2. Academic Validation
  3. TROP2 expression and therapeutic targeting in uterine carcinosarcoma

TROP2 expression and therapeutic targeting in uterine carcinosarcoma

  • Gynecol Oncol. 2025 Jun:197:129-138. doi: 10.1016/j.ygyno.2025.04.590.
Sara Moufarrij 1,  Higinio Dopeso 2,  David N Brown 2,  Hunter Green 2,  Kaitlyn Gill 2,  Julia Tengelin 2,  Melica N Brodeur 2,  William A Zammarrelli 3rd 1,  Nancy Varice 2,  Michelle Wu 2,  Achim Jungbluth 2,  Yingjie Zhu 2,  Xiaoping Chen 3,  Arnaud Da Cruz Paula 1,  Thais Basili 2,  Elisa de Stanchina 3,  Nadeem R Abu-Rustum 4,  Carol Aghajanian 5,  Lora H Ellenson 2,  M Herman Chui 2,  Britta Weigelt 6
Affiliations

Affiliations

  • 1 Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 2 Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 3 Antitumor Assessment Core Facility, Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
  • 4 Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of OB/GYN, Weill Cornell Medical College, New York, NY, USA.
  • 5 Gynecologic Medical Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
  • 6 Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: weigeltb@mskcc.org.
PMID: 40344963 DOI: 10.1016/j.ygyno.2025.04.590
Abstract

Objective: Uterine carcinosarcoma (UCS) is a rare and aggressive type of endometrial carcinoma (EC), and novel therapeutic strategies are needed. We sought to assess TROP2 expression in archival UCSs and TROP2 antibody-drug conjugate (ADC) targeting in patient-derived UCS Organoid (PDO) and xenograft (PDX) models.

Methods: TROP2 protein (immunohistochemistry) and mRNA (qRT-PCR) expression were assessed in 72 archival UCS tissues. Nine UCS PDO models were established and molecularly characterized by panel sequencing; then, TROP2 levels were determined and the efficacy of the TROP2 ADC sacituzumab govitecan (SG) defined in the UCS PDO and PDX models (n = 2).

Results: TROP2 protein and mRNA expression were detected in ≥90 % of primary UCSs, and those with a predominant carcinomatous component or with homologous differentiation had higher TROP2 expression than those with a predominant sarcomatous component or with heterologous differentiation (p < 0.001 and p = 0.022, respectively). UCS PDOs displayed TROP2 expression and molecular profiles (median 88 %, range 50-100 % of mutation in primary UCSs present in PDOs) reflective of their respective primary UCSs. All 9 UCS PDOs responded in a dose-dependent manner to SG treatment, with a median IC50 of 167.7pM (range 51.4pM-3.2 nM). In addition, both UCS PDX models with high and low TROP2 protein expression had a significant reduction in tumor volume with SG treatment (p = 0.03 and p = 0.02, respectively).

Conclusions: We demonstrate that the majority of UCSs have detectable TROP2 expression. Our findings on the SG response in UCS PDO and PDX models warrant further studies on TROP2 targeting for patients with this aggressive disease.

Keywords

Antibody–drug conjugate; Carcinosarcoma; Endometrial cancer; Organoid model.

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