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Study Identifies Key Biologic Features of Upper Tract Urothelial Carcinoma

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Key Points

  • The FGFR3 gene is hyperactive in upper tract urothelial carcinomas, particularly in tumors with very low T-cell signatures, and that inhibition of FGFR3 upregulates genes in the interferon-gamma pathway, suggesting a link between FGFR3 and the immune system.
  • The authors reported other findings from the molecular dissection of upper tract urothelial carcinoma: most are luminal-papillary, and the sporadic upper tract urothelial cancer is characterized by a lower tumor mutational burden than urothelial carcinoma of the bladder.

A new study published by Robinson et al in Nature Communications aimed to learn more about the biologic characteristics of upper tract urothelial carcinoma to help develop more targeted therapies.

“We discovered the defining biologic characteristics of [upper tract urothelial tumors] that set them apart from urothelial cancer of the bladder,” said senior author Bishoy Faltas, MD, of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, and an oncologist who specializes in urothelial cancers at NewYork-Presbyterian/Weill Cornell Medical Center.

Only about 10% of cancers affecting the lining of the urinary tract arise in the upper segment that collects and carries urine from the kidneys to the bladder. These upper tract urothelial carcinomas tend to be more aggressive than bladder cancers, and are usually not detected until they are at a more advanced stage.

Findings

To understand the key biologic features of upper tract urothelial carcinoma, Dr. Faltas and colleagues sequenced all the genes and their RNA messages in tumors collected from patients at Weill Cornell Medicine, Baylor College of Medicine, and MD Anderson Cancer Center. Then, they compared their data to the molecular profiles of urothelial carcinoma of the bladder from the Cancer Genome Atlas.

The genetic information they analyzed helped to explain why there is a lower number of T cells in upper tract urothelial carcinomas. They found that the FGFR3 gene is hyperactive in these cancers, particularly in tumors with very low T-cell signatures, and that inhibition of FGFR3 upregulates genes in the interferon-gamma pathway, suggesting a link between FGFR3 and the immune system.

When the investigators treated urothelial cancer cells that displayed hyperactive FGFR3 signaling with the FGFR3 inhibitor erdafitinib in the laboratory, it increased the activity of the BST2 gene, a hallmark of immune system activation. “By inhibiting FGFR3, we are able to upregulate genes that are associated with activation of the antitumor immune response,” said Dr. Faltas. “In the future, we could potentially use this strategy to reverse the T-cell depletion in these tumors.”

The authors reported other findings from the molecular dissection of upper tract urothelial carcinomas: most are luminal-papillary, and the sporadic upper tract urothelial carcinoma is characterized by a lower tumor mutational burden than urothelial carcinoma of the bladder.

Dr. Faltas said the findings suggest that combining FGFR3 inhibitors like erdafitinib with programmed cell death protein 1/programmed cell death ligand 1 inhibitors may be a potential strategy for treating upper tract urothelial carcinomas. “Our paper provides the biologic rationale for the combination, and shows how FGFR3 signaling and the immune response are linked,” he said.

The U.S. Food and Drug Administration approved erdafitinib for treating metastatic cancers in the lining of the urinary tract in April 2019.

“We are hoping that in the future,” Dr. Faltas said, “as we gain a deeper understanding of the drivers of the unique biology [of upper tract urothelial carcinomas], that we will be able to develop specifically targeted treatment strategies for this cancer.” 

Disclosure: For full disclosures of the study authors, visit nature.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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