Upper Tract Urothelial Cancer (UTUC) Genomic Profiling and Correlation Regarding Benefit of Platinum-Based Chemotherapy - Beyond the Abstract

Upper tract urothelial cancers (UTUC) are rare urothelial cancers that have historically been treated similarly to bladder urothelial cancers though outcomes have been worse than their lower tract bladder urothelial cancer counterparts.¹

Treatment has historically centered on cisplatin-based chemotherapy similar to bladder cancer and while attempts at neoadjuvant chemotherapy (NAC) have shown responses in both prospective^2,3 and retrospective trials,⁴ higher level of evidence showed benefit in the phase III trial POUT trial⁵ that showed adjuvant platinum-based chemotherapy showed improvement in disease-free and recurrence-free survival, as well as adjuvant nivolumab in the CheckMate 274 trial⁶ and in the AMBASSADOR trial⁷ (though the latter two adjuvant immunotherapy trials were mostly for lower tract bladder cancer with a minority of UTUC patients capped at roughly 20 - 22%).

However, the use of biomarkers to predict response to treatment remains an area of active investigation. This pilot project⁸ attempts to understand the role of transcriptome-based molecular subtypes, specifically using the Decipher Bladder®,⁹ a clinical-grade, transcriptome-wide assay that has been validated in the peri-operative setting for bladder cancer, and evaluate its role in this consecutive series of UTUC patients. Our series reveals that all four patients had non-luminal molecular subtypes including basal (N = 4) and mixed basal/claudin-low (N = 2) subtypes. The best clinical response achieved was stable disease in a patient who had basal/claudin-low subtype with residual ypT3 after neoadjuvant chemotherapy. However, the remaining 3 patients were all treated with platinum-based chemotherapy for eventual metastatic disease but all three showed progressive disease with limited overall survival, highlighting their aggressive course. Perhaps the non-luminal subtype and lack of FGFR alteration may partly explain the poor overall outcomes while the real-world benefit of next generation sequencing for clinical use in UTUC patients requires further clarification in a larger cohort study. All four cases had basal molecular markers, although two patients had additional mixed claudin-low molecular subtype with increased stromal markers on the Decipher Bladder® GRID. The co-occurrence of non-luminal subtype and sarcomatoid variant histology has been reported in other series where basal MIBC has been enriched with both squamous and sarcomatoid features,^10,11 even though another series showed UTUC patients are enriched with luminal subtype and a generally T-cell depleted contexture.¹²

The genomic characteristics of patients who undergo nephroureterectomy and their association with response to systemic chemotherapy in UTUC have not been studied extensively and this narrative describes the clinical course and genomic characteristics and outcomes of this limited series of patients.⁸ In contrast, molecular markers in bladder cancer have been evaluated and suggested to predict both pathological upstaging at radical cystectomy and response to NAC. Non-luminal tumors showed higher chances of upstaging in a cystectomy-only setting without NAC¹³ but in contrast, were suggested to benefit the most from NAC in a separate multi-institutional MIBC study,¹⁴ although again mostly in a lower tract bladder cancer setting. Notably, all four cases within the present UTUC profiling study had a non-luminal subtype, with only one out of four cases being treated with true neoadjuvant chemotherapy. Although none of these cases showed a convincing response, the aggressive behavior of non-luminal tumors was validated in the present study as reflected by the high pathologic tumor stage. Moreover, whereas previous efforts on transcriptomic subtyping revealed many luminal-type tumors among UTUC,¹² the present study solely included non-luminal tumors.

While the initial goal of this small pilot project was to determine feasibility and pave the way for a future prospective trial to predict the response to neoadjuvant chemotherapy in UTUC, since the initiation of this project, additional clinical trials including the POUT study which demonstrated the benefits of adjuvant chemotherapy showing improvement in three-year disease-free survival (DFS) in favor of adjuvant chemotherapy has shaped the landscape of treatment in UTUC. In addition, the CheckMate 274 trial and the AMBASSADOR trial both showed that adjuvant immunotherapy improved DFS, although the subgroup of UTUC patients was capped at around 20% enrollment. In addition, the UTUC population in the CheckMate 274 trial had seemingly suboptimal responses with subgroup analyses hazard ratios (HR) for disease recurrence or death of 1.23 and 1.56 for renal pelvis and ureter, respectively. There are now several trials, including one being led by ECOG-ACRIN 8192 (clinicaltrials.gov NCT04628767) that utilizes neoadjuvant durvalumab in addition to gemcitabine/cisplatin prior to nephroureterectomy in high-grade UTUC that would ultimately answer the question regarding utility of a neoadjuvant approach with checkpoint inhibitors but the role of predictive biomarkers such as the use of molecular markers, require validation in these larger prospective trials.

Written by: Jeanny B. Aragon-Ching, MD, GU Oncology, Inova Schar Cancer Institute, Fairfax, VA

References:

1. Aragon-Ching, J. B. & Wang, H. Contemporary treatment and survival differences in patients with urothelial versus nonurothelial bladder and upper tract carcinomas: Analyses from the National Cancer Database (NCDB). Journal of Clinical Oncology 40, 463-463, doi:10.1200/JCO.2022.40.6_suppl.463 (2022).
2. Coleman, J. A. et al. Multicenter Phase II Clinical Trial of Gemcitabine and Cisplatin as Neoadjuvant Chemotherapy for Patients With High-Grade Upper Tract Urothelial Carcinoma. J Clin Oncol 41, 1618-1625, doi:10.1200/JCO.22.00763 (2023).
3. Margulis, V. et al. Phase II Trial of Neoadjuvant Systemic Chemotherapy Followed by Extirpative Surgery in Patients with High Grade Upper Tract Urothelial Carcinoma. J Urol 203, 690-698, doi:10.1097/JU.0000000000000644 (2020).
4. Foerster, B. et al. Efficacy of Preoperative Chemotherapy for High Risk Upper Tract Urothelial Carcinoma. J Urol 203, 1101-1108, doi:10.1097/JU.0000000000000737 (2020).
5. Birtle, A. et al. Adjuvant chemotherapy in upper tract urothelial carcinoma (the POUT trial): a phase 3, open-label, randomised controlled trial. Lancet 395, 1268-1277, doi:10.1016/S0140-6736(20)30415-3 (2020).
6. Bajorin, D. F. et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med 384, 2102-2114, doi:10.1056/NEJMoa2034442 (2021).
7. Apolo, A. B. et al. Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma. N Engl J Med, doi:10.1056/NEJMoa2401726 (2024).
8. Hwang, M. W. et al. Upper tract urothelial cancer (UTUC) genomic profiling and correlation regarding benefit of platinum-based chemotherapy. Explor Target Antitumor Ther 5, 1261-1270, doi:10.37349/etat.2024.00274 (2024).
9. Decipher Bladder Test. 
10. Choi, W. et al. Intrinsic basal and luminal subtypes of muscle-invasive bladder cancer. Nat Rev Urol 11, 400-410, doi:10.1038/nrurol.2014.129 (2014).
11. Narayan, V. M. et al. Genomic Analysis and Treatment Response of a Bladder Urothelial Carcinoma With Sarcomatoid Variant Histology. Clin Genitourin Cancer 17, e888-e892, doi:10.1016/j.clgc.2019.05.019 (2019).
12. Robinson, B. D. et al. Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling. Nat Commun 10, 2977, doi:10.1038/s41467-019-10873-y (2019).
13. Lotan, Y. et al. Molecular Subtyping of Clinically Localized Urothelial Carcinoma Reveals Lower Rates of Pathological Upstaging at Radical Cystectomy Among Luminal Tumors. Eur Urol 76, 200-206, doi:10.1016/j.eururo.2019.04.036 (2019).
14. McConkey, D. J. et al. A Prognostic Gene Expression Signature in the Molecular Classification of Chemotherapy-naive Urothelial Cancer is Predictive of Clinical Outcomes from Neoadjuvant Chemotherapy: A Phase 2 Trial of Dose-dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin with Bevacizumab in Urothelial Cancer. Eur Urol 69, 855-862, doi:10.1016/j.eururo.2015.08.034 (2016).