May 2024

UROLOGY

NEW BIOMARKER MAY PREDICT TREATMENT RESPONSE IN BLADDER CANCER

Featuring: Joshua Meeks, ‘05 MD, ‘03 PhD, ‘06, ‘11 GME

​Patients with metastatic urothelial cancer and increased expression of the NECTIN4 gene had a dramatically better response to antibody treatment than patients with reduced gene expression, according to recent findings published in the Journal of Clinical Oncology.

“Our group identified that tumors with amplification of NECTIN4 had a 96 percent response to enfortumab vedotin, compared to only 32 percent in non-amplified. This could serve as a biomarker to select patients for enfortumab vedotin plus pembrolizumab, or even enfortumab vedotin alone, when there are other drugs in this space,” said Joshua Meeks, ‘05 MD, ‘03 PhD, ‘06, ‘11 GME, the Edward M. Schaeffer, MD, PhD Professor of Urology and an associate professor of Biochemistry and Molecular Genetics, who was a co-author of the study.

Bladder cancer is the fourth-leading cause of death in the U.S. and more than 83,000 new cases will be diagnosed in 2024, according to estimates from the American Cancer Society.

​Urothelial cancer, the most common type of bladder cancer, arises from mutated urothelial cells lining the inside of the bladder or urinary tract. The current five-year survival rate is more 70 percent. However, survival rates for metastatic forms of the cancer are less than 40 percent, according to the Bladder Cancer Advocacy Network.

Last year, the FDA granted accelerated approval of a combination therapy, enfortumab vedotin antibody therapy plus pembrolizumab chemotherapy, for locally advanced or metastatic bladder cancer. This approval was supported by a previous clinical trial which found that the average survival in patients who received the therapy was nearly double that of patients who did not.  

“We are really living in a completely unique time where the standard of care for metastatic bladder cancer changed overnight,” said Meeks, who is also a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Enfortumab vedotin (EV) is an anti-NECTIN4 antibody drug that targets NECTIN4, which is known to be highly expressed in bladder cancer cells. The challenge is that not all bladder cancer cells express the gene, meaning that not all patients will respond to the therapy, according to Meeks.

“We don’t really know why some tumors express it and not others,” Meeks said.

​In the current study, the investigators sought to determine whether increased expression of NECTIN4 could predict EV response in patients with metastatic urothelial cancer.

Using fluorescence microscopy, the investigators assessed NECTIN4 copy number variations (CNVs) in biopsy tumor samples from patients with metastatic urothelial cancer who were treated with EV and not treated with EV. CNVs were correlated with NECTIN4 protein expression, EV treatment responses and survival.

Ultimately, they discovered that tumors with increased NECTIN4 expression had a 96 percent response rate to EV, compared to only 32 percent in tumors with non-increased NECTIN4 expression.

The findings suggest that increased NECTIN4 expression is a biomarker of EV response and long-term survival for metastatic urothelial cancer.

“This biomarker needs further validation and prospective validation in EV trials. We have a grant with the authors funded by the Department of Defense to evaluate biomarkers and mechanisms of EV response to patients with urothelial cancer,” Meeks said.

​This work was supported by the BMBF-funded Advanced Clinician Scientist Program Bonn of the Medical Faculty of the University of Bonn and the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Young Investigator Academy UroAgeCare; the DFG under Germany’s Excellence Strategy; the Else Kröner-Fresenius Foundation/EKFS, the Clinician Scientist program of the IZKF of the FAU, the TOPeCS funding line of the IZKF of the FAU, an advanced research grant of the IZKF of the FAU Erlangen-Nürnberg, and a Young Clinical Scientist Fellowship of the Bavarian Center for Cancer Research.

This article was originally published in the Feinberg School of Medicine News Center on May 24, 2024. 
Joshua Meeks, ‘05 MD, ‘03 PhD, ‘06, ‘11 GME, the Edward M. Schaeffer, MD, PhD Professor of Urology and an associate professor of Biochemistry and Molecular Genetics, was a co-author of the study published in the Journal of Clinical Oncology.

Refer a Patient

Northwestern Medicine welcomes the opportunity to partner with you in caring for your patients. ​

You May Also Like