Bladder cancer genomic landscape study aims to spawn new biomarker-guided therapies

Bladder cancer genomic landscape study aims to spawn new biomarker-guided therapies

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

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

As a patient advocacy organization, BCAN aimed to complement The Cancer Genome Atlas (TCGA) findings on bladder cancer with the goal of directly helping patients, said BCAN co-founder Diane Zipursky Quale.

“We’ve been looking to try to better understand metastatic disease by doing genomic sequencing,” Quale said. “The idea was also to be able to provide patients with the genomic report that would perhaps contain clinical trials for them or perhaps highlight mutations that might be actionable.”

While many patients with bladder cancer in the metastatic setting receive genomic profiling, there are few approved treatments available for patients with potentially actionable mutations, according to Matt Milowsky, lead author of the UC-study. GENOME and co-director of the urological oncology program at the University. from the 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% of participants had potential treatment options identified. by NGS, while only 5% 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 United States for bladder cancer: Janssen Balversa’s FGFR inhibitor (erdafitinib), for patients with locally advanced or metastatic bladder cancer who has alterations in the FGFR2 or FGFR3 gene. There are also several immunotherapies approved for bladder cancer patients, including Keytruda from Merck (pembrolizumab), Opdivo from Bristol Myers Squibb (nivolumab), Tecentriq from Genentech (atezolizumab), and Bavencio from Merck KGaA and Pfizer (avelumab). Immunotherapies are an option as adjuvant or neoadjuvant therapy and for patients who are not eligible for platinum-based chemotherapy. However, the immunotherapy landscape continues to change as Genentech announced in November that it would withdraw its indication for Tecentriq in first-line PD-L1-positive bladder cancer in the United States.

“Hopefully with further 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 seem potentially exploitable. It would make sense that there was an opportunity here.”

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

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

Researchers also explored T-cell inflammation and immune subtypes in metastatic bladder cancer. They characterized the tumor microenvironment (TME) of UC-GENOME participants using 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, researchers assessed whether immune subtypes or genetic mutations were predictive or prognostic of response to chemotherapy or immunotherapy in a model that combined participants’ clinical and immunogenomic data. They found that patients with B-cell genetic signatures, stroma-rich subtypes, or claudin signatures had poorer outcomes with immune checkpoint inhibitors. Groups of patients who performed better included those with elevated TMB and M1 macrophage signatures.

Milowsky said there haven’t been many predictive biomarkers identified in the setting of metastatic bladder cancer, which means oncologists continue to treat all patients with the same therapies, even if some patients don’t benefit. none of these treatments.

“One of the things that excites me is the pursuit [push] towards the development of predictive biomarkers and the use of more sophisticated machine learning algorithms to do so by incorporating clinical data and genomic data,” he continued. “The more data we generate and the more we validate the models we develop in other datasets, the more confident we will be to integrate these biomarkers into clinical trials to guide therapy in a study. »

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

The organization is accepting proposals for the Translational Clinical Trials Award and expects to select a project in March 2023, Quale said. The aim of the study, she added, is to identify “new strategies and agents to reduce the burden of 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 cystectomy, which removes all or part of the bladder in patients with muscle-invasive bladder cancer. , she said.

BCAN offers several grants, including Young Investigator Awards and Innovation Awards, to encourage researchers to continue their work in bladder cancer. Milowsky also noted how the involvement of a patient advocacy organization like BCAN in the UC-GENOME project has helped keep patients at the center of research. “It’s a really unique mechanism for research,” he said.

“BCAN has been funding bladder cancer research for years because no one else was doing it,” Quale said. The translational clinical trial award, she noted, contemplates early phase, investigator-initiated clinical trials that are unlikely to be funded by pharmaceutical companies or other entities.

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

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