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Bladder Cancer Genomic Landscape Study Aims to Engender New Biomarker-Guided Therapies

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NEW YORK – In a collaborative effort supported by the Bladder Cancer Advocacy Network (BCAN), researchers from cancer centers across the US have explored the genomic landscape of bladder cancer to potentially inform new biomarker-guided treatment strategies.

The findings from the project, called Urothelial Cancer – Genomic Analysis to Improve Patient Outcomes and Research (UC-GENOME), were published this month in Nature Communications. Researchers performed next-generation sequencing on samples from 218 patients with metastatic urothelial carcinoma, identifying potential actionable mutations for further study and exploring biomarkers of response to immunotherapy and chemotherapy.

As a patient advocacy organization, BCAN aimed to supplement the findings of The Cancer Genome Atlas (TCGA) in bladder cancer with the goal of helping patients directly, said Diane Zipursky Quale, BCAN's cofounder.

"We looked at trying to gain a better understanding of metastatic disease by doing genomic sequencing," Quale said. "The idea was also to be able to get patients the genomic report that would maybe have some clinical trials for them or maybe highlight mutations that might be actionable."

While many bladder cancer patients in the metastatic setting do receive genomic profiling, there are few approved treatments available for patients with potentially actionable mutations, according to Matt Milowsky, senior author of the UC-GENOME study and codirector of the urologic oncology program at the University of North Carolina School of Medicine.

Milowsky said the group was trying to assess the uptake of targeted therapies in bladder cancer through the UC-GENOME study, but found that 69.3 percent of participants had potential treatment options identified by NGS, while only 5 percent received therapy based on NGS results, including 2.7 percent of patients who were enrolled in a clinical trial.

There is only one targeted therapy approved in the US for bladder cancer: Janssen's FGFR inhibitor Balversa (erdafitinib), for patients with locally advanced or metastatic bladder cancer that has FGFR2 or FGFR3 gene alterations. There are also several immunotherapies approved for bladder cancer patients, including Merck's Keytruda (pembrolizumab), Bristol Myers Squibb's Opdivo (nivolumab), Genentech's Tecentriq (atezolizumab), and Merck KGaA and Pfizer's Bavencio (avelumab). Immunotherapies are an option as an adjuvant or neoadjuvant therapy and for patients who are ineligible for platinum-based chemo. However, the immunotherapy landscape continues to change as Genentech said in November it would withdraw its indication of Tecentriq in first-line PD-L1-positive bladder cancer in the US.

"Hopefully with additional research, we will be able to develop more targeted therapies for patients with this disease," Milowsky said. "Bladder cancer is rich in mutations and copy number alterations, and many of them appear potentially actionable. It would make sense that there would be opportunity here."

The study found that metastatic bladder cancer patients were more likely to harbor a mutation in TP53 E285K than non-metastatic patients from TCGA. In the UC-GENOME cohort, 57 percent of patients harbored a TP53 mutation, making it the most frequently mutated gene. The researchers hypothesized that the presence of TP53 mutations is a result of upregulated APOBEC activity, which is a driver of cancer progression. They also found that 18 percent of participants harbored a mutation in tumor suppressor gene RB1.

Other common mutations were in chromatin modifying genes KMT2D, ARID1A, KDM6A, KMT2C, EP300, KMT2A, CREBBP, and SMARCA4; in DNA damage repair genes BRCA2, PRKDC, ATM, ERCC2, and FANCA; in genes associated with aberrant kinase signaling FGFR and PIK3CA; and in amplifications of CCND1, MDM2, ERBB2, CCNE1, and EGFR.

The researchers also explored T-cell inflammation and immune subtypes in metastatic bladder cancer. They characterized the tumor microenvironment (TME) of UC-GENOME participants through immune gene expression signatures. They found a higher proportion of stroma-rich subtypes, with higher immune gene expression signature scores, in these metastatic patients.

In an exploratory analysis, the researchers evaluated whether any immune subtypes or gene mutations were predictive or prognostic of response to chemo or immunotherapy in a model that combined clinical and immunogenomic data from the participants. They found patients with B cell gene signatures, stroma-rich subtypes, or claudin signatures performed worse on immune checkpoint inhibitors. The groups of patients who performed better included those with high TMB and M1 macrophage signature.

Milowsky said there haven't been many predictive biomarkers identified in the metastatic bladder cancer setting, which means oncologists continue to treat all patients with the same therapies, despite some patients not benefiting from those treatments.

"One of the things that's exciting for me is the continued [push] toward developing predictive biomarkers and using more sophisticated machine learning algorithms to do that by incorporating clinical data and genomic data," he continued. "The more of that data we generate and the more validation of the models that we develop in other datasets, the more confident we will be to embed those biomarkers within clinical trials to guide therapy within a study."

The UC-GENOME study also created a biobank of clinically annotated specimens and their associated molecular data to become a resource for future translational research in bladder cancer. To that end, BCAN is also offering a Translational Clinical Trial Award of up to $3 million to support a potential clinical study in bladder cancer.

The organization is accepting proposals for the translational clinical trial award and expects to select a project in March 2023, Quale said. The goal of the study, she added, is to identify "novel strategies and agents to reduce the burden on bladder cancer patients or to improve the quality of life for bladder cancer." One goal is to find alternative treatment options that could reduce the number of patients who need a cystectomy, which removes all or part of the bladder for patients with muscle-invasive bladder cancer, she said.

BCAN has several grants available, including young investigator awards and innovation awards, to encourage researchers to continue their work in bladder cancer. Milowsky also noted how having a patient advocacy organization like BCAN involved with the UC-GENOME project helped keep patients at the center of the research. "It's a really unique mechanism for research," he said.

"BCAN has been funding bladder cancer research for years because nobody else was doing it," Quale said. The translational clinical trial award, she noted, is considering early-phase, investigator-initiated clinical trials that are unlikely to get funded by pharma or other entities.

"We're really looking to change the model," she said. "We're looking at projects that have the potential to generate the evidence to move the needle in clinical practice, and have an impact sooner rather than later on patient care."

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