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Exploring novel therapeutic targets in small bowel adenocarcinoma: insights from claudin 18.2, nectin-4, and HER3
1Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
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.
Insights
Nectin-4 expression in small bowel adenocarcinoma (SBA) is linked to shorter survival and may indicate a poor prognosis. Claudin 18.2, nectin-4, and HER3 show potential as new antibody drug targets for SBA treatment.
Area of Science:
- Oncology
- Gastroenterology
- Translational Research
Background:
- Small bowel adenocarcinoma (SBA) is a rare cancer with limited treatment options and poor outcomes.
- Investigating novel biomarkers is crucial for developing targeted therapies for SBA.
Purpose of the Study:
- To evaluate 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 analyze their association with clinicopathological features and prognosis.
Main Methods:
- Retrospective review of 51 SBA patients treated between 2010 and 2023.
- Immunohistochemical staining for claudin 18.2, nectin-4, HER3, and PD-L1.
- Overall survival (OS) analysis in relation to protein expression, excluding microsatellite instability-high cases.
Main Results:
- High expression rates for nectin-4 (82%) and HER3 (88%) were observed; 35% expressed claudin 18.2.
- Nectin-4 positivity was significantly associated with shorter OS (12.6 vs. 43.2 months, HR 5.12, P=0.006).
- PD-L1 positivity (CPS ≥5) and nectin-4 positivity were independent adverse prognostic factors for OS.
Conclusions:
- Claudin 18.2, nectin-4, and HER3 are promising therapeutic targets for SBA.
- Nectin-4 positivity is an independent predictor of unfavorable prognosis in SBA patients.
- Targeting these proteins may offer new therapeutic strategies for small bowel adenocarcinoma.
