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September 10, 2025

Prognostic Indicators of Preoperative Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel Efficacy in Locally Advanced Gastroesophageal and Gastric Cancer: Integrating Biomarker Analysis and Clinicopathological Factors

Key Points

Major pathological response rates were 22.4% in patients with resectable gastric cancer, indicating the efficacy of preoperative FLOT.
Among 116 patients, 30.2% exhibited CLDN18.2 positivity, and maintained positivity was more common in those without major pathological response.
HER2 and PD-L1 statuses did not correlate with pathological response to preoperative FLOT, raising questions about their predictive role.
CLDN18.2 expression decreased significantly after treatment, suggesting the potential need for further investigation of targeted therapies.

Abstract

PURPOSE Perioperative fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) is a standard treatment for locally advanced gastric/gastroesophageal junction cancer (GC/GEJC). The impact of biomarker status on the efficacy of perioperative FLOT remains unclear. This study evaluated the association between clinicopathological features, including biomarker status, and the efficacy of perioperative FLOT in patients with resectable GC/GEJC. PATIENTS AND METHODS A retrospective observational study was conducted by reviewing medical records of patients treated with perioperative FLOT between February 2020 and March 2024. Eligible patients had histologically confirmed adenocarcinoma, resectable disease at stages cT2-4a and/or N0-3, M0, and underwent biomarker testing. RESULTS Among 116 eligible patients, human epidermal growth factor receptor 2 (HER2) positivity was observed in 7.8%, whereas PD-L1 combined positive score (CPS) of ≥1, ≥5, and ≥10 was detected in 90.5%, 44.0%, and 15.5% of patients, respectively. Claudin-18 isoform 2 (CLDN18.2) positivity (2+/3+ in ≥75% of tumor cells) was observed in 30.2% of patients. Major pathological response (MPR) and pathological complete response (pCR) rates were 22.4% (95% CI, 15.3 to 31.0) and 8.6% (95% CI, 4.2 to 15.3), respectively. Diffuse-type histology was a negative indicator for pathological response. CLDN18.2 expression decreased significantly after preoperative FLOT, with the median H-score declining from 285.0 to 187.5 ( P < .001) in patients with CLDN18.2 positivity at initiation. Maintained CLDN18.2 positivity was more frequently observed in patients without MPR compared with those with MPR (53.8% v 12.5%, P = .05). CONCLUSION HER2, PD-L1, and CLDN18.2 statuses were not linked to pathological response to FLOT in resectable GC/GEJC. CLDN18.2 expression significantly decreased after preoperative FLOT but remained higher in patients without MPR, suggesting that CLDN18.2-targeted therapy may warrant investigation in the perioperative setting.

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