Background/Objectives: Despite the introduction of targeted therapies such as Nivolumab, survival outcomes for patients with esophageal adenocarcinoma remain poor. During tumorigenesis, some tumors develop auxotrophy by downregulation of Argininosuccinate Synthetase-1 (ASS1), making them reliant on external arginine supply and thus potentially susceptible to arginine deprivation therapy. Arginine deprivation therapy with agents such as pegargiminase has shown improved survival in patients with pleural mesothelioma exhibiting ASS1 loss in tumor cells. Therefore, we investigated the prevalence of ASS1 loss in esophageal adenocarcinoma.Methods: First, we compared the staining patterns of three antibodies for ASS1 with RNA in situ Scope analysis results to identify the most reliable antibody for ASS1 immunohistochemical staining in esophageal adenocarcinoma. Subsequently, we performed ASS1 immunohistochemical staining on samples from 97 patients who underwent curative resection. The staining results were classified into three categories based on expression levels: negative, low-positive, and positive.Results: Among all included patients, 6.2% exhibited an ASS1 loss, and 6.2% showed low ASS1 expression. Notably, patients with an ASS1 loss did not demonstrate a response to neoadjuvant therapy. Patients with ASS1 loss or low expression were significantly younger.Conclusions: Our findings indicate that approximately 12.4% of patients with esophageal adenocarcinoma may be eligible and could potentially benefit from arginine deprivation therapy. This underscores the urgent need for clinical trials evaluating the efficacy of pegargiminase in this patient population. Additionally, incorporating ASS1 immunohistochemical staining into pre-neoadjuvant biopsy assessments should be considered to optimize neoadjuvant treatment strategies and advance the implementation of personalized cancer therapy.
背景/目的：尽管已引入纳武利尤单抗等靶向疗法，食管腺癌患者的生存预后仍不理想。在肿瘤发生过程中，部分肿瘤通过下调精氨酸琥珀酸合成酶-1（ASS1）表达产生营养缺陷型代谢，使其依赖外源性精氨酸供应，从而可能对精氨酸剥夺疗法敏感。针对肿瘤细胞存在ASS1缺失的胸膜间皮瘤患者，聚乙二醇化精氨酸酶（pegargiminase）等药物介导的精氨酸剥夺疗法已显示出生存获益。因此，本研究旨在探究食管腺癌中ASS1缺失的发生率。 方法：首先，我们通过对比三种ASS1抗体的染色模式与RNA原位Scope分析结果，筛选出适用于食管腺癌ASS1免疫组化染色的最可靠抗体。随后，对97例接受根治性切除术患者的样本进行ASS1免疫组化染色。根据表达水平将染色结果分为三类：阴性、低阳性和阳性。 结果：在所有纳入患者中，6.2%存在ASS1缺失，另有6.2%表现为ASS1低表达。值得注意的是，ASS1缺失患者对新辅助治疗无应答。ASS1缺失或低表达患者的年龄显著更轻。 结论：本研究结果表明，约12.4%的食管腺癌患者可能适合并有望从精氨酸剥夺疗法中获益。这凸显了开展临床试验评估聚乙二醇化精氨酸酶对该患者群体疗效的迫切需求。此外，应考虑将ASS1免疫组化染色纳入新辅助治疗前活检评估体系，以优化新辅助治疗策略，推动个体化癌症治疗的实践。
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