Trop-2 Overexpression in Poorly Differentiated Endometrial Endometrioid Carcinoma: Implications for Immunotherapy With hRS7, a Humanized Anti–Trop-2 Monoclonal Antibody. Issue 9 (1st November 2011)

• Record Type: Journal Article
• Authors: Bignotti, Eliana; Ravaggi, Antonella; Romani, Chiara; Falchetti, Marcella; Lonardi, Silvia; Facchetti, Fabio; Pecorelli, Sergio; Varughese, Joyce; Cocco, Emiliano; Bellone, Stefania; Schwartz, Peter E.; Rutherford, Thomas J.; Santin, Alessandro D.
• Is Part Of: International journal of gynecological cancer. Volume 21:Issue 9(2011)
• Page Start: 1613
• Page End: 1621
• Publication Date: 2011-11-01
• Subjects: Endometrial cancer -- Endometrioid carcinoma -- Immunotherapy -- Natural killer cells -- Trop-2 protein; Generative organs, Female -- Cancer -- Periodicals; 616.99465
• DOI: 10.1097/IGC.0b013e318228f6da
• Languages: English
• ISSNs: 1048-891X

Abstract

Abstract : Objective: We evaluated the expression of human trophoblast cell surface marker (Trop-2) in endometrial endometrioid carcinoma (EEC) and the potential application of hRS7, a humanized monoclonal anti–Trop-2 antibody, as a therapeutic agent against poorly differentiated EEC. Methods: Trop-2 expression was evaluated by immunohistochemistry in 131 EEC with different degrees of differentiation and 32 normal endometrial controls (NEC). Trop-2 expression was also evaluated by quantitative real-time polymerase chain reaction and flow cytometry in 3 primary EEC cell lines derived from patients harboring poorly differentiated EEC. Finally, the sensitivity of grade 3 EEC cell lines to hRS7 antibody-dependent cellular cytotoxicity was tested in standard 5-hour 51 Cr release assays. Results: Trop-2 expression was detected in 126 (96.2%) of 131 EEC samples. Tumor tissues showed markedly increased Trop-2 positivity compared with NEC ( P = 0.001). Trop-2 expression was significantly higher in all grades of EEC versus NEC. Grade 3 tumors displayed significantly stronger Trop-2 immunostaining compared with grade 1 EEC ( P = 0.01). High Trop-2 expression by quantitative real-time polymerase chain reaction and flow cytometry was found in 1 grade 3 EEC primary cell line (EEC-ARK-1). Unlike Trop-2–negative EEC cell lines, EEC-ARK-1 was found highly sensitive to hRS7-mediated antibody-dependent cellular cytotoxicity in vitro (range of killing, 33.9%–50.6%; P = 0.004). Human serum did not significantly inhibit hRS7-mediated cytotoxicity against EEC-ARK-1 ( P = 0.773). Conclusions: Trop-2 is highly expressed in EEC, and its expression is significantly higher in poorly differentiated EEC when compared with well-differentiated EEC. Primary grade 3 EECs overexpressing Trop-2 are highly sensitive to hRS7-mediated cytotoxicity in vitro. hRS7 may represent a novel therapeutic agent for the treatment of high-grade EEC refractory to standard treatment modalities.