Predictive Biomarkers in Sarcomatoid and Rhabdoid Bladder Urothelial Carcinoma

Antibody-drug conjugates (ADCs) have revolutionized the treatment metastatic urothelial carcinoma. These include sacituzumab govitecan targeting TROP-2 and enfortumab vedotin targeting NECTIN-4. The conventional urothelial cancers express TROP-2 and NECTIN-4, the protein targets of these ADCs. However, little is known about the expression of these proteins in undifferentiated subtypes including sarcomatoid or rhabdoid features. A recent study aimed to investigate the expression of TROP-2 and NECTIN-4 in undifferentiated bladder urothelial carcinoma (BUC) cases to determine whether ADC treatment can be potentially effective in these tumor subtypes.

The study included 35 patients with undifferentiated BUC. TROP-2 protein expression was detectable in 20% of patients while NECTIN-4 protein expression was present in 29% of patients. Co-expression of TROP-2 and NECTIN-4 was present in 20% of patients, while 71% were negative for both markers. The investigators observed HER-2 expression in 40% of cases and PD-L1 expression in 66% of cases.

The findings from this study indicate the differences in the expression of TROP-2 or NECTIN-4 expression in undifferentiated BUC to identify candidates for ADC treatment. The small number of patients in this study is a limitation. Understanding not only the expression of surface targets for ADC binding but also of downstream proteins that impact the cytotoxicity induced by the payload drugs is critical for developing biomarkers for ADC responses.

Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine

References:

Brunelli M, Gobbo S, Malpeli G, et al. TROP-2, NECTIN-4 and predictive biomarkers in sarcomatoid and rhabdoid bladder urothelial carcinoma. Pathologica. 2024;116(1):55-61. doi:10.32074/1591-951X-937

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