TROP2 expression and therapeutic targeting in uterine carcinosarcoma.

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 IC(50) 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.