Protein expression of claudin 18.2, Nectin-4, HER-3, and PD-L1 in small bowel adenocarcinoma: Exploring potential targets of antibody drugs.
Authors: Fujii Hiroyuki , Shoji Hirokazu , Hirano Hidekazu , Hirose Toshiharu , Okita Natsuko Tsuda , Takashima Atsuo , Kato Ken 
Published: June 2024

4176

Background: Small bowel adenocarcinoma (SBA) is a rare cancer and improved treatment strategies are needed. To explore potential targets of existing antibody drugs for SBA, we examined the protein expression of Claudin 18.2, Nectin-4, HER-3, and PD-L1 in SBA and analyzed the associated clinicopathological features and prognosis. Methods: We retrospectively reviewed patients diagnosed with SBA who underwent adjuvant or palliative chemotherapy between July 2010 and July 2023 at our hospital. Immunohistochemistry staining of Claudin 18.2, Nectin-4, HER-3, and PD-L1 was performed for pathological samples. We also assessed overall survival (OS) in patients receiving palliative chemotherapy to examine the association between prognosis and expression of each protein, excluding patients with microsatellite instability-high (MSI-H) treated with immunotherapy. Results: Pathological samples and clinical data were available for 51 patients aged 23–82 years. The primary lesion was in the duodenum in 49% of these patients and in the jejunum or ileum in 51%. There was no recurrence after surgery and adjuvant chemotherapy in 12% of the patients, while 88% received oxaliplatin-based palliative chemotherapy for unresectable SBA. Among those with unresectable SBA, 4 (8%) had MSI-H and were treated with immunotherapy. Claudin 18.2, Nectin-4, and HER-3 positivity was 35%, 82%, and 88%, respectively. All cases had expression of at least one of these molecules, and 25% had expression of all three. Two molecules were co-expressed in 55% of the patients, most frequently Nectin-4 and HER-3. Nectin-4 expression was observed in all primary lesions in the jejunum or ileum (100%), compared with 60% in the duodenum ( p < 0.001). The distribution of combined positive score (CPS) for PD-L1 was < 1, 1-5, and ≥ 5 for 33%, 32%, and 35%, respectively. CPS was higher in Nectin-4 positive samples compared with negative samples (median CPS 2.5% vs 0%, p = 0.077). Among patients receiving palliative chemotherapy, OS did not differ according to the Claudin 18.2 expression (17.0 vs. 13.7 months, HR 0.91, p = 0.800) or HER-3 expression (17.0 vs. 9.7 months, HR 0.40, p = 0.166). However, patients with Nectin-4 expression had significantly shorter OS than those without Nectin-4 expression (12.6 vs. 43.2 months, HR 5.12, p = 0.006). Similarly, OS was shorter in patients with PD-L1 CPS ≥ 5 compared with CPS < 5 (9.7 vs. 18.0 months, HR 2.60, p = 0.028). Multivariate analysis revealed that Nectin-4 expression (HR 4.55, p = 0.020) was an independent adverse prognostic factor for OS. Conclusions: Claudin 18.2, Nectin-4, and HER-3 are highly expressed in SBA, indicating they are potential targets for existing antibody drugs. In particular, Nectin-4-positive SBA exhibited poor prognosis and high PD-L1 expression, suggesting that a combination of immunotherapy and Nectin-4-targeting therapy may be effective.