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Headshot of Matt Milowsky
UNC Lineberger’s Matthew Milowsky, MD, FASCO.

A comprehensive genomic analysis in more than 200 patients with metastatic urothelial carcinomas may help inform how a patient would respond to immunotherapy, report UNC Lineberger Comprehensive Cancer Center researchers and colleagues. About 90% of urothelial carcinomas are bladder cancers. These results, derived from a computational model based on the initial molecular findings of the UC-GENOME study, are published in Nature Communications.

The Bladder Cancer Advocacy Network (BCAN) initiated this multi-institutional nationwide collaboration, which has helped establish a biobank of samples for use by researchers in the field.

When mutations occur in urothelial cells, which line the urinary system, they can develop into urothelial carcinoma, the most common form of bladder cancer. The average age of people diagnosed with bladder cancer is 73; in the U.S. there will be an estimated 81,180 new cases of bladder cancer and about 17,100 deaths in 2022.

Focused on helping patients now and in the future

“The overarching goal of our study was to provide every patient with metastatic urothelial cancer the opportunity to become an exceptional responder and to develop a rich clinical database and biorepository for future collaborative research efforts,” said Matthew Milowsky, MD, FASCO, the George Gabriel and Frances Gable Villere Distinguished Professor at the UNC School of Medicine and co-corresponding author of the article.

Headshot of Jeffrey Damrauer
Jeffrey S. Damrauer, PhD.

“Most significantly, these findings provide a potential way to predict response to immunotherapies by integrating clinical and molecular features,” said Milowsky, who is also section chief of Genitourinary Oncology in the UNC Division of Oncology and co-director of the Urologic Oncology Program at UNC Lineberger.

UC-GENOME enrolled 218 patients with metastatic urothelial cancer. Based on genetic sequencing analyses of their tumor tissue, 69.3% of people in the study had potential treatment options, but only 5% went on to receive therapy based on their genomic profiles.

“Two of the likely reasons for limited use of sequencing-directed treatment were the absence of FDA-approved targeted therapies at the time of patient accrual and the approval and use of immune checkpoint inhibitor therapy during the course of the study,” said lead author Jeffrey S. Damrauer, PhD, Bladder Cancer Research Program manager at UNC Lineberger and who co-led the study with Wolfgang Beckabir, a graduate student in UNC School of Medicine’s MD/PhD program. “We hope, that moving forward, genomically informed decisions can lead to patients being matched with the therapy that gives them a high likelihood to achieve the best outcome.”

Stroma-rich subtype may have higher risk

Researchers also uncovered a striking finding: one of the molecular subtypes, stroma-rich, was overrepresented in UC-GENOME tumor samples compared with non-metastatic samples. This enrichment suggests that patients with the stroma-rich subtype may have an increased chance of developing metastatic disease.

William Y. Kim, MD, is a UNC Lineberger member and associate professor in the UNC School of Medicine.
UNC Lineberger’s William Y. Kim, MD.

Through integrating all of the analyses with clinical data, the team also found that a subset of genomic and clinical features could predict whether or not a patient would respond to immunotherapy. While these findings are encouraging to the authors, they state that future work by UNC and others is needed to validate their findings.

“This trial was developed through BCAN with philanthropic funding in collaboration with other academic institutions,” said UNC Lineberger’s William Y. Kim, MD, Rush S. Dickson Distinguished Professor of Medicine and professor of Genetics at UNC School of Medicine and a co-corresponding author on the paper. “BCAN is already working to develop a new funding mechanism to utilize the biospecimens collected in this study alongside our analyses so that all patients can benefit from a better understanding of bladder cancer biology.”

Authors and disclosures

In addition to Milowsky, Damrauer, Kim and Beckabir, the other authors at UNC include Jeff Klomp, PhD, Mi Zhou, PhD, Benjamin G. Vincent, MD, Sara E. Wobker, MD, MPH, and Katherine A. Hoadley, PhD. Elizabeth R. Plimack, MD, MS, Fox Chase Cancer Center, Temple Health, Philadelphia; Matthew D. Galsky, MD, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York; Noah M. Hahn, MD, Johns Hopkins University School of Medicine, Baltimore; Peter H. O’Donnell, MD, University of Chicago; Gopa Iyer, MD, Memorial Sloan Kettering Cancer Center, New York; David I. Quinn, MD, University of Southern California Norris Comprehensive Cancer Center, Los Angeles; and Diane Zipursky Quale, JD, Bladder Cancer Advocacy Network, Bethesda, MD.

This project was sponsored by the Bladder Cancer Advocacy Network through donations from the James Family Foundation, The JPB Foundation and The Gerald C. McNamara and Renee K. Petrofes Charitable Fund. Additional funding was provided through the Cancer Center Core Support Grant #P30-CA016086 and NIH grant #R01-CA241810.

Quinn received payment for advisory board involvement from Astellas, BMS, Merck, Pfizer, Roche/Genentech, and Seattle Genetics, as well as employment and stock options from Abbvie. No other authors have competing interests relating to this study.