Heterogenous NECTIN4 expression in urothelial high-risk non-muscle-invasive bladder cancer.
Stefan GarczykStephan DegenerFelix BischoffTician SchnitzlerAnne SalzReinhard GolzAlexander BuchnerGerald B SchulzUrsula SchneiderNadine T GaisaRuth KnüchelPublished in: Virchows Archiv : an international journal of pathology (2022)
High-grade non-muscle-invasive bladder cancer (HG NMIBC) patients are at high risk (HR) of progression to muscle-invasion. Bladder-preserving therapies for this patient subgroup are limited, and additional treatments are desirable. Recently, enfortumab vedotin, targeting cancer-associated NECTIN4, has been approved for the treatment of advanced urothelial carcinoma. However, data on the expression of NECTIN4 and its therapeutic potential for HR NMIBC are scarce. Here, NECTIN4 was immunohistochemically analyzed in urothelial HG NMIBC by studying cohorts of carcinoma in situ (CIS)/T1HG (N = 182 samples), HG papillary tumors from mixed-grade lesions (mixed TaHG) (N = 87) and papillary HG tumors without a history of low-grade disease (pure TaHG/T1HG) (N = 98) from overall 225 patients. Moreover, inter-lesional NECTIN4 heterogeneity in multifocal HG NMIBC tumors was determined. A high prevalence of NECTIN4 positivity was noted across HG NMIBC subgroups (91%, N = 367 samples), with 77% of samples showing moderate/strong expression. Heterogenous NECTIN4 levels were observed between HG NMIBC subgroups: non-invasive areas of CIS/T1HG and pure TaHG/T1HG samples showed NECTIN4 positivity in 96% and 99%, with 88% and 83% moderate/strong expressing specimens, respectively, whereas significantly lower NECTIN4 levels were detected in mixed TaHG lesions (72% positivity, 48% of samples with moderate/strong NECTIN4 expression). Moreover, higher NECTIN4 heterogeneity was observed in patients with multifocal mixed TaHG tumors (22% of patients) compared to patients with multifocal CIS/T1HG and pure TaHG/T1HG tumors (9% and 5%). Taken together, NECTIN4-directed antibody-drug conjugates might be promising for the treatment of HR NMIBC patients, especially for those exhibiting CIS/T1HG and pure TaHG/T1HG tumors without a history of low-grade disease.
Keyphrases
- muscle invasive bladder cancer
- high grade
- fluorescent probe
- low grade
- end stage renal disease
- aqueous solution
- living cells
- ejection fraction
- chronic kidney disease
- newly diagnosed
- poor prognosis
- peritoneal dialysis
- prognostic factors
- randomized controlled trial
- clinical trial
- patient reported outcomes
- patient reported
- drug delivery
- open label
- binding protein
- case report
- deep learning
- cell migration
- phase iii
- study protocol
- big data
- urinary tract