위암 환자에서의 claudin 18.2 발현 양상에 대한 병리학적 분석

Abstract

Claudin 18.2 is a tight junction protein expressed on the cellular surface of normal gastric epithelium, and its expression is frequently upregulated in gastric cancer. Due to the recent success of zolbetuximab - a monoclonal antibody agent targeting claudin 18.2 - in two phase 3 trials (SPOTLIGHT and GLOW), it has emerged as a promising therapeutic target in gastric cancer. In this systematic study, the same antibody clones and evaluation methods were utilized for assessing claudin 18.2 expression, to provide the consistency of the overall analysis.

Part 1 of this study focused on investigating the clinicopathologic features and survival outcomes of claudin 18.2 positive tumors in patients with stage I-III gastric cancer. This study aimed to provide insights for the potential application of claudin 18.2-targeted treatment in earlier stages of gastric cancer. Claudin 18.2 positivity was observed in 46.5% of the total 299 patients, with slightly higher rate among stage I patients (51.1%). Claudin 18.2 positivity was associated with a younger age (median, 61 vs 66 years, p<0.001), a shallower depth of invasion (p=0.014), Borrmann type 4 morphology (p=0.008) and diffuse histological type (p=0.011). However, it was not an independent prognostic factor in a localized setting. These findings aligned with previous research conducted in patients with advanced gastric cancer.

In part 2, the heterogeneity of claudin 18.2 expression was investigated in 166 patients with stage IV gastric cancer. paired tissue samples of primary and metastatic tumors from 135 of these patients were thoroughly analyzed, revealing a concordance rate over 50%. Notably, patients with peritoneal metastasis displayed the highest rate of claudin 18.2 positivity, suggesting that patients with peritoneal metastasis could potentially derive the greatest benefit from claudin 18.2-targeted therapy in terms of systemic disease control. Furthermore, this study provided specific cutoff values to maximize the efficacy of claudin 18.2-targeted treatment, recommending a threshold of 120 for H-score and 30% for the percentage of tumor cells exhibiting moderate to strong intensity. Additionally, this study revealed a high prevalence of intratumoral heterogeneity, pointing out the limitations of endoscopic biopsy in representing the entire tumor characteristics. These findings may provide a deeper insight for the complexities of claudin 18.2 expression status in stage IV gastric cancer.