Characterization of Targets for Antibody-Drug Conjugates in Advanced Urothelial Carcinoma - Expert Commentary
These drugs target proteins that are present on the tumor cell surface, with SG targeting TROP2 and EV targeting NECTIN-4. Treatment with SG and EV is not dependent on confirmed target expression in patients. Bahlinger et al. aimed to characterize the expression of target proteins and determine whether this is correlated with clinical features.
The investigators collected gene expression data for 405 patients from the TCGA database and subsequently validated findings on an independent cohort of 247 patients from the Comprehensive Cancer Center Erlangen Metropole Region Nuremberg (CCC-EMN) database. TACSTD2 and NECTIN-4 were highly expressed at the mRNA level and their gene expression levels were correlated (p < 0.001). Both markers were associated with molecular subtypes (p = 0.0002). Neuroendocrine-like subtypes exhibited lower expression of TACSTD2 and NECTIN-4. Luminal subtypes showed significantly higher expression levels of NECTIN-4 than basal/squamous tumors (p < 0.001). There was no prognostic effect on clustering patients by expression levels. Similarly, expression levels of TACSTD2 and NECTIN-4 remained high across both clusters of low versus high expression of PD-1 and PD-L1. Protein expression for both markers was also high. Only 6.5% and 10.6% of samples exhibited complete absence of TROP2 expression and NECTIN-4, respectively. Complete loss of expression of both proteins was only found in sarcomatoid and neuroendocrine aUC while complete NECTIN-4 loss was observed in squamous differentiated or basal/squamous tumors. These differences in protein expression were not correlated with survival (p = 0.23).
While the findings from this study indicate ubiquitous expression of ADC target proteins and a lack of prognostic effect, subtle differences in target protein expression may impact tumor sensitivity to treatment. Immunohistochemical testing of target proteins in tumor sections is easy to implement and could identify high responders to SG or EV. However, due to the retrospective design of the study, it is unclear whether expression levels of TROP2 and NECTIN-4 fluctuate in response to disease progression or treatment. Prospective studies and evaluating expression changes throughout treatment with SG or EV would provide further insight into these patterns.
Written by: Bishoy M. Faltas, MD, Director of Bladder Cancer Research, Englander Institute for Precision Medicine, Weill Cornell Medicine
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