Spatial Heterogeneity in Expression of Targets of Antibody-Drug Conjugates in Bladder Cancer

Antibody-drug conjugates (ADCs) targeting HER2, NECTIN4, and TROP-2 have emerged as effective therapeutic options for patients with muscle-invasive bladder cancer (MIBC). A recent study by Dernbach et al. examined the heterogeneity of these ADC targets in MIBC primary tumors and metastases, analyzing their correlation with molecular subtypes and clinical outcomes. Tissue samples from 251 MIBC patients were analyzed using immunohistochemistry, with expression patterns compared between tumor front (TF) and tumor center (TC) regions.

The investigators analyzed 1281 cores for HER2, 1231 for NECTIN4, and 1266 for TROP-2, along with 67 matched lymph node metastases and 16 distant metastases. HER2 showed higher positivity in the TC than the TF (3% vs 1% for 3+ staining). TROP-2 exhibited high overall expression (58% score 3+), while NECTIN4 displayed significant heterogeneity with stronger expression in the TC. Interestingly, spatial overexpression of TROP-2 and NECTIN4 at the TF relative to TC correlated with better disease-free survival in multivariate analysis. Molecular subtype analysis revealed HER2 expression was associated with urothelial-like and genomically unstable subtypes, TROP-2 was widely expressed except in mesenchymal-like subtypes, and NECTIN4 showed absence in basal, mesenchymal-like, and small-cell/neuroendocrine-like subtypes.

Paired lymph node metastases showed higher marker expression than primary tumors. Distant metastases, however, showed reduced NECTIN4 expression. Additionally, lymph node metastases revealed considerable heterogeneity for HER2 compared to matched primary tumors.

The findings underscore the importance of obtaining multiple biopsies, particularly from the tumor center and distant metastasis, to evaluate ADC target expression in MIBC accurately. This spatial heterogeneity has significant implications for personalized treatment strategies.

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

References:

Dernbach G, Eich ML, Dragomir MP, Anders P, Jurczok N, Stief C, Jurmeister P, Schlomm T, Klauschen F, Horst D, Schulz GB, Schallenberg S. Spatial expression of HER2, NECTIN4, and TROP-2 in Muscle-Invasive Bladder Cancer and metastases: Implications for pathological and clinical management. Modern Pathology. 2025. doi: https://doi.org/10.1016/j.modpat.2025.100753.

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