Exploring novel therapeutic targets in small bowel adenocarcinoma: insights from claudin 18.2, nectin-4, and HER3 expression analysis.

BACKGROUND

Small 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 METHODS

We 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.

RESULTS

Pathological 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.

CONCLUSIONS

Claudin 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.