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Neoantigens are derived from somatic mutations in the tumors but are absent in normal tissues. Emerging evidence suggests that neoantigens can stimulate tumor-specific T-cell-mediated antitumor immune responses, and therefore are potential immunotherapeutic targets. We developed ImmuneMirror as a stand-alone open-source pipeline and a web server incorporating a balanced random forest model for neoantigen prediction and prioritization. The prediction model was trained and tested using known immunogenic neopeptides collected from 19 published studies. The area under the curve of our trained model was 0.87 based on the testing data. We applied ImmuneMirror to the whole-exome sequencing and RNA sequencing data obtained from gastrointestinal tract cancers including 805 tumors from colorectal cancer (CRC), esophageal squamous cell carcinoma (ESCC) and hepatocellular carcinoma patients. We discovered a subgroup of microsatellite instability-high (MSI-H) CRC patients with a low neoantigen load but a high tumor mutation burden (> 10 mutations per Mbp). Although the efficacy of PD-1 blockade has been demonstrated in advanced MSI-H patients, almost half of such patients do not respond well. Our study identified a subset of MSI-H patients who may not benefit from this treatment with lower neoantigen load for major histocompatibility complex I (P  < 0.0001) and II (P  = 0.0008) molecules, respectively. Additionally, the neopeptide YMCNSSCMGV-TP53G245V, derived from a hotspot mutation restricted by HLA-A02, was identified as a potential actionable target in ESCC. This is so far the largest study to comprehensively evaluate neoantigen prediction models using experimentally validated neopeptides. Our results demonstrate the reliability and effectiveness of ImmuneMirror for neoantigen prediction. [ABSTRACT FROM AUTHOR]

Gastrointestinal (GI) cancers remain a significant global health burden, accounting for a substantial number of cases and deaths. Regrettably, the inadequacy of dependable biomarkers hinders the precise forecasting of patient prognosis and the selection of appropriate therapeutic sequencing for individuals with GI cancers, leading to suboptimal outcomes for numerous patients. The intricate interplay between tumor-infiltrating lymphocytes (TILs) and the tumor immune microenvironment (TIME) has been shown to be a pivotal determinant of response to anti-cancer therapy and consequential clinical outcomes across a multitude of cancer types. Therefore, the assessment of TILs has garnered global interest as a promising prognostic biomarker in oncology, with the potential to improve clinical decision-making substantially. Moreover, recent discoveries in immunotherapy have progressively changed the landscape of cancer treatment and significantly prolonged the survival of patients with advanced cancers. Nonetheless, the response rate remains constrained within solid tumor sufferers, even when TIL landscapes appear comparable, which calls for the development of our understanding of cellular and molecular cross-talk between TIME and tumor. Hence, this comprehensive review encapsulates the extant literature elucidating the TILs’ underlying molecular pathogenesis, prognostic significance, and their relevance in the realm of immunotherapy for patients afflicted by GI tract cancers. Within this review, we demonstrate that the type, density, and spatial distribution of distinct TIL subpopulations carries pivotal implications for the prediction of anti-cancer treatment responses and patient survival. Furthermore, this review underscores the indispensable role of TILs in modulating therapeutic responses within distinct molecular subtypes, such as those characterized by microsatellite stability or programmed cell death ligand-1 expression in GI tract cancers. The review concludes by outlining future directions in TIL-based personalized medicine, including integrating TIL-based approaches into existing treatment regimens and developing novel therapeutic strategies that exploit the unique properties of TILs and their potential as a promising avenue for personalized cancer treatment. [ABSTRACT FROM AUTHOR]

Background: A functional single-nucleotide polymorphism (SNP), 135G>C in the 5'UTR of the RAD51 gene, affects gene transcription activity with implications for the repair of damaged DNA related to tumorigenesis. Previous limited reported genetic studies to link the 135G>C polymorphism of RAD51 gene to the risk of gastrointestinal tract (GIT) cancers, especially esophageal cancer (EC), have been inconclusive. Materials and Methods: The polymorphism was evaluated by RFLP-PCR in 252 EC patients and 252 healthy controls from Amritsar, Punjab, India, for case–control study. For a meta-analysis, a total of 78 studies on GIT cancers were assessed, out of which 14 eligible studies (including the present study) comprising 2842 cases and 3224 controls were included. Odds ratios (ORs) with 95% confidence intervals (CIs) and Chi-square test were used to assess the association in different inheritance models. Results: The GC genotype (OR: 0.45, 95% CI: 0.29–0.68) and C allele (OR: 0.52, 95% CI: 0.36–0.75) were significantly lower (P = 0.0005) in cases as compared to controls. There was no significant association with any genetic model in the meta-analysis. Conclusion: C allele provides protection for EC in the studied population contrary to previous reports in Polish, Chinese population probably due to ethic differences. Compared with previous meta-analysis on individual GIT cancers, present meta-analysis included all GIT cancers but found no association. [ABSTRACT FROM AUTHOR]

Remarkable progress has occurred over the past two decades in identifying microbiomes affecting the human body in numerous ways. The microbiome is linked to gastrointestinal (GI) tract cancer. The purpose of this study was to determine if there is a common microbiome among GI tract cancers and how the microbiome affects the disease. To ensure ethnic consistency, Korean patients with GI tract cancer were selected. Fusobacterium nucleatum is an enriched bacteria in all cancer tissues. F. nucleatum is a Gram-negative obligate anaerobe that promotes colorectal cancer. Through Gene Set Enrichment Analysis (GSEA) and Differentially Expressed Genes (DEG) analyses, the upregulation of the G2M checkpoint pathway was identified in the F. nucleatum-high group. Cell viability and G2M checkpoint pathway genes were examined in MC 38 cells treated with F. nucleatum. F. nucleatum upregulated the expression of G2M checkpoint pathway genes and the cell proliferation of MC 38 cells. F. nucleatum facilitated cancer's use of G2M checkpoint pathways and F. nucleatum could be a therapeutic target in Korean GI tract cancer. [ABSTRACT FROM AUTHOR]

The human gastrointestinal tract, which constitutes the digestive system, contains a large number of virus particles that maintain organizational homeostasis and health. Conversely, viral pathogens have also attracted attention for their involvement in the pathogenesis of certain cancers, including gastrointestinal cancers. To aid prevention and treatment of these cancers, the relevance of gastrointestinal viral factors as potential risk factors needs to be carefully investigated. This review summarizes and discusses the available literature on the relationship between the development of esophageal, gastric, and colorectal cancers and their corresponding viruses. This review reveals that research on the association between colorectal cancer and viruses, in particular, is still in its infancy compared to the association between HPV and esophageal cancer and between EBV and gastric cancer. [ABSTRACT FROM AUTHOR]

Aim: Periodontitis has been proposed to lead to Helicobacter pylori infection, which could cause many gastrointestinal tract cancers. This study aimed to determine the association or otherwise between periodontitis and survival outcomes in individuals with respect to H. pylori infection. Materials and Methods: The study population comprised 4955 subjects aged 20–90 who had received both periodontal examination and H. pylori serum test in the Third National Health and Nutrition Examination Survey (NHANES III) database. Logistic regression models were used to analyse the association between periodontitis and H. pylori seropositivity (H. pylori infection). Survival analysis was performed using the NHANES III linked to mortality data. Cox proportional hazard regression was carried out to investigate the association between periodontitis and gastrointestinal tract cancer mortality in individuals with/without H. pylori infection. Results: Compared to periodontal health, periodontitis was significantly associated with increased odds of H. pylori infection (OR = 1.271, 95% CI = 1.177–1.372). Periodontitis significantly increased the mortality risk from all causes (HR = 1.574, 95% CI = 1.327–1.866) and all cancers (HR = 1.948, 95% CI = 1.701–2.232), including gastrointestinal (GI) tract cancer (HR = 4.140, 95% CI = 3.656–4.687), gastric cancer (HR = 4.288, 95% CI = 3.969–4.632), and colorectal cancer (HR = 4.814, 95% CI = 3.849–6.020) in subjects with H. pylori infection after adjusting for health‐related factors. Periodontitis was significantly related to the decreased survival time in subjects with GI tract (p =.001) or colorectal cancer (p =.002) and H. pylori infection. Conclusion: Our study demonstrated that periodontitis was significantly associated with higher mortality risk of GI tract, gastric, and colorectal cancer in subjects with H. pylori infection. Owing to an interactive effect between periodontitis and H. pylori infection on cancer mortality, H. pylori infection has a significant moderating effect in regulating the association between periodontitis and mortality due to all cancers, including GI tract cancer and colorectal cancer. [ABSTRACT FROM AUTHOR]

Brain metastasis (BM) frequently occurs in patients with cutaneous melanoma, lung, and breast cancer; although, BM rarely arises from cancers of the gastrointestinal tract (GIT). The reported incidence of GIT cancer BM is less than 4%. In the last few years, effective systemic therapy has prolonged the survival of GIT patients and consequently, the incidence of developing BM is rising. Therefore, the epidemiology and biology of BM arising from GIT cancer requires a more comprehensive understanding. In spite of the development of new therapeutic agents for patients with metastatic GIT cancers, survival for patients with BM still remains poor, with a median survival after diagnosis of less than 4 months. Limited evidence suggests that early detection of isolated intra-cranial lesions will enable surgical resection plus systemic and/or radiation therapy, which may lead to an increase in overall survival. Novel diagnostic methods such as blood-based biomarker biopsies may play a crucial role in the early detection of BM. Circulating tumor cells and circulating cell-free nucleic acids are known to serve as blood biomarkers for early detection and treatment response monitoring of multiple cancers. Blood biopsy may improve early diagnosis and treatment monitoring of GIT cancers BM, thus prolonging patients' survivals. [ABSTRACT FROM AUTHOR]

Background Unrestrained eating behavior, as a potential proxy for diet frequency, timing, and caloric intake, has been questioned as a plausible risk factor for digestive system cancers, but epidemiological evidence remains sparse. Objectives We investigated prospectively the associations between unrestrained eating behavior and digestive system cancer risk. Methods Participants in the Nurses' Health Study who were free of cancer and reported dietary information in 1994 were followed for ≤18 y. Cox models were used to estimate HRs and 95% CIs for unrestrained eating (eating anything at any time, no concern with figure change, or both) and risk of digestive system cancers. Results During follow-up, 2064 digestive system cancer cases were documented among 70,450 eligible participants in analyses of eating anything at any time, In total, 2081 digestive system cancer cases were documented among 72,468 eligible participants in analyses of no concern with figure change. In fully adjusted analyses, women with the behavior of eating anything at any time had a higher risk of overall digestive system cancer (HR: 1.22; 95% CI: 1.10, 1.35), overall gastrointestinal tract cancer ((HR: 1.33; 95% CI: 1.18, 1.50), buccal cavity and pharynx cancer (HR: 1.50; 95% CI: 1.02, 2.21), esophageal cancer (HR: 1.62; 95% CI: 1.01, 2.62), small intestine cancer (HR: 1.92; 95% CI: 1.02,3. 59), and colorectal cancer (HR: 1.20; 95% CI: 1.04, 1.38), and a non–statistically significant increased risk of stomach cancer (HR: 1.54; 95% CI: 0.96,2.48), compared with women without this behavior. No statistically significant association was observed for pancreatic cancer and liver and gallbladder cancer. The combined effect of eating anything at any time and having no concern with figure change was associated with a significantly increased risk of overall digestive system cancer (HR: 1.27; 95% CI: 1.10, 1.46), overall gastrointestinal tract cancer (HR: 1.45; 95% CI: 1.23, 1.71), and colorectal cancer (HR: 1.34; 95% CI: 1.11, 1.63), compared with women exhibiting the opposite. Conclusions Unrestrained eating behavior was independently associated with increased risk of gastrointestinal tract cancers. The potential importance of unrestrained eating behavior modification in preventing gastrointestinal tract cancers should be noted. [ABSTRACT FROM AUTHOR]

The widespread use of tumor DNA mismatch repair (MMR) protein immunohistochemistry in gastrointestinal tract (GIT) carcinomas has unveiled cases where the MMR protein status differs between synchronous/metachronous tumors from the same patients. This study aims at examining the frequency, patterns and molecular etiologies of such inter-tumoral MMR discordances. We analyzed a cohort of 2159 colorectal cancer (CRC) patients collected over a 5-year period and found that 1.3% of the patients (27/2159) had ≥ 2 primary CRCs, and 25.9% of the patients with ≥ 2 primary CRCs (7/27) exhibited inter-tumoral MMR discordance. We then combined the seven MMR-discordant CRC patients with three additional MMR-discordant GIT carcinoma patients and evaluated their discordant patterns and associated molecular abnormalities. The 10 patients consisted of 3 patients with Lynch syndrome (LS), 1 with polymerase proofreading-associated polyposis (PAPP), 1 with familial adenomatous polyposis (FAP), and 5 deemed to have no cancer disposing hereditary syndromes. Their MMR discordances were associated with the following etiologies: (1) PMS2-LS manifesting PMS2-deficient cancer at an old age when a co-incidental sporadic MMR-proficient cancer also occurred; (2) microsatellite instability-driven secondary somatic MSH6-inactivation occurring in only one—and not all—PMS2-LS associated MMR-deficient carcinomas; (3) "compound LS" with germline mutations in two MMR genes manifesting different tumors with deficiencies in different MMR proteins; (4) PAPP or FAP syndrome-associated MMR-proficient cancer co-occurring metachronously with a somatic MMR-deficient cancer; and (5) non-syndromic patients with sporadic MMR-proficient cancers co-occurring synchronously/metachronously with sporadic MMR-deficient cancers. Our study thus suggests that inter-tumoral MMR discordance is not uncommon among patients with multiple primary GIT carcinomas (25.9% in patients with ≥ 2 CRCs), and may be associated with widely varied molecular etiologies. Awareness of these patterns is essential in ensuring the most effective strategies in both LS detection and treatment decision-making. When selecting patients for immunotherapy, MMR testing should be performed on the tumor or tumors that are being treated. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this meta-analysis was to assess the associations between inflammatory bowel disease (IBD) and risk of the gastric, small bowel and colorectal cancer. Methods: We searched the PubMed and Web of Science for observational studies published before June 2020, and the quality of each included study was evaluated according to the Newcastle–Ottawa–Scale. Results: Twenty-six studies comprising 531 449 IBD patients and more than 65 million reference individuals were included. Although IBD was significantly associated with 67% increased risk of the total gastric, small bowel and colorectal cancer. After stratifying by cancer location, IBD mainly increased the risk of intestinal cancer instead of gastric cancer. Furthermore, Crohn's disease (CD) significantly increased the risk of both small bowel cancer and colorectal cancer, while ulcerative colitis (UC) only increased the risk of colorectal cancer. In subgroup analysis, associations between IBD and risk of total gastric, small bowel and colorectal cancer were similar between male and female, except for that male IBD patients but not female had a significantly higher risk of small bowel cancer. Additionally, IBD patients in different geographical areas had different associations with risk of various gastrointestinal tract cancers. Conclusions: IBD is mainly associated with increased risk of cancers in the lower gastrointestinal tract, including small bowel cancer and colorectal cancer. Because studies about the association between IBD and risk of gastric cancer and the populations in Asia are limited, more observational studies are required in the future. [ABSTRACT FROM AUTHOR]

Aim: To investigate the co-existence of cholelithiasis in patients with gastrointestinal (GI) cancer both in preoperative and postoperative periods. Methods: We retrospectively analyzed the data of patients who underwent GI tract cancer surgery in the general surgery clinic of a university hospital between January 2013 and December 2019 for the presence of 'cholelithiasis' in the preoperative and postoperative periods. Age, gender, tumor type and localization and presence of the cholelithiasis in the patients were determined. In addition, the cases were divided into two as upper GI tract and lower GI tract according to tumor location and the relationship with cholelithiasis was evaluated. Results: A total of 680 GI cancer patients were included in the study. Localization of GI cancers were; colon in 211 cases (31%), rectum in 195 cases (28.7%), gastric in 187 cases (27.5%), periampullary region in 55 cases (8.1%), and small intestine in 32 cases (4.7%). In the preoperative period, 69 (10.1%) patients were associated with cholelithiasis. Thirty-one (5.1%) patients had accompanying cholelithiasis in the postoperative period. Coexistence of cholelithiasis according to cancer location was not statistically significant in the preoperative and postoperative periods. Conclusions: Our available data make it difficult to distinguish the roles of cholelithiasis on gastrointestinal cancers, because no statistically causal relationship was found between cholelithiasis and gastrointestinal cancers. However, the role of asymptomatic and symptomatic stones, which may or may not require cholecystectomy, in the development of GI tract cancers should not be ignored. [ABSTRACT FROM AUTHOR]

Background/Aim: The aim of this study was to examine the efficacy and safety of direct oral anticoagulants for cancer-associated venous thromboembolism (VTE) in patients with active cancer . Patients and Methods: This study included patients with advanced unresectable/metastatic upper gastrointestinal (GI) or hepatopancreatobiliary (HPB) cancers with high risks of VTE and bleeding. Results: No significant differences were noted in potential bleeding factors between the rivaroxaban (n=105) and low-molecular-weight heparin (LMWH) (n=69) groups. Rivaroxaban exhibited similar risk of recurrent/aggravated VTE compared with LMWH (p=0.625) but increased risk of major bleeding (17.4% vs. 7.6%; p=0.072), clinically relevant bleeding (31.9% vs. 14.3%; p=0.019), and total bleeding (40.6% vs. 19%; p=0.010). The multivariate analysis regarded rivaroxaban as a significant factor for major bleeding (p=0.043) and clinically relevant bleeding (p=0.043). Conclusion: Rivaroxaban exhibits comparable efficacy but increases bleeding risks compared with LMWH in patients with active unresectable/metastatic upper GI tract or HPB cancers, requiring extra caution of higher major bleeding risks. [ABSTRACT FROM AUTHOR]

An altered oral microbiota has been linked with the development of several oral diseases, such as dental caries, periodontal disease, and oral stomatitis. Moreover, poor oral health has been linked to head and neck cancer, particularly oral cancer. In recent years a growing number of studies indicate that oral microbiota could be involved in the development of primary tumours outside of head and neck region. The aim of this article is to review the recent studies based on high-throughput technology to present evidences of a relationship between oral microbiota and "non-head and neck tumours." Oral dysbiosis seem to be more pronounced in patients with tumours of gastrointestinal tract, in particular oesophageal, gastric, pancreatic, and colorectal cancers, paving the way for developing specific oral microbiota test to allow early cancer detection. Regarding other tumour types, the results are promising but highly preliminary and still debated. Currently, there are several factors that limit the generalization of the results, such as the small sample size, the lack of adequate clinical information about patients, the different sequencing techniques used, and biological sample heterogeneity. Although only at the beginning, the analysis of oral microbiota could be the next step in the evolution of cancer therapy and will help clinicians to develop individualised approaches to cancer prevention and treatment. [ABSTRACT FROM AUTHOR]

Enhancement of antibody-dependent cellular cytotoxicity (ADCC) with some modalities may be a promising approach to enhance the efficacy of therapeutic monoclonal antibodies (mAbs). It has previously been demonstrated that the removal of fucose from antibody oligosaccharides (defucosylation) leads to augmentation of ADCC activity. To establish clinically relevant evidence of this procedure, the present study evaluated trastuzumab- and cetuximab-mediated ADCC by comparing defucosylated mAbs with conventional mAbs using peripheral blood mononuclear cells (PBMCs). PBMCs were isolated from 20 patients with gastrointestinal tract cancer and 10 healthy volunteers. ADCCs were measured using PBMCs as effector cells and two gastric cancer cell lines as target cells. ADCCs were significantly enhanced with defucosylated mAbs compared with conventional mAbs using PBMC from the healthy donors and patients with cancer. The results confirmed that the cetuximab- and trastuzumab-mediated ADCCs in advanced disease were impaired in comparison to those in early disease or healthy individuals. However, when the defucosylated mAbs were used instead of the conventional mAbs, the ADCC activities in the advanced cases were almost comparable with those in early disease or healthy individuals. Furthermore, the expression of ADCC associated molecules were modified toward immunosuppressive status with a mitogen-activated protein kinase inhibitor in vitro, the conventional cetuximab- and trastuzumab-mediated ADCC was downregulated, and the defucosylated mAbs overcome the downregulation of ADCC. In conclusion, defucosylated therapeutic mAbs may enhance ADCC activities in patients with cancer, which may lead to more effective anti-cancer treatments. [ABSTRACT FROM AUTHOR]

Purpose: This study seeks to evaluate the natural history, outcome, and possible prognostic factors in patients with brain metastases derived from gastrointestinal cancers. Methods: The clinical features, prognostic factors, and the effects of different treatment modalities on survival were retrospectively investigated in 103 patients with brain metastases derived from gastrointestinal cancers. Results: The median time from diagnosis of primary tumor to brain metastasis was 22.00 months. The interval between diagnosis of primary tumor relapse and brain metastasis was 8.00 months. The median follow-up time was 7.80 months. The median survival time after diagnosis of brain metastases was 4.10 months for all patients and 1.17 months for patients who received only steroids (36.9 %), 3.97 months for patients who only received whole-brain radiation therapy (WBRT 31.1 %), 11.07 months for patients who received gamma-knife surgery alone or/and WBRT (20.4 %), and 13.70 months for patients who underwent surgery and radiotherapy (12 patients, 11.6 %) ( P < 0.001). Multivariate analysis revealed that recursive partitioning analysis (RPA) class, extracranial metastasis, and chemotherapy were independent prognostic factors. Brain metastasis derived from gastrointestinal tract cancer is rare, and overall patient survival is poor. Conclusion: RPA class, chemotherapy after brain metastases, and treatment regimens were independent prognostic factors for the survival of patients with brain metastases derived from gastrointestinal cancers. [ABSTRACT FROM AUTHOR]

Purpose: In order to broaden the possibility for anti-MAGE-3 immune targeting, it is important to identify HLA-A24-restricted epitopes derived from MAGE-3, since HLA-A24 is one of the most common alleles in Japanese and Asian people. In the present study, we defined a new MAGE-3 derived, HLA-A24-binding peptide presented as a CTL epitope on gastrointestinal cancer cells. Materials and Methods: A panel of MAGE-3-derived peptides (9mer and 10mer) with the HLA-A24-binding motif was selected, and identification of MAGE-3-derived, HLA-A24-restricted CTL epitopes was performed by a reverse immunology approach. To induce MAGE-3-peptide specific CTLs, PBMCs were repeatedly stimulated with monocyte-derived, mature DCs pulsed with the peptides. Subsequent peptide-induced T cells were tested for their specificities by ELISPOT, tetramer and cytotoxic assay. CTL clones were then obtained from the CTL line by limiting dilution. Results: The peptide-inducing CTLs revealed that MAGE-3(113)-peptide was reacted as a CTL epitope in a HLA-A24-restricted fashion, confirmed by ELISPOT and cytotoxic assays. In addition, the MAGE-3(113)-specific CTL clones, confirmed by tetramer assay, showed that the MAGE-3(113) epitope is naturally processed and presented as the CTL epitope on MAGE-3-expressing gastrointestinal cancer cells by evaluating the cold target inhibition assays. Conclusion: The newly identified MAGE-3(113)-peptide epitope is naturally processed and presented as the CTL epitope on MAGE-3-expressing gastrointestinal cancer cells, indicating that anti-MAGE-3 immune targeting with the MAGE-3(113) peptide is a promising approach for treatment. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Immunotherapy has become the standard-of-care in many solid tumors. Despite the significant recent achievements in the diagnosis and treatment of cancer, several issues related to patients' selection for immunotherapy remain unsolved. Multiple lines of evidence suggest that, in this setting, the vision of a single biomarker is somewhat naïve and imprecise, given that immunotherapy does not follow the rules that we have experienced in the past for targeted therapies. On the other hand, additional immune-related biomarkers that are reliable in real-life clinical practice remain to be identified. Recently, the immune-checkpoint blockade has been approved in the US irrespective of the tumor site of origin. Further histology-agnostic approvals, coupled with with tumor-specific companion diagnostics and guidelines, are expected in this field. In addition, immune-related biomarkers can also have a significant prognostic value. In this review, we provide an overview of the role of these biomarkers and their characterization in the management of lung cancer, melanoma, colorectal cancer, gastric cancer, head and neck cancer, renal cell carcinoma, urothelial cancers, and breast cancer. [ABSTRACT FROM AUTHOR]

The use of immunohistochemistry (IHC) as a companion diagnostic is an increasingly important part of the case workup by pathologists and is often central to clinical decision making. New predictive molecular markers are constantly sought for to improve treatment stratification parallel to drug development. Unfortunately, official biomarker guidelines lag behind, and pathologists are often left hesitating when medical oncologists request off-labelled biomarker testing. We performed a literature review of five commonly requested off-label IHC predictive biomarkers in gastrointestinal tract (GIT) malignancies: HER2, mismatch repair (MMR), PD-L1, BRAF V600E and ROS1. We found that HER2 amplification is rare and poorly associated to IHC overexpression in extracolonic and extragastric GIT cancers; however in KRAS wild type colorectal cancers, which fail conventional treatment, HER2 IHC may be useful and should be considered. For MMR testing, more evidence is needed to recommend reflex testing in GIT cancers for treatment purposes. MMR testing should not be discouraged in patients considered for second line checkpoint inhibitor therapy. With the exception of gastric tumors, PD-L1 IHC is a weak predictor of checkpoint inhibitor response in the GIT and should be replaced by MMR in this context. BRAF inhibitors showed activity in BRAF V600E mutated cholangiocarcinomas and pancreatic carcinomas in non-first line settings. ROS1 translocation is extremely rare and poorly correlated to ROS1 IHC expression in the GIT; currently there is no role for ROS1 IHC testing in GIT cancers. Overall, the predictive biomarker literature has grown exponentially, and official guidelines need to be updated more regularly to support pathologists' testing decisions. [ABSTRACT FROM AUTHOR]