Although urothelial carcinoma (UC) is a common malignancy, upper tract UC (UTUC) is relatively rare. Despite advances in diagnostic techniques and surgical management, the survival outcomes of UTUC patients remain poor. Therefore, the identification of reliable prognostic biomarkers is essential to improve risk stratification and guide clinical decision-making.
Antibody–drug conjugates (ADCs) represent a novel therapeutic strategy that combines the specificity of monoclonal antibodies with the cytotoxic effects of chemotherapy. Several clinical studies have demonstrated the efficacy of TROP2-targeting ADC sacituzumab govitecan in advanced UC. However, the clinicopathological significance and prognostic role of TROP2 expression in UC, particularly in UTUC, have not been fully elucidated. Thus, a comprehensive analysis of TROP2 expression in UTUC may provide important insights into UC biology, prognosis, and treatment strategies.
Key Findings
In our study, we investigated the expression patterns of TROP2 in surgically resected UTUC specimens and analyzed their clinicopathological and prognostic relevance. Additionally, in silico and bioinformatics analyses were performed to validate and extend our findings. The major results are summarized as follows:
- TROP2 overexpression was associated with papillary morphology, low tumor grade, early pathological T stage, and favorable clinical outcome. Notably, high TROP2 expression was identified as an independent prognostic factor in multivariate survival analyses. These findings were consistent with in silico validation.
- In silico analysis showed that TACSTD2 expression was significantly higher in luminal papillary subtype than in basal/squamous, stroma-rich, and neuroendocrine-like subtypes of UTUC. Additionally, TACSTD2 expression was significantly higher in the FGFR3-mutated subtype compared to the TP53-mutated subtype.
- We demonstrated that high TACSTD2/TROP2 expression was significantly associated with NECTIN-4/Nectin-4 expression in both the Hiroshima UTUC cohort and in silico analysis.
- RNA-sequencing analyses revealed that the TACSTD2 high group was significantly enriched in gene sets related to tumor metabolic reprogramming, whereas TACSTD2-low tumors showed signatures related to extracellular matrix remodeling and epithelial–mesenchymal transition (EMT).
These findings have several important implications for clinical practice in urologic oncology. First, assessment of TROP2 protein expression by IHC may provide prognostic information and support clinical decision-making in UTUC. Second, we previously reported that Nectin-4 expression was associated with papillary morphology, low grade, early pT stage, and a favorable prognosis, mirroring the clinicopathological features observed for TROP2 in the present study. Nectin4 is also known as ADC target, and has shown the therapeutic efficacy of enfortumab vedotin in metastatic and advanced UC. Thus, combined evaluation of TROP2 and Nectin-4 expression may improve prognostic stratification and help guide personalized therapeutic strategies in UC.
Limitations
Although TROP2 is the molecular target of sacituzumab govitecan, the relationship between immunohistochemically detected TROP2 expression and clinical response to ADC remains largely unclear. Prospective studies integrating molecular profiling of TROP2 with treatment outcomes will be necessary to establish its utility as a predictive biomarker in UC.
Conclusion
This study provides a comprehensive evaluation of TROP2 expression in UTUC using immunohistochemical and transcriptomic analyses. Elevated TROP2 levels were linked to favorable clinicopathological features, improved survival outcomes, luminal-type characteristics, and FGFR3 alterations. Assessment of TROP2 expression may contribute to improved prognostication and support patient stratification and clinical decision-making in UTUC. Furthermore, this biological context may be relevant for future studies investigating TROP2-targeted approaches.
Written by: Go Kobayashi,1 Yohei Sekino,2 Tetsutaro Hayashi,2 Hikaru Nakahara,3 Kohei Kobatake,2 Hiroyuki Kitano,2 Keisuke Goto,2 Hiroaki Niitsu,3 Takao Hinoi,3 Kazuhiro Sentani,1 Nobuyuki Hinata2
- Department of Molecular Pathology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Department of Urology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
- Department of Clinical and Molecular Genetics, Hiroshima University Hospital, Hiroshima, Japan