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TROP-2, NECTIN-4 and predictive biomarkers in sarcomatoid and rhabdoid bladder urothelial carcinoma
Matteo Brunelli1, Stefano Gobbo2, Giorgio Malpeli3
1Department of Diagnostics and Public Health, University of Verona, Italy.
Introduction:
The surface protein TROP-2/TACSTD2 and the cell adhesion protein NECTIN-4/NECTIN4 are responsible for the efficacy of anticancer therapies based on antibody-drug conjugates (ADC) targeting intracellular microtubules. In contrast with common histologic subtypes of bladder urothelial carcinoma (BUC), little is known of TROP-2 and NECTIN-4 expression in sarcomatoid and rhabdoid BUC.
Aims:
In this study, we aimed to analyze TROP-2 and NECTIN-4 expression and additional predictive biomarkers by immunohistochemistry and fluorescence in situ hybridization (FISH) on 35 undifferentiated BUC (28 sarcomatoid and 7 rhabdoid). Wide genomic investigation was also performed on 411 BUC cases of the PanCancer Atlas, focusing on genes related to the microtubule pathways.
Results:
Seven of 35 (20%) undifferentiated BUC showed expression of TROP-2. NECTIN-4 was expressed in 10 cases (29%). Seven cases (20%) co-expressed TROP-2 and NECTIN-4. HER-2 FISH was amplified in 5 cases (14%) while HER-2 immunoexpression was observed in 14 cases (40%). PD-L1 scored positive for combined proportion score (CPS) in 66% of cases and for tumor proportion score (TPS) in 51% of cases. Pan-NTRK1-2/3 was elevated in 9 cases (26%) and FGFR-2/3 was broken in 7 of 35 cases (20%). Of 28 sarcomatoid BUC, 9 (32%) were negative for all (TROP-2, NECTIN-4, PD-L1, HER-2, FGFR and pan-NTRK) biomarkers and 3 (11%) expressed all five biomarkers. Among cases with rhabdoid dedifferentiation, 1 of 7 (14%) showed activation of all biomarkers, whereas 2 of 7 (28%) showed none. The mRNA analysis identified microtubule-related genes and pathways suitable for combined ADC treatments in BUC.
Conclusion:
Sarcomatoid and rhabdoid BUC do harbor positive expression of the ADC targets TROP-2 or NECTIN-4 in a relatively modest subset of cases, whereas the majority do not. Different combinations of other positive biomarkers may help the choice of medical therapies. Overall, these findings have important clinical implications for targeted therapy for BUC.
Insights
This study investigated TROP-2 and NECTIN-4 expression in rare bladder cancer subtypes, finding limited expression but highlighting other biomarkers for targeted therapies. These findings impact treatment strategies for bladder urothelial carcinoma (BUC).
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Antibody-drug conjugates (ADCs) targeting TROP-2/TACSTD2 and NECTIN-4/NECTIN4 are effective anticancer therapies.
- Expression of these targets in sarcomatoid and rhabdoid bladder urothelial carcinoma (BUC) is not well understood.
Purpose of the Study:
- To analyze TROP-2 and NECTIN-4 expression in undifferentiated BUC.
- To investigate additional predictive biomarkers and microtubule-related gene pathways in BUC.
Main Methods:
- Immunohistochemistry and fluorescence in situ hybridization (FISH) on 35 undifferentiated BUC cases.
- Genomic investigation of 411 BUC cases from the PanCancer Atlas.
Main Results:
- TROP-2 expression in 20% and NECTIN-4 in 29% of undifferentiated BUC.
- Co-expression of TROP-2 and NECTIN-4 observed in 20% of cases.
- Varied expression of HER-2, PD-L1, NTRK, and FGFR was noted, with some cases negative for all tested biomarkers and others expressing multiple.
Conclusions:
- Sarcomatoid and rhabdoid BUC show modest expression of ADC targets TROP-2/NECTIN-4.
- Combinations of other biomarkers may guide targeted therapy selection.
- Findings have clinical implications for BUC targeted therapy.
