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Claudin-18 expression in small bowel adenocarcinoma: a clinico-pathologic study.

ABSTRACT: Non-ampullary small bowel adenocarcinoma is a rare neoplasm with an ominous prognosis, whose incidence is higher in some chronic immuno-inflammatory conditions, such as coeliac and Crohn's disease. Recently, claudin 18.2, a transmembrane protein normally expressed in gastric mucosa, has been recognized as a novel pan-cancer therapeutic target, and several clinical trials with claudin-18-directed drugs have shown promising results on various gastrointestinal malignancies. This is the first study focusing on claudin-18 expression in small bowel adenocarcinomas. The immunohistochemical expression of claudin-18 (clone 43-14A) was assessed in 81 small bowel adenocarcinomas of diverse aetiologies and correlated with several clinico-pathologic features and patient survival. We found that 28% of adenocarcinomas were immunoreactive for claudin-18, with cutoff values of ≥1% at any intensity, while 6% of cancers showed immunoexpression of ≥75% with 2+/3+ score. Moreover, claudin-18 (≥1%) was positively associated with cytokeratin 7 (CK7) and MUC5AC expression, showing CK7+/MUC5AC+ carcinomas the highest rate of positive cases, whereas a negative correlation was found between claudin-18 and CDX2 expression. In addition, some cancer-adjacent dysplastic growths and foci of gastric-type metaplasia in Crohn's disease-associated cases showed claudin-18 immunoreactivity. Survival analysis showed a non-significant trend towards a worse cancer-specific survival for claudin-18-positive cases. A fraction of small bowel adenocarcinomas, mainly sporadic or Crohn's disease-associated, and often exhibiting a non-intestinal immunoprofile, expressed claudin-18, suggesting that claudin-18-directed targeted therapy is worth investigating in such cancers.

SUBMITTER: Arpa G

PROVIDER: S-EPMC9734203 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Claudin-18 expression in small bowel adenocarcinoma: a clinico-pathologic study.

Arpa Giovanni G Fassan Matteo M Guerini Camilla C Quaquarini Erica E Grillo Federica F Angerilli Valentina V Guzzardo Vincenza V Lonardi Sara S Bergamo Francesca F Lenti Marco Vincenzo MV Pedrazzoli Paolo P Paulli Marco M Di Sabatino Antonio A Vanoli Alessandro A

Virchows Archiv : an international journal of pathology 20220804 6

Non-ampullary small bowel adenocarcinoma is a rare neoplasm with an ominous prognosis, whose incidence is higher in some chronic immuno-inflammatory conditions, such as coeliac and Crohn's disease. Recently, claudin 18.2, a transmembrane protein normally expressed in gastric mucosa, has been recognized as a novel pan-cancer therapeutic target, and several clinical trials with claudin-18-directed drugs have shown promising results on various gastrointestinal malignancies. This is the first study ...[more]

PMID: 35925388

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Project description:BackgroundSmall bowel adenocarcinoma (SBA) is a rare malignancy with few established chemotherapy options and a dismal prognosis. We investigated the expression of claudin 18.2, nectin-4, human epidermal growth factor receptor 3 (HER3), and programmed death-ligand 1 (PD-L1) in SBA to identify potential antibody drug targets and analyzed associated clinicopathological features and prognosis.Materials and methodsWe retrospectively reviewed patients diagnosed with SBA who underwent adjuvant or palliative chemotherapy at our hospital between July 2010 and July 2023. Pathological samples were immunohistochemically stained for claudin 18.2, nectin-4, HER3, and PD-L1. Overall survival (OS) was assessed in patients receiving palliative chemotherapy to examine its association with the expression of each protein, excluding those with microsatellite instability-high who were treated with immunotherapy.ResultsPathological samples and clinical data were available for 51 patients. The primary lesion was in the duodenum in 49% of these patients and in the jejunum or ileum in 51%. Positive rates for claudin 18.2, nectin-4, and HER3 were 35%, 82%, and 88%, respectively. All cases expressed at least one of the proteins, and 25% expressed all three proteins. The PD-L1 combined positive score (CPS) was <1, 1-5, and ≥5 in 33%, 32%, and 35%, respectively; nectin-4-positive samples showed higher CPS. Neither claudin 18.2 nor HER3 positivity was associated with OS. However, nectin-4 positivity was associated with significantly shorter OS [12.6 versus 43.2 months, hazard ratio (HR) 5.12, P = 0.006]. Similarly, PD-L1 CPS ≥5 was associated with shorter OS relative to CPS <5 (9.7 versus 18.0 months, HR 2.60, P = 0.028). Multivariate analysis identified nectin-4 positivity (HR 4.55, P = 0.020) as an independent adverse prognostic factor for OS.ConclusionsClaudin 18.2, nectin-4, and HER3 are potential therapeutic targets in SBA, and nectin-4 positivity is independently associated with an unfavorable prognosis. These proteins may represent new therapeutic targets for SBA.

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.

Dataset Information

Claudin-18 expression in small bowel adenocarcinoma: a clinico-pathologic study.

Publications

Claudin-18 expression in small bowel adenocarcinoma: a clinico-pathologic study.

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