significant impact of LM on the survival of SBA patients and identifies key risk factors for its occurrence. The developed nomogram aids in targeted screening and personalized treatment planning.

Exploring the immune microenvironment in small bowel adenocarcinoma using digital image analysis.

Small bowel adenocarcinoma (SBA) is a rare malignancy of the small intestine associated with late stage diagnosis and poor survival outcome. High expression of immune cells and immune checkpoint biomarkers especially programmed cell death ligand-1 (PD-L1) have been shown to significantly impact disease progression. We have analysed the expression of a subset of immune cell and immune checkpoint biomarkers in a cohort of SBA patients and assessed their impact on progression-free survival (PFS) and overall survival (OS). 25 patient samples in the form of formalin fixed, paraffin embedded (FFPE) tissue were obtained in tissue microarray (TMAs) format. Automated immunohistochemistry (IHC) staining was performed using validated antibodies for CD3, CD4, CD8, CD68, PD-L1, ICOS, IDO1 and LAG3. Slides were scanned digitally and assessed in QuPath, an open source image analysis software, for biomarker density and percentage positivity. Survival analyses were carried out using the Kaplan Meier method. Varying expressions of biomarkers were recorded. High expressions of CD3, CD4 and IDO1 were significant for PFS (p = 0.043, 0.020 and 0.018 respectively). High expression of ICOS was significant for both PFS (p = 0.040) and OS (p = 0.041), while high PD-L1 expression in tumour cells was significant for OS (p = 0.033). High correlation was observed between PD-L1 and IDO1 expressions (Pearson correlation co-efficient = 1) and subsequently high IDO1 expression in tumour cells was found to be significant for PFS (p = 0.006) and OS (p = 0.034). High levels of immune cells and immune checkpoint proteins have a significant impact on patient survival in SBA. These data could provide an insight into the immunotherapeutic management of patients with SBA.

Disproportionately Low Albumin and High Neutrophil-to-Lymphocyte Ratio in Small Bowel Adenocarcinoma Patients With Long-Duration Crohn's Disease.

Although Crohn's disease (CD) is a known risk factor of small bowel adenocarcinoma (SBA), early diagnosis remains a significant clinical challenge. Identification of biomarkers for SBA may lead to early detection. This is a retrospective study comparing albumin levels and neutrophil-to-lymphocyte ratio (NLR) of patients with long-standing CD who underwent small bowel resection with and without malignancy. Forty-two patients with CD were included in this study (11 with SBA). Median NLR before surgery was 8.5 (interquartile range 6.2-31.3) in patients with SBA and 3.8 (interquartile range 2.8-5.3) for patients without SBA ( P < 0.05). Mean albumin levels before surgery were significantly lower among patients with SBA compared with patients without SBA (2.6 ± 0.6 g/dL vs 3.5 ± 0.6 g/dL, respectively, P < 0.05), despite patients with SBA being under longer total parenteral nutrition treatment duration. CD patients with SBA diagnosis have increased NLR and lower albumin before surgery compared with CD patients without detection of SBA.

Localized Small Bowel Adenocarcinoma Management: Evidence Summary.

Simple SummarySmall bowel adenocarcinoma is a rare but aggressive disease that requires peri-operative treatment. Due to its rarity, there is little data on small bowel adenocarcinoma treatment, and most recommendations come from expert agreements or analogies to the management of colon cancer. In this Review, we summarize the current evidence on the management of localized small bowel adenocarcinoma, including future biomarker research perspectives that may help identify high-risk small bowel adenocarcinomas.Small bowel cancers are rare diseases whose prognosis is poorer than that of colon cancers. Due to disease rarity, there is little data on small bowel adenocarcinoma (SBA) treatment, and most recommendations come from expert agreements or analogies to the management of colon cancer. Although relatively high rates of local recurrence are observed for duodenal malignancies, distant metastatic relapse remains common and requires adjuvant systemic therapy. Given the similarities between SBA and colorectal cancer, radiotherapy and chemotherapy strategies used for the latter disease are frequently pursued for the former disease, specifically for tumors located in the duodenum. However, no previous randomized study has evaluated the benefit of adjuvant chemotherapy on the overall survival of SBA patients. Most previous studies on treatment outcomes and prognostic factors in this context were based on large international databases, such as the Surveillance, Epidemiology, and End Results or the National Cancer Database. Studies are required to establish and validate prognostic and predictive markers relevant in this context to inform the use of (neo) adjuvant treatment. Among those, deficient mismatch repair tumors represent 20% of SBAs, but their impact on chemosensitivity remains unknown. Herein, we summarize the current evidence on the management of localized SBA, including future perspectives.

Evaluation of somatic and germline variants in patients with small bowel adenocarcinoma reveals clinically actionable targets.

4159 Background: Small bowel adenocarcinoma (SBA) is a rare gastrointestinal cancer with a poor prognosis and limited treatment options. Because the treatments for colorectal cancer showed limited efficacy in SBA, the NCCN guide strongly encourages SBA patients to participate in clinical trials. In this study, we aimed to explore clinically actionable variants in a large cohort of patients with SBA to assist oncologists to select the matched trials for patients. Methods: To explore therapeutic targets in 84 Chinese SBA patients, a deep sequencing panel (OncoPanscan, Genetron health) was used to characterize somatic alterations including point mutations, indels, copy number alterations, gene fusions as well as pathogenic germline variants. Results: Recurrent somatic mutations included TP53 (57%), KRAS (56%), APC (31%), SMAD4 (21%), MDM2 (13%), CTNNB1 (12%), KMT2C (12%), SOX9 (12%), ARID2 (12%), FAT3 (11%), FBXW7 (10%), SPTA1(10%) and PIK3CA (10%). Of the entire cohort, we observed five activating PIK3CA mutations (R108H; G364R; E542K; E545K, n = 2) which may be sensitive to FDA-approved PIK3CA inhibitor alpelisib. Additionally, patients with loss-of-function mutation in NF1 (n = 2), STK11 (n = 1) and PTEN (n = 1) can be targeted with MEK inhibitor selumetinib and mTOR inhibitor everolimus, respectively. Except for one V600E mutation, all mutations in BRAF are either type 2 (L597R, n = 1) or type 3 (N581S, n = 1; D594N, n = 4) which were sensitive to MEK inhibitor trametinib. We also found four type 2 MAP2K1 activating mutations (K57E, K57N, and F53L) which can be targeted by trametinib. Furthermore, oncogenic ERBB2/HER2 mutations were seen in 4 patients including S310F (n = 1), V842I (n = 2) and V777L (n = 1). We also found one patient harbored ERBB2/HER2 high magnification amplification. These five patients were candidates for HER2-targeted therapy clinical trials. Interestingly, one IDH1 mutation (R132C) carrier in our cohort might benefit from ivosidenib. In addition, we observed targetable gene amplification of MDM2 (n = 2) and FGF3/4/19 (n = 2). There were two patients with MLH1 loss-of-function germline mutations that may benefit from immunotherapy. Among 78 patients with available MSI status, three were designated as microsatellite instability. The median TMB of microsatellite stable patients was 2.82 mutations/Mb. Lastly, we observed five deleterious germline mutations, three for SBDS, one each for APC and ERCC5. Taken together, at least 33 (39%) patients in our cohort harbored actionable genetic alterations. Conclusions: Through comprehensive genomic characterization of Chinese SBA patients, we identified actionable variants of multiple signaling pathways in plenty. NGS profiling results can guide physicians to enroll a significant portion of SBA patients in genomically-matched clinical trials.

Development and validation of prognostic nomograms for patients with metastatic small bowel adenocarcinoma: a retrospective cohort study

We aimed to explore factors associated with prognosis in patients with metastatic small bowel adenocarcinoma (SBA) as well as to develop and validate nomograms to predict overall survival (OS) and cancer-specific survival (CSS). Relevant information of patients diagnosed between 2004 and 2016 was extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Nomograms for predicting 1- and 3-year OS and CSS were established with potential risk factors screened from multivariate cox regression analysis. The discrimination and accuracy of the nomograms were assessed by concordance index (C-index), calibration plots, and the area under receiver operating characteristic curve (AUC). In total, 373 SBA patients with M1 category were enrolled. Multivariate analysis revealed that age, size and grade of primary tumor, primary tumor surgery, and chemotherapy were significant variables associated with OS and CSS. The C-index values of the nomogram for OS were 0.715 and 0.687 in the training and validation cohorts, respectively. For CSS, it was 0.711 and 0.690, respectively. Through AUC, decision curve analysis (DCA) and calibration plots, the nomograms displayed satisfactory prognostic predicted ability and clinical application both in the OS and CSS. Our models could be served as a reliable tool for prognostic evaluation of patients with metastatic SBA, which are favorable in facilitating individualized survival predictions and clinical decision-making.

Prognostic Value of Lymph Node Evaluation in Stage II Small Bowel Adenocarcinoma: An Updated Analysis of Surveillance, Epidemiology, and End Results Database.

BackgroundDue to the lack of large-scale clinical trials, the treatment strategies of small bowel adenocarcinoma (SBA) are controversial, especially for stage II patients. According to the National Comprehensive Cancer Network (NCCN) guideline, few lymph nodes (LNs) examined (<5 for duodenum or <8 for jejunal/ileal primary location) are one of the high-risk features for stage II patients, for whom adjuvant chemotherapy is recommended. This consensus is originally drawn from data in the Surveillance, Epidemiology, and End Results Database (SEER) between 1988 and 2010. However, the surgical modalities and chemotherapy strategies changed a lot after 2004 for SBA patients. The previous data may not represent a true picture of current therapeutics. Thus, we reanalyzed the SEER database and updated the cutoff point of LN numbers resected with respect to cancer-specific survival (CSS) using the latest SEER information.MethodsPatients diagnosed with stage II SBA and who underwent curative surgery between 2004 and 2018 were extracted from the SEER database. CSS was calculated using the Kaplan–Meier method and compared by log-rank test. Maximum survival differences based on total LNs examined for duodenal and jejunoileal tumors were determined separately with the cut-point analysis and maximum log-rank χ2 statistic. A nomogram model was constructed based on the multivariate Cox analysis to predict 5‐ and 10‐year CSS and was then validated with an internal cohort.ResultsA total of 935 stage II SBA patients met the inclusion criteria. The greatest difference in survival was found in patients who had removal of at least 5 LNs for duodenal and 12 LNs for jejunoileal tumors. Multivariate Cox analysis showed that age, T stage, histology grade, primary site, and LN numbers were independent prognostic factors for survival. The C index of nomogram model was 0.701 (95% CI, 0.661–0.741, p < 0.001).ConclusionsThe number of LNs harvested is an important prognostic factor for survival in stage II SBA patients. LN number examined <5 remains a high-risk factor for duodenum, but the cutoff point for jejunal/ileal tumors should rise from 8 to 12. Appropriate radical lymphadenectomy should be performed in stage II SBA surgery.

P209 Disproportionate low albumin and high neutrophil-to-lymphocyte ratio in small bowel adenocarcinoma in long-term Crohn’s disease patients

Abstract Background Although Crohn’s disease (CD) is a known risk factor for small bowel adenocarcinoma (SBA), early diagnosis remains a significant clinical challenge with many cases diagnosed inadvertently during small bowel resection or biopsies performed for presumed active or structuring CD. Identification of biomarkers for SBA may lead to early detection and improved prognosis in CD patients. The aim of the study was to explore a possible association between two simple laboratory values – serum albumin levels and neutrophil-to-lymphocyte ratio (NLR) and SBA in CD patients. Methods A retrospective case-control study comparing long-standing (&amp;gt;10 years) CD patients who have undergone small bowel (SB) resection with carcinoma detection by histopathology examination, compared with long-standing CD patients who underwent SB resection without malignancy detection at a ratio of 1:3 of cases to controls. Demographics, disease behavior, NLR, albumin levels and total parenteral nutrition (TPN) status during the three months period prior to surgery were retrieved and compared between groups. Results Forty-two patients with long-standing CD were included (11 with SBA and 31 patients without SBA). Median age was 55 [Interquartile range (IQR) 44–65] in the malignancy group and 37 (IQR 31–47) in the no-malignancy group (p-value &amp;lt; 0.05). Median NLR in the three months prior to surgery was 8.5 (IQR 6.2–31.3) in SBA patients and 3.8 (IQR 2.8–5.3) for patients without SBA (p &amp;lt; 0.05). Mean albumin levels during the three months period prior to surgery were significantly lower among patients with SBA compared with patients without SBA (2.6 ± 0.6 g/dL versus 3.5 ± 0.6 g/dL, respectively, p &amp;lt; 0.05), despite SBA patients being treated with TPN for significantly longer duration. Conclusion CD patients with SBA have statistically significant increased NLR and lower albumin compared with surgically treated CD patients without SBA. If corroborated by further studies, high NLR and disproportionate low albumin levels in long-duration CD patients may be useful biomarkers of SBA.

Molecular profiling and identification of prognostic factors in Chinese patients with small bowel adenocarcinoma.

Small bowel adenocarcinoma (SBA) is a rare malignancy with a poor prognosis and limited treatment options. Despite prior studies, molecular characterization of this disease is not well defined, and little is known regarding Chinese SBA patients. In this study, we conducted multigene next‐generation sequencing and 16S ribosomal RNA gene sequencing on samples from 76 Chinese patients with surgically resected primary SBA. Compared with colorectal cancer and Western SBA cohorts, a distinctive genomic profile was revealed in Chinese SBA cohorts. According to the levels of clinical actionability to targetable alterations stratified by OncoKB system, 75% of patients harbored targetable alterations, of which ERBB2, BRCA1/2, and C‐KIT mutations were the most common targets of highest‐level actionable alterations. In DNA mismatch repair–proficient (pMMR) patients, significant associations between high tumor mutational burden and specific genetic alterations were identified. Moreover, KRAS mutations/TP53 wild‐type/nondisruptive mutations (KRASmut/TP53wt/non‐dis ) were independently associated with an inferior recurrence‐free survival (hazard ratio [HR] = 4.21, 95% confidence interval [CI] = 1.94‐9.14, P < .001). The bacterial profile revealed Proteobacteia, Actinobacteria, Firmicutes, Bacteroidetes, Fusobacteria, and Cyanobacteria were the most common phyla in SBA. Furthermore, patients were clustered into three subgroups based on the relative abundance of bacterial phyla, and the distributions of the subgroups were significantly associated with the risk of recurrence stratified by TP53 and KRAS mutations. In conclusion, these findings provided a comprehensive molecular basis for understanding SBA, which will be of great significance in improving the treatment strategies and clinical management of this population.

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

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.

Circulating tumor DNA-based genomic profiling of small bowel adenocarcinoma.

3523 Background: Small bowel adenocarcinoma (SBA) is a rare malignancy, with lower incidence, later stage at diagnosis, and worse overall survival compared to other intestinal cancers, such as colorectal cancer (CRC). Since the majority of small bowel tumors are not accessible to endoscopic biopsy, comprehensive genomic profiling using circulating tumor DNA (ctDNA) may enable non-invasive detection of targetable genomic alterations (GA) in SBA patients. In this study, we characterize the ctDNA GA landscape in SBA. Methods: Analysis of 299 ctDNA samples prospectively collected from 265 SBA patients between 2017 to 2020 was performed using a 73 gene next generation sequencing panel (Guardant360). A subset of patients underwent longitudinal analysis of changes in GA associated with systemic therapy. Results: Of the 265 patients, 160 (60.3%) were male; the median age was 66 (range: 21-93 years). The most common GA identified in SBA patients included TP53 [58%], KRAS [44%], and APC [40%]. MSI was detected in 3.4% of SBA patients. When stratified by primary tumor location, APC, KRAS, TP53, PIK3CA, and ARID1A were the most common GA identified in both duodenal and jejunal adenocarcinomas. ERBB2, BRCA2 and CDK6 alterations were enriched in duodenal adenocarcinoma, while NOTCH and BRAF alterations were enriched in jejunal adenocarcinoma. The most common currently-targetable GA identified were ATM [18%], PIK3CA [17%], EGFR [15%], CDK4/6 [11%], BRAF [10%], and ERBB2 [10%]. Unique differences in GA between SBA and CRC were identified: i) the majority of ERBB2 alterations are mutations (89%) in the extracellular domain and kinase domain, not amplifications (11%); ii) the majority of BRAF alterations are non V600E mutations (69%) and amplifications (28%); iii) there is a significantly lower rate of APC mutations (40%). Alterations in DNA damage response pathway proteins, including ATM and BRCA 1/2, were identified in 30% of SBA patients. ATM alterations were more common in patients ³65 years old. The most common mutations predicted to be related to clonal hematopoiesis of indeterminate potential were TP53, KRAS and GNAS. Longitudinal ctDNA analysis in 4 SBA patients revealed loss of mutations associated with therapeutic response (TP53 R342*, MAPK3 R189Q) and acquired mutations associated with therapeutic resistance (NF1 R1968*, MET S170N, RAF1 L613V). Conclusions: This study represents the first large-scale blood-based ctDNA genomic profiling of SBA. SBA represents a unique molecular entity with differences in frequency and types of GA compared to CRC. Variations in GA were noted based on anatomic origin within the small intestine. Longitudinal ctDNA monitoring revealed novel GA associated with therapeutic resistance. Identification of multiple targetable GA may facilitate clinical decision making and improve patient outcomes in SBA, especially when a tissue biopsy is not feasible or sufficient for comprehensive genomic profiling.

Management of small bowel adenocarcinoma: making the most of the available evidence to inform routine practice.

Small bowel adenocarcinoma (SBA) is a rare disease, for which few studies have been conducted so far. Therefore, most treatment recommendations have been extrapolated from trials in colorectal cancer. In this review, we revise available data that could improve the management of SBA, with a particular focus on systemic therapy. For advanced/irresectable disease, first-line doublet chemotherapy remains standard of care. It is uncertain whether extending treatment to triplet chemotherapy brings added benefit. Pembrolizumab is an accepted treatment modality for mismatch repair-deficient tumors, yet might also be active in microsatellite stable tumors. More trials with immunotherapy are underway. Although there is no place for anti-EGFR monotherapy, the addition of cetuximab to chemotherapy should be investigated further. Two trials suggest an added value of bevacizumab to chemotherapy, yet larger trials are needed to confirm these data. For localized disease, the role of (neo)adjuvant chemotherapy is under investigation. For decades, patients with SBA have probably been treated suboptimal by basing treatment recommendations on data from colorectal cancer. An effort for SBA-specific trials and/or inclusion of SBA patients in basket trials is of utmost importance in order to improve outcome for these patients.

ZEBRA: An IRCI/ACCRU (RU021502I) Multicenter Phase II Study of Pembrolizumab in Patients With Advanced Small Bowel Adenocarcinoma (SBA)

Background: Small bowel adenocarcinoma (SBA) is rare, and no standard of care exists for metastatic SBA beyond first-line FOLFOX/CAPOX. Later-line therapy has been extrapolated from colorectal cancer (CRC) studies, though SBA is biologically distinct with higher rates microsatellite instability (MSI-H) and intratumoral T-lymphocyte infiltration. We hypothesize that pembrolizumab, a PD-1 inhibitor, will induce antitumor response. Methods: Previously treated advanced SBA patients received pembrolizumab 200 mg IV q3 weeks until disease progression (PD), toxicity, or to 35 dose maximum. Primary endpoint was confirmed overall response rate (ORR) with secondary survival and safety endpoints. Outcomes were stratified by tumor location, microsatellite stability (MSS) or instability (MSI-H), and PD-L1 level. Findings: 40 patients were treated for median duration of 4 cycles (range 1-35). MSI status was available for 36 patients (90%). All 40 patients are off study treatment due to: PD (75%), death (10%), 35 cycles completed (8%), refusal (3%), and adverse effects (AE, 5%). Three confirmed partial responses (PR) (8%; 95% CI: 2-20) did not meet pre-defined success criteria. Median overall survival (OS) 7 . 1 mo (95% CI: 5 . 1-17 . 1) and median progression free survival (PFS) 2 . 8 mo (95% CI: 2 . 7-4 . 2) were similar across primary tumor sites. One confirmed PR was seen in 32 MSS/MSI-low patients (3%). MSS response correlated with high tumor mutation burden (TMB). Two of four MSI-H patients had a confirmed PR (50%) and remain alive without progression. 25 patients (63%) had grade ≥ 3 AEs, 11 pts (28%) had grade 4/5 AEs. Interpretation: In the largest study of SBA to date, and the first using immunotherapy, pembrolizumab did not achieve the hypothesized response rate; however, we did identify responses in certain biomarker-selected cohorts. Trial Registration: RU021502I (ACCRU), MISP #52192 (Merck), NCT02949219 (clinicaltrials.gov). Funding Statement: Primary study funding and investigational product was provided by the Merck Investigator Studies Program (MISP), and additional site-specific funding provided by the Kavanagh Family Foundation (MDACC) and Kevin T. Doner Memorial Fund (MDACC). Declaration of Interests: None to declare Ethics Approval Statement: Ethics board review and human research protections monitoring were performed at each institution. The trial was conducted according to ICH GCP.

Nomograms predict survival of patients with small bowel adenocarcinoma: a SEER-based study.

Small bowel adenocarcinoma (SBA) is a rare malignant tumor with a poor prognosis. Most patients with SBA are diagnosed with advanced-stage disease. Due to the lack of randomized controlled trials and prospective studies, it is difficult to predict the prognosis of patients with SBA. Thus, this study aimed to establish a prognostic nomogram for evaluating the prognosis of SBA patients. The clinical features and follow-up data of all patients diagnosed with SBA during 2004-2016 were summarized from the Surveillance, Epidemiology, and End Results (SEER) database. We separated these patients into training and validation groups. Multivariate Cox regression analyses were performed to identify independent prognostic variables for predicting cancer-specific survival (CSS) and overall survival (OS). According to the independent risk factors, we established nomograms and used the calibration curves to evaluate the accuracy. The data of 3301 patients with SBA were collected from the SEER database. The multivariate analysis showed that age, marital status, tumor site, grade, TNM stage and surgical history were associated with CSS and OS (P < 0.05). Based on these results, we established nomograms of CSS and OS that can predict the 3- and 5-year survival rates of SBA patients (C-index > 0.7). The calibration curves showed that the predicted survival was very close to the actual survival. We analyzed the independent risk factors for prognosis of SBA patients, and established nomograms to predict the 3- and 5-year survival rates of OS and CSS. These new prognostic tools can help clinicians to predict the survival of patients with SBA, further to guide treatment strategy.

Personalized four-category staging for predicting prognosis in patients with small bowel Adenocarcinoma: an international development and validation study.

BackgroundLog odds of positive lymph nodes (LODDS) classification showed superiority over 8th edition N staging in predicting survival of small bowel adenocarcinoma (SBA) patients. The aim of this study was to develop and validate the Tumor, LODDS, and Metastasis (TLM) staging of SBA.MethodsTotally 1789 SBA patients from the Surveillance, Epidemiology, and End Results (SEER) database between 1988–2010, 437 patients from SEER database between 2011–2013 and 166 patients from multicenters were categorized into development, validation and test cohort, respectively. The TLM staging was developed in the development cohort using Ensemble Algorithm for Clustering Cancer Data (EACCD) method. C-index was used to assess the performance of the TLM staging in predicting cancer-specific survival (CSS) and was compared with the traditional 8th edition TNM staging.FindingsFour-category TLM staging designed for the development cohort showed higher discriminatory power than TNM staging in predicting CSS in the development cohort (0.682 vs. 0.650, P < 0.001), validation cohort (0.682 vs. 0.654, P = 0.022), and test cohort (0.659 vs. 0.611, P = 0.023), respectively. TLM staging continued to show its higher predictive efficacy than the 8th TNM in TNM stage II/III patients or in patients with lymph node yield less than 8.InterpretationTLM staging showed a better prognostic performance than the 8th TNM staging especially TNM stage II/III or patients with lymph node yield less than 8 and therefore, could serve to complement the TNM staging in patients with SBA.FundingA full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Adjuvant chemotherapy impact on the overall survival of completely resected small bowel adenocarcinoma: An updated meta-analysis.

e16806 Background: While the small intestine represents around 75% of the length and more than 90% of the gastrointestinal tract mucosal surface, it contributes around 2% of gastrointestinal tumors. Adenocarcinoma which constitutes 40% of all small bowel tumors is the most common histology. Complete surgical resection of early-stage small bowel adenocarcinoma (SBAC) is the only proven potentially curative therapy. Due to the rarity of this disease and the absence of randomized trials, the benefit of postoperative adjuvant chemotherapy (ACT) in patients with completely resected localized SBAC has been controversial. A meta-analysis conducted in 2018 found no survival benefit for adjuvant therapies in SBAC. However, this meta-analysis combined studies that used adjuvant chemotherapy and chemoradiotherapy and included studies contaminated by other less chemosensitive histologies and more advanced and sometimes metastatic disease. The purpose of this meta-analysis is to evaluate the impact of ACT on the overall survival (OS) of patients with completely resected SBAC incorporating more recent studies. Methods: A review of the medical literature was conducted using online databases. Inclusion criteria consisted of resected small bowel adenocarcinoma, English language, publications from 2000 to the present, and comparative studies reporting OS with hazard ratios (HR) or Kaplan-Meier curves of patients that underwent ACT versus those that did not. Adjuvant chemoradiotherapy studies and those that reported aggregate OS for a cohort with mixed histologies were excluded. A meta-analysis was conducted using an inverse variance method with a random-effects model. Results: Nine retrospective series which included 2082 patients were selected and analyzed. The majority of SBAC patients that received ACT belonged to stages II &amp; III. ACT was found to be significantly associated with better OS in patients with completely resected SBAC (HR 0.66, 95%CI: 0.56-0.78, p &lt; 0.001). Conclusions: This is the first meta-analysis to show that adjuvant chemotherapy is associated with a survival benefit in patients with completely resected small bowel adenocarcinoma. In the absence of randomized clinical trials, this meta-analysis represents the most compelling data supporting the use of ACT in this patient population.

Small bowel adenocarcinoma: Results from a nationwide prospective ARCAD-NADEGE cohort study of 347 patients.

Small bowel adenocarcinoma (SBA) is a rare tumour. We conducted a prospective cohort to describe the prevalence, survival and prognostic factors in unselected SBA patients. The study enrolled patients with all stages of newly diagnosed or recurrent SBA at 74 French centres between January 2009 and December 2012. In total, 347 patients were analysed; the median age was 63 years (range 23-90). The primary tumour was in the duodenum (60.6%), jejunum (20.7%) and ileum (18.7%). The prevalence of predisposing disease was 8.7%, 6.9%, 1.7%, 1.7% and 0.6% for Crohn disease, Lynch syndrome, familial adenomatous polyposis, celiac disease and Peutz-Jeghers syndrome, respectively. At diagnosis, 58.9%, 5.5% and 35.6% of patients had localised and resectable, locally advanced unresectable and metastatic disease, respectively. Crohn disease was significantly associated with younger age, poor differentiation and ileum location, whereas Lynch syndrome with younger age, poor differentiation, early stage and duodenum location. Adjuvant chemotherapy (oxaliplatin-based in 89.9%) was performed in 61.5% of patients with locally resected tumours. With a 54-months median follow-up, the 5-year overall survival (OS) was 87.9%, 78.2% and 55.5% in Stages I, II and III, respectively. The median OS of patients with Stage IV was 12.7 months. In patients with resected tumours, poor differentiation (p = 0.047) and T4 stage (p = 0.001) were associated with a higher risk of death. In conclusion, our study showed that the prognosis of advanced SBA remains poor. Tumour characteristics differed according to predisposing disease. In SBA-resected tumours, the prognostic factors for OS were grade and T stage.