HER2, NECTIN4, and TROP-2 Expression Heterogeneity in Bladder Cancer - Expert Commentary
The researchers 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 was predominantly negative (83%) but showed higher positivity in the TC compared to TF (3% vs 1% for score 3+). 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 was associated with better disease-free survival in multivariate analysis. Accurate assessment required four biopsies for HER2 and NECTIN4 and three for TROP-2.
Analysis of molecular subtypes 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 expression of all three markers compared to primary tumors (HER2 3+: 16% vs 2%; NECTIN4 3+: 32% vs 5%; TROP-2 3+: increased in 39% of cases). 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, for accurate evaluation of ADC target expression in MIBC. This spatial heterogeneity has significant implications for personalized treatment strategies, especially considering the increased risk of relapse associated with HER2 and NECTIN4 overexpression in the tumor center.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
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