2. UroToday Home
  3. Conference Highlights
  4. SUO 2023
  5. SUO 2023 Upper Tract Urothelial Carcinoma

SUO 2023

SUO 2023: Defining the Biology of Upper Tract Urothelial Carcinoma and How This Shapes Therapy

(UroToday.com) The 2023 SUO annual meeting included a session on urothelial cancer, featuring a presentation by Dr. Bishoy Faltas discussing the biology of upper tract urothelial carcinoma and how it shapes therapy. Dr. Faltas started by highlighting that upper tract urothelial carcinoma makes up 5-10% of all urothelial carcinomas, and has a unique epidemiologic association with arsenic exposure and aristolochic acid. Additionally, upper tract urothelial carcinoma presents with muscle invasion (pT2+) in 60% of cases versus 20-30% of bladder cancers. Upper tract urothelial carcinoma has more advanced disease at presentation, but similar outcomes as bladder cancer after controlling for stage.

Upper tract urothelial carcinoma and bladder urothelial carcinomas have different anatomy and embryologic origins, but are there one or two diseases? Indeed, there are genomic differences between these two entities as highlighted in two European Urology articles.1,2 The MD Anderson Cancer Center study collected 31 upper tract urothelial carcinoma samples and carried out whole-exome sequencing of DNA, RNA sequencing, and protein analysis.1 Whole-exome sequencing identified mutations in FGFR3 (74.1%; 92% low-grade, 60% high-grade), KMT2D (44.4%), PIK3CA (25.9%), and TP53 (22.2%). Additionally, APOBEC and CpG were the most common mutational signatures. The Memorial Sloan Kettering cohort2 assessed tumor and germline DNA from patients with upper tract urothelial carcinoma (n=83) and bladder urothelial carcinoma (n=102), using a custom next-generation sequencing assay to identify somatic mutations and copy number alterations in 300 cancer-associated genes. Genes altered more commonly in high-grade upper tract urothelial carcinoma included FGFR3 (35.6% vs 21.6%; p=0.065), HRAS (13.6% vs 1.0%; p=0.001), and CDKN2B (15.3% vs 3.9%; p=0.016). Genes that were less frequently mutated in high-grade upper tract urothelial carcinoma included TP53 (25.4% vs 57.8%; p<0.001), RB1 (0.0% vs 18.6%; p<0.001), and ARID1A (13.6% vs 27.5%; p=0.050).

Work from Dr. Faltas’ lab assessing genetics of upper tract urothelial carcinoma culminated in a 2019 Nature Communication publication,3 with several highlights. First, they noted that upper tract urothelial carcinoma is predominantly a luminal-papillary subtype, which was also confirmed in the MSKCC cohort:

Second, upper tract urothelial carcinoma has a T-cell depleted immune contexture with higher FGFR3 and PPARG signaling in upper tract urothelial carcinoma:

image-2.jpg

Third, high FGFR3 expression is enriched in upper tract urothelial carcinoma and correlates with its T-cell depleted immune microenvironment. Additionally, cells with FGFR3 knock out show upregulation of IFN-related genes:

image-3.jpg

Fourth, erdafitinib upregulates IFN-related genes in urothelial cell lines with FGFR3 activating fusions:

image-4.jpg

Finally, sporadic upper tract urothelial carcinoma is characterized by a lower total mutational burden than urothelial carcinoma of the bladder.

This early work has recently been shown to provide dividends for several phase 3 clinical trials. At the 2023 ESMO clinical congress, results of Thor cohort 1 trial were presented and subsequently published in the New England Journal of Medicine. This phase 3 trial assessed erdafitinib versus chemotherapy in patients with metastatic urothelial carcinoma with susceptible FGFR3/2 alterations who had progression after one or two previous treatments that included an anti-PD-1 or anti-PD-L1. Overall, this trial favored treatment with erdafitinib (HR 0.64, 95% CI 0.47-0.88), and in patients with upper tract urothelial carcinoma treatment favored erdafitinib with a HR of 0.34 (95% CI 0.18-0.64). Interestingly, erdafitinib did not favor patients with lower urinary tract tumors (HR 0.82, 95% CI 0.56-1.18).

Also at ESMO 2023, results of Thor cohort 2 were presented and subsequently published in Annals of Oncology.5 This cohort assessed erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations. In the subgroup analysis assessing upper tract urothelial carcinoma, treatment was not statistically significant but did favor pembrolizumab (HR 1.52, 95% CI 0.91-2.54).

For the remainder of his presentation, Dr. Faltas highlighted recently in press work from his group assessing the evolution of genomic, transcriptomic, and single-cell protein markers of metastatic upper tract urothelial carcinoma. There are several key findings from this extensive study. First, there are unique gene alterations when comparing primary to metastatic upper tract urothelial carcinoma:

image-5.jpg

Second, copy number alterations are unique when comparing primary to metastatic upper tract urothelial carcinoma. Specifically, the frequency of RAF1 amplification was significantly higher in metastatic upper tract urothelial carcinoma (33.3%) compared to primary upper tract urothelial carcinoma (p = 0.03):

image-6.jpg

Third, there is genomic heterogeneity between primary and matched metastatic upper tract urothelial carcinoma. On average, only 17.6% (range 7.3–36.4%) of mutations were shared by primary and matched metastatic samples:

image-7.jpg

Fourth, when assessing the stability of molecular subtype and immune contexture assignments between primary and metastatic upper tract urothelial carcinoma, Dr. Faltas and colleagues found that 83.3% of primary tumor samples were luminal-papillary, and the rest were basal/squamous. Additionally, among the metastatic tumors, 45.5%, 27.3%, 9.1% and 18.2% were luminal-papillary, luminal-unstable, stroma-rich, and basal/squamous, respectively:

image-8.jpg

Fifth, the majority of upper tract urothelial carcinoma tumors (76.5%) clustered into the T-cell depleted subgroup:

image-9.jpg

Sixth, single cell profiling of upper tract urothelial carcinoma’s tumor immune contexture reveals intra-tumoral plasticity, with the following single cell spatial profiling embedded on Uniform Manifold Approximation and Projection method:

image-10.jpg 

Finally, samples classified as immune-inflamed by the RNA-seq based classifier had a significantly higher number of T-cells with CD8 protein expression:

image-11.jpg

Dr. Faltas concluded his presentation by discussing the biology of upper tract urothelial carcinoma and how it shapes therapy with the following take-home points:

  • Most upper tract urothelial carcinomas are luminal papillary with a T-cell depleted immune contexture driven by FGFR3 activation
  • Molecular subtype and immune contexture assignments are stable between primary and metastatic upper tract urothelial carcinoma
  • Randomized phase III clinical trials confirmed the predicted differential effects of FGFR3 inhibitors in upper tract urothelial carcinoma compared to bladder cancer based on biological differences
  • We are working toward upper tract urothelial carcinoma-specific precision medicine strategies based on a deeper understanding of upper tract urothelial carcinoma biology

Presented by: Bishoy M. Faltas, MD, Weill Cornell Medicine, New York, NY

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 Society of Urologic Oncology (SUO) Annual Meeting, Washington, D.C., Tues, Nov 28 – Fri, Dec 1, 2023. 

References:

  1. Moss TJ, Qi Y, Xi L, et al. Comprehensive Genomic Characterization of Upper Tract Urothelial Carcinoma. Eur Urol 2017 Oct;72(4):641-649.
  2. Sfakianos JP, Cha EK, Iyer G, et al. Genomic Characterization of Upper Tract Urothelial Carcinoma. Eur Urol 2015 Dec;68(6):970-977.
  3. Robinson BD, Vlachostergios PJ, Bhinder B, et al. Upper tract urothelial carcinoma has a luminal-papillary T-cell depleted contexture and activated FGFR3 signaling. Nat Commun 2019 Jul 5;10(1):2977.
  4. Loriot Y, Matsubara N, Park SH, et al. Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2023 Nov 23;389(21):1961-1971.
  5. Siefker-Radtke AO, Matsubara N, Park SH, et al. Erdafitinib versus pembrolizumab in pretreated patients with advanced or metastatic urothelial cancer with select FGFR alterations: Cohort 2 of the randomized phase III THOR trial. Ann Oncol. 2023 Oct 21 [Epub ahead of print].
  6. Ohara K, Rendeiro AF, Bhinder B, et al. The evolution of genomic, transcriptomic, and single-cell protein markers of metastatic upper tract urothelial carcinoma. Nat Communications 2023 In Press.