Loss of Argininosuccinate Synthetase-1 (ASS1) Occurs in Esophageal Adenocarcinoma and Represents a Promising Biomarker for Therapy with Pegargiminase

Our plain-English summary of Loss of Argininosuccinate Synthetase-1 (ASS1) Occurs in Esophageal Adenocarcinoma and Represents a Promising Biomarker for Therapy with Pegargiminase, by K. Knipper, S.I. Lyu, E. Tzitzili, et al (Cancers, 2025).

The study

• Authors: K. Knipper, S.I. Lyu, E. Tzitzili, S.M. Spielmann, C.J. Bruns, T. Schmidt, F.C. Popp, A. Quaas
• Journal: Cancers
• Published: 2025;17(22)
• Cited by: 2 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

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.

In plain English

This study did not examine asbestos. It was a retrospective study of 97 patients with esophageal adenocarcinoma who had surgery intended to cure the cancer at the University Hospital of Cologne, Germany, between 2007 and 2024. The authors stained tumor tissue for ASS1, a protein cells use to make the amino acid arginine. They first compared three antibodies with an RNA test in 50 tumor samples and chose the one that matched best. Six patients (6.2%) had complete ASS1 loss, and six (6.2%) had low ASS1. In the loss group, the loss was uniform throughout the tumors and their metastases. Patients with loss or low ASS1 were significantly younger. All patients with ASS1 loss who had treatment before surgery showed only a minor response to it. Overall survival did not differ significantly by ASS1 status. The article mentions pleural mesothelioma only to describe other researchers' trials of pegargiminase, a drug aimed at tumors lacking ASS1. The authors concluded that clinical trials of pegargiminase in esophageal adenocarcinoma are warranted. They named the retrospective design and differing antibodies and cut-offs between studies as limitations.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective single-centre cohort study of tumor tissue staining (immunohistochemistry for ASS1), with an antibody comparison against RNAScope RNA testing
• Who was studied: 97 patients with esophageal adenocarcinoma who had curative-intent tumor resection at the University Hospital of Cologne, Germany, 2007 to 2024. Survival analyses included 67 patients with at least 30 days of follow-up. A tissue microarray of 50 patients was used for the antibody comparison.
• Exposure: No asbestos or other fiber exposure was studied. The factor examined was ASS1 protein expression in tumor cells, graded as positive (more than 10% of cancer cells), low positive (more than 0% and no more than 10%), or negative (0%).
• Main results:
  • Of the 97 tumors, 6 (6.2%) showed complete ASS1 loss and 6 (6.2%) showed low ASS1 expression. The majority (87.6%) were ASS1 positive.
  • Patients with ASS1 loss or low ASS1 expression were significantly younger than patients with positive ASS1 expression (p = 0.007).
  • All patients with ASS1 loss who received neoadjuvant therapy (treatment before surgery) showed only a minor response to it. Minor response was defined as 10% or more vital residual tumor cells.
  • Patients with ASS1 loss or low expression more often had neoadjuvant or perioperative therapy, but the difference was not statistically significant (p = 0.063).
  • In the six ASS1-loss patients, the loss was uniform throughout the whole tumor sections. It was also uniform in the corresponding lymph node metastases and in one brain metastasis.
  • Overall survival did not differ significantly between patients with ASS1 loss or low expression (n = 10) and patients with positive ASS1 expression (n = 57) (p = 0.721).
  • A higher Clavien-Dindo grade of surgical complications was associated with positive ASS1 expression (p = 0.018).
  • In multivariable analysis, two factors were independent risk factors for worse overall survival. Severe complications (Clavien-Dindo IIIb or higher) had HR = 4.766 (95% CI 1.450–15.677, p = 0.010). Higher tumor stage ((y)pT 2 or higher) had HR = 4.542 (95% CI 1.363–15.132, p = 0.014). ASS1 status was not among these factors.
• The authors' conclusion: The authors concluded that, because pegargiminase has been effective in other cancer types and a subgroup of esophageal adenocarcinomas lack ASS1, clinical trials of this therapy in esophageal adenocarcinoma are warranted. They also suggested adding ASS1 staining to the assessment of biopsies and tumor specimens.
• Limitations the authors state:
  • The study was retrospective, so the survival (prognostic) analyses could be affected by variables not collected in the data bank.
  • Antibodies and cut-offs used to define ASS1 deficiency vary between studies, which complicates comparison.
  • The authors suggested the lack of a survival difference may be due to small cohort size.

Topics

Medical terms in this study, explained in our Lexicon: Adenocarcinoma, Biomarker, Pegargiminase (ADI-PEG20), Nivolumab (Opdivo), Carcinogenesis, Pleural Mesothelioma, Immunohistochemistry, Neoadjuvant Therapy.

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