Clinical Implications of the Molecular and Genomic Landscape of Upper Tract Urothelial Carcinoma

This review highlights the genomic and molecular characterization advances recently made in upper tract urothelial carcinoma (UTUC) research. As we discussed, UTUC possesses distinctive molecular and genomic signatures, warranting its consideration as an independent entity. This aggressive malignancy is characterized by significant diagnostic challenges, often leading to pathological understaging or overtreatment. Therefore, there is an urgent need for new risk stratification methods, with molecular profiling playing a pivotal role in this endeavor.

Fujii et al. highlight how different molecular clusters can be correlated with different disease behavior profiles, outcomes, and potential treatment responses.¹ Their results establish a framework for disease characterization and motivate future research in this arena. Similarly, Huelster et al. demonstrate the performance of ctDNA in identifying muscle-invasive and non-organ-confined disease.² On a similar note, Tamura et al. show the utility of this biomarker in detecting disease recurrence up to 2 years after radical nephroureterectomy.³

A central focus of research in the coming years should be identifying molecular targets and standardizing molecular-based approaches in diagnosing and characterizing UTUC. In this regard, Nectin-4, a transmembrane protein expressed in approximately 60% of urothelial cancers, serves as a therapeutic target for enfortumab vedotin (EV), an antibody-drug conjugate. The recently published EV-302 trial compared the efficacy of EV and pembrolizumab against platinum-based chemotherapy in patients with treatment-naïve locally advanced or metastatic urothelial carcinoma. A total of 27% of their population had upper tract disease as the primary disease site. Results were promising, showing improved progression-free survival (median 12.5 months vs 6.3 months; P<0.001) and overall survival (median 31.5 months vs 16.1 months; P<0.001) in the combination arm compared with chemotherapy.⁴ Further prospective evaluations of targeted therapies in UTUC are warranted to standardize this approach.

In our manuscript, we also underscore future perspectives such as three-dimensional microscopy and tumor microenvironment analyses, which can facilitate the identification of pro-tumorigenic elements within tumor specimens, achieving single-cell resolution. Additionally, the analysis of extracellular vesicles may offer valuable insights into paracrine signaling that promotes tumorigenesis.

In summary, we believe that molecular and genomic characterization tools mark a milestone in the diagnosis, treatment, and prognostication of UTUC. Recent evidence highlights the performance of novel techniques such as ctDNA and genomic analyses and underscores the potential application of these techniques in conjunction with targeted therapy.

Written by: Salvador Jaime-Casas, MD,¹ Abhishek Tripathi, MD,¹ Sumanta K Pal, MD,¹ and Wesley Yip, MD²

Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
Division of Urology and Urologic Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.

References:

Fujii Y, Sato Y, Suzuki H, et al (2021) Molecular classification and diagnostics of upper urinary tract urothelial carcinoma. Cancer Cell 39:793-809.e8
Huelster HL, Gould B, Schiftan EA, et al (2024) Novel Use of Circulating Tumor DNA to Identify Muscle-invasive and Non–organ-confined Upper Tract Urothelial Carcinoma. Eur Urol 85:283–292
Tamura D, Abe M, Hiraki H, et al (2024) Postoperative recurrence detection using individualized circulating tumor <scp>DNA</scp> in upper tract urothelial carcinoma. Cancer Sci 115:529–539
Powles T, Valderrama BP, Gupta S, et al (2024) Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. New England Journal of Medicine 390:875–888

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