Trop-2 in Upper Tract Urothelial Carcinoma

Abstract

Trophoblast cell surface antigen 2 (Trop-2, encoded by TACSTD2) is the target protein of sacituzumab govitecan, a novel antibody-drug conjugate for locally advanced or metastatic urothelial carcinoma. However, the expression status of Trop-2 in upper tract urothelial carcinoma (UTUC) remains unclear. We performed immunohistochemical analysis of 99 UTUC samples to evaluate the expression status of Trop-2 in patients with UTUC and analyze its association with clinical outcomes. Trop-2 was positive in 94 of the 99 UTUC samples, and high Trop-2 expression was associated with favorable progression-free survival (PFS) and cancer-specific survival (p = 0.0011, 0.0046). Multivariate analysis identified high Trop-2 expression as an independent predictor of favorable PFS (all cases, p = 0.045; high-risk group (pT3≤ or presence of lymphovascular invasion or lymph node metastasis), p = 0.014). Gene expression analysis using RNA sequencing data from 72 UTUC samples demonstrated the association between high TACSTD2 expression and favorable PFS (all cases, p = 0.069; high-risk group, p = 0.029). In conclusion, we demonstrated that Trop-2 is widely expressed in UTUC. Although high Trop-2 expression was a favorable prognostic factor in UTUC, its widespread expression suggests that sacituzumab govitecan may be effective for a wide range of UTUC.

Comparison of molecular profiles of upper tract urothelial carcinoma vs. urinary bladder cancer in the era of targeted therapy: a narrative review

“…Similarly, in our data, Trop-2 positivity rates did not differ significantly among the UTUC subtypes (Table 2). In our previous study (54), high Trop-2 expression was associated with a good prognosis in UTUC, and the findings also confirmed that the high TASCSTD2 expression group still showed a favorable prognosis in gene expression analysis using RNA sequencing data. These findings were inconsistent with those reported for UBC; high Trop-2 expression was associated with increased tumor aggressiveness and poor prognosis.…”

“…Therefore, evaluation of the expression of Trop-2 in solid tumors is clinically important to predict the efficacy of sacituzumab govitecan. The Trop-2-positive rate in UTUC was found in 94% (94/99) of UTUC cases in our previous study (54), while it was reported to be 83% in UBC (53). This finding suggests that UTUC also has a high Trop-2-positivity rate and is a treatment option for advanced UTUC and UBC.…”

“…Here, we have focused on the differences in the expression status of therapeutic target proteins (specifically PD-L1, Nectin-4, and Trop-2) between UTUC and UBC and discussed the efficaciousness of each targeted drug in UTUC. Table 2 summarizes the expression status of therapeutic target proteins in UTUC and UBC primary tissues analyzed by immunohistochemical analysis (50)(51)(52)(53)(54). We also analyzed the positive rates of each protein in different molecular subtypes of UTUC: luminal (GATA3+/CK5/6−), basal (GATA3−/CK5/6+), and double-negative [considered as p53-like or neuroendocrine-like subtype (GATA3−/CK5/6−)] subtypes, since immunohistochemical staining for GATA3 and cytokeratin 5/6 (CK5/6) is reportedly sufficient to determine molecular subtypes (49,(55)(56)(57).…”

Systematic review of recent advancements in antibody-drug and bicycle toxin conjugates for the treatment of urothelial cancer

“…It is highly expressed in multiple cancers, including urothelial carcinoma, with several studies reporting expression rates greater than 90%. 64 , 65 High TROP2 expression levels in advanced cancers portend a poor prognosis. In UC, TROP2 expression has been reported as being higher than that of nectin-4, indicating its suitability as a target for an ADC treating bladder cancer 66 ( Table 3 ).…”

Trop-2 as a Therapeutic Target in Breast Cancer

“…Expression on these normal epithelial cells is at a much lower level than in epithelial tumors, making Trop-2 an ideal therapeutic target [ 1 , 2 , 3 ]. When Trop-2 is overexpressed, it acts as an oncogene promoting tumor proliferation, growth, invasion, and metastasis in epithelial cancers such as breast, colon, prostate, pancreatic, urothelial, and lung [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. High Trop-2 expression is associated with a poor prognosis in multiple cancer types, with worse overall survival and disease-free survival outcomes [ 12 , 13 , 14 , 15 , 16 ].…”