Precision Medicine in Urothelial Carcinoma: Current Markers to Guide Treatment and Promising Future Directions

Miller, Eric J.; Galsky, Matthew D.

doi:10.1007/s11864-023-01151-7

Cited by 3 publications

(2 citation statements)

References 80 publications

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“…Putative reasons which may contribute to affect the consistency and comparability of available findings in this setting (and more generally the assessment of PD-L1 expression as a biomarker in BC) are (1) intrinsic to the study population, including a small number of patients overall [50,58,62], an exceedingly low recurrence rate after BCG treatment, and/or unbalanced subgroup size (i.e., BCG responders vs. non responders) [53]; (2) intrinsic to the treatment, including the frequency and/or timing of BCG administration and type of BCG reagents; (3) intrinsic to the method, such as PD-L1 assessment through heterogeneous assays, antibody clones, cellular populations, scoring systems, and cut-off points (see next section); and (4) intrinsic to the tumor/tissue sample, due to the intra-tumoral heterogeneity of PD-L1 expression and the dynamic nature of the tumor microenvironment [66,67]. Furthermore, the constantly changing of the molecule over time (temporal heterogeneity) has been proven by the discrepancy over different tumor stages, as well as between metastatic sites and corresponding primary tumors, revealed by several authors [68,69].…”

Section: Prognostic Role Of Pd-l1 In Nmibc: Focus On Bcg Immunotherapymentioning

confidence: 99%

Integrating the PD-L1 Prognostic Biomarker in Non-Muscle Invasive Bladder Cancer in Clinical Practice—A Comprehensive Review on State-of-the-Art Advances and Critical Issues

Sanguedolce,

Falagario,

Zanelli

et al. 2024

JCM

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Bladder cancer (BC) is one of the most prevalent cancers worldwide. Non-muscle invasive bladder cancer (NMIBC), comprising the majority of initial BC presentations, requires accurate risk stratification for optimal management. This review explores the evolving role of programmed cell death ligand 1 (PD-L1) as a prognostic biomarker in NMIBC, with a particular focus on its implications in the context of Bacillus Calmette-Guérin (BCG) immunotherapy. The literature suggests a potential association between elevated PD-L1 status and adverse outcomes, resistance to BCG treatment, and disease progression. However, conflicting findings and methodological issues highlight the heterogeneity of PD-L1 assessment in NMIBC, probably due to the complex biological mechanisms that regulate the interaction between PD-L1 and the tumor microenvironment. The identification of PD-L1 as a prognostic biomarker provides ground for tailored therapeutic interventions, including immune checkpoint inhibitors (ICIs). Nevertheless, challenges such as intratumoral heterogeneity and technical issues underscore the need for standardized protocols and larger, homogeneous trials. This review contributes to the ongoing debate on the personalized management of NMIBC patients, focusing on the advances and perspectives of incorporating PD-L1 as a biomarker in this setting.

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Section: Prognostic Role Of Pd-l1 In Nmibc: Focus On Bcg Immunotherapymentioning

confidence: 99%

Integrating the PD-L1 Prognostic Biomarker in Non-Muscle Invasive Bladder Cancer in Clinical Practice—A Comprehensive Review on State-of-the-Art Advances and Critical Issues

Sanguedolce,

Falagario,

Zanelli

et al. 2024

JCM

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“… 7 - 9 In addition, we recently showed that membranous NECTIN4 expression frequently decreased during metastatic spread and correlates with EV response in patients with mUC. 10 In light of other effective treatment alternatives such as trophoblast cell surface antigen 2 (TROP2)- or human epidermal growth factor receptor 2 (HER2)–directed ADC or fibroblast growth factor receptor inhibitors, a better understanding of the molecular basis for EV responses is urgently needed to improve the rational use of this effective drug for patients with mUC 11 - 15 and to optimize its ongoing clinical development in earlier UC stages and other solid tumors. 16 - 19 …”

Section: Introductionmentioning

confidence: 99%

NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer

Klümper,

Tran,

Zschäbitz

et al. 2024

JCO

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PURPOSE The anti-NECTIN4 antibody-drug conjugate enfortumab vedotin (EV) is approved for patients with metastatic urothelial cancer (mUC). However, durable benefit is only achieved in a small, yet uncharacterized patient subset. NECTIN4 is located on chromosome 1q23.3, and 1q23.3 gains represent frequent copy number variations (CNVs) in urothelial cancer. Here, we aimed to evaluate NECTIN4 amplifications as a genomic biomarker to predict EV response in patients with mUC. MATERIALS AND METHODS We established a NECTIN4-specific fluorescence in situ hybridization (FISH) assay to assess the predictive value of NECTIN4 CNVs in a multicenter EV-treated mUC patient cohort (mUC-EV, n = 108). CNVs were correlated with membranous NECTIN4 protein expression, EV treatment responses, and outcomes. We also assessed the prognostic value of NECTIN4 CNVs measured in metastatic biopsies of non–EV-treated mUC (mUC-non-EV, n = 103). Furthermore, we queried The Cancer Genome Atlas (TCGA) data sets (10,712 patients across 32 cancer types) for NECTIN4 CNVs. RESULTS NECTIN4 amplifications are frequent genomic events in muscle-invasive bladder cancer (TCGA bladder cancer data set: approximately 17%) and mUC (approximately 26% in our mUC cohorts). In mUC-EV, NECTIN4 amplification represents a stable genomic alteration during metastatic progression and associates with enhanced membranous NECTIN4 protein expression. Ninety-six percent (27 of 28) of patients with NECTIN4 amplifications demonstrated objective responses to EV compared with 32% (24 of 74) in the nonamplified subgroup ( P < .001). In multivariable Cox analysis adjusted for age, sex, and Bellmunt risk factors, NECTIN4 amplifications led to a 92% risk reduction for death (hazard ratio, 0.08 [95% CI, 0.02 to 0.34]; P < .001). In the mUC-non-EV, NECTIN4 amplifications were not associated with outcomes. TCGA Pan-Cancer analysis demonstrated that NECTIN4 amplifications occur frequently in other cancers, for example, in 5%-10% of breast and lung cancers. CONCLUSION NECTIN4 amplifications are genomic predictors of EV responses and long-term survival in patients with mUC.

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Pre-treatment metastatic biopsy: a step towards precision oncology for urothelial cancer

Klümper,

Cox,

Sjödahl

et al. 2024

Nat Rev Urol

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Precision Medicine in Urothelial Carcinoma: Current Markers to Guide Treatment and Promising Future Directions

Cited by 3 publications

References 80 publications

Integrating the PD-L1 Prognostic Biomarker in Non-Muscle Invasive Bladder Cancer in Clinical Practice—A Comprehensive Review on State-of-the-Art Advances and Critical Issues

Integrating the PD-L1 Prognostic Biomarker in Non-Muscle Invasive Bladder Cancer in Clinical Practice—A Comprehensive Review on State-of-the-Art Advances and Critical Issues

NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer

Pre-treatment metastatic biopsy: a step towards precision oncology for urothelial cancer

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