Claudin 18.2 determination in locally advanced gastric and gastroesophageal adenocarcinoma treated with neoadjuvant chemotherapy.
Authors: Gervaso Lorenzo , Cella Chiara Alessandra , Lobrano Renato , De Pascale Stefano , Benini Lavinia , Spada Francesca , De Roberto Giuseppe , Fumagalli Romario Uberto , Guerini Rocco Elena , Fazio Nicola 
Published: January 2025

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Background:
Gastric and esophago-gastric adenocarcinoma (GAC) represent a major unmet need. For tumors amenable with curative intent, prognosis remains poor with 5-year survival rates below 40%. Several strategies have been added to surgery including peri-operative chemotherapy which represents the standard of care for locally advanced GAC. Claudins is a family of transmembrane junctional proteins which acts in paracellular permeability, transport and communication. Claudin 18.2 (CLDN), a tissue-specific variant, is physiologically expressed in both gastric mucosa and gastric cancer. In metastatic GAC, CLDN positivity settles around 40% of cases and the addition of target therapy zolbetuximab to chemotherapy resulted in a significant improvement in overall survival. However, limited data are present about CLDN in early-stage disease. The aim of our study is to assess rates of expression of CDLN in locally advanced GAC treated with neoadjuvant chemotherapy and correlate it with clinical outcomes.
Methods:
We conducted a multi-omics prospective trial at IEO enrolling patients with locally advanced GAC treated with peri-operative chemotherapy and surgery. Pre-chemotherapy endoscopic samples were selected for CDLN determination. Positive cases were defined as moderate-to-strong membranous staining in ≥ 75% of tumor cells by IHC using the VENTANA CLDN18 (43-14A) Assay. CLDN expression was analyzed for correlation with pathologic complete response (pCR), tumor regression grade (TRG), event‐free survival (EFS), and overall survival (OS). Survival was calculated using Kaplan–Meier method and log-rank tests. Statistical analyses were performed using SPSS software (version 29.0.2.0).
Results:
We included 48 patients, 67% male, median age 62 years (35-78). 31 tumors originated from gastric body, 14 from the junctional region and 4 from distal esophagus. Most frequent histotypes were diffuse (43%) and tubular (39%). Five cases (11%) presented microsatellite instability. All patients received neoadjuvant chemotherapy, mainly FLOT (92%) and underwent surgery, with 93% of R0 resection. Three patients (6%) achieved pCR and 18 had a TRG 1A or B. Of the total, 20 cases were defined as positive (42%). After a median follow-up of 20 months, 12 patients relapsed and 3 died. No significant association was observed for CDLN positivity and pCR or TRG1 rate, as well as for primary site or histotype. PFS and OS were not statistically different according to claudin status, even though numerically shorter in CDLN positive cases (PFS: 31 vs 33 months, p=.43; OS: 36 vs 39 months, p =.10).
Conclusions:
In our study of locally advanced GAC, rate of CDLN positivity was 40%, similarly to advanced stage. However, no differences in pCR rate, regression grade and survival outcomes have been observed. Larger studies and longer follow-up are required to assess the impact of CDLN in early-stage GAC.