Abstract 5200: Patient-derived esophageal squamous cell carcinoma organoids and analysis of MDR1 expression levels in clinical specimens for promoting personalized medicine

Abstract Background: Esophageal cancer is the 7th leading cause of cancer-related mortality as of 2022, with esophageal squamous cell carcinoma (ESCC) comprising 90% of cases in Japan. The Japanese Clinical Oncology Group (JCOG) reported that preoperative DCF therapy (Docetaxel + Cisplatin + 5-Fluorouracil) improves prognosis over CF therapy (Cisplatin + 5-Fluorouracil). However, some patients exhibit resistance to DCF therapy, leading to recurrence or metastasis post-surgery. Tumor heterogeneity contributes to these outcomes. MDR1, a multidrug resistance protein, shows variable expression levels, and cancer tissues are composed of tumor cells alongside diverse microenvironmental components. To address this, accurate models are essential. Recently, three-dimensional patient-derived organoids (3D-PDOs) have gained attention as cost-effective platforms replicating cancer heterogeneity. Method: 3D-PDOs were derived from pre-treatment ESCC biopsy specimens. Their histological morphology was compared with clinical specimens, and responses to Docetaxel, Cisplatin, and 5-Fluorouracil were assessed. Additionally, 78 ESCC cases treated with preoperative DCF therapy followed by surgery (2012-2018) were analyzed. Immunohistochemistry (IHC) was performed on biopsy specimens to evaluate MDR1 expression and its association with prognosis. Results: 3D-PDOs formed three-dimensional epithelial aggregates. ESCC PDOs exhibited irregular edges compared to the spherical, well-defined shapes of normal PDOs. IHC revealed protein expression variability in 3D-PDOs, reflecting clinical specimen heterogeneity. Expression trends in PDOs matched those in clinical samples, demonstrating their histological accuracy. In one case, a therapeutic experiment with Docetaxel, Cisplatin, and 5-Fluorouracil showed significant efficacy for Docetaxel and Cisplatin but resistance to 5-Fluorouracil. MDR1 analysis in biopsy specimens indicated MDR1-positive cases had significantly shorter recurrence-free survival than MDR1-negative cases, though no significant difference was observed in 5-year overall survival. MDR1 IHC on 3D-PDOs used in treatment experiments confirmed MDR1 expression, consistent with observed 5-FU resistance and suggesting a high recurrence risk in this case. Conclusion: 3D-PDOs are valuable for analyzing histological features and therapeutic resistance in heterogeneous ESCC cases. MDR1 analysis demonstrated potential utility in predicting postoperative recurrence risk, supporting its role in personalized treatment strategies. Citation Format: Yasushige Takeda, Kazuhiro Noma, Hajime Kashima, Akito Shimizu, Tasuku Matsumoto, Seitarou Nishimura, Tatsuya Takahashi, Hijiri Matsumoto, Kento Kawasaki, Tomoyoshi Kunitomo, Maeda Naoaki, Satoru Kikuchi, Shunsuke Tanabe, Toshiaki Oohara, Hiroshi Tazawa, Hiroshi Nakagawa, Toshiyoshi Fujiwara. Patient-derived esophageal squamous cell carcinoma organoids and analysis of MDR1 expression levels in clinical specimens for promoting personalized medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5200.