Bladder Cancer's Standard Treatment Changes for First Time in 40 Years... Clue to Predicting Its Effectiveness Found [Reading Science]

Seoul National University and Mount Sinai Team Analyzes Genomic Data from Patients in Routine Clinical Practice

Focus on NECTIN4 Gene Expression and Tumor Mutational Burden... Potential for Personalized Cancer Treatment

A clue has been found that could help predict which patients will benefit from the standard treatment for metastatic bladder cancer, which changed for the first time in about 40 years. The findings suggest that analyzing the activity of certain genes and the extent of mutations in cancer tissue before treatment can help gauge the effectiveness of combination therapy. The results are seen as expanding the potential for personalized cancer treatment, given the wide variation in patients' responses to therapy.

On October 15, Jo Byeori, a research assistant professor at the Institute of Genomic Medicine, Seoul National University College of Medicine, and a joint research team from Mount Sinai in the United States said they had confirmed that expression of the NECTIN4 gene and tumor mutational burden (TMB) are associated with the effectiveness of combination cancer therapy. The team analyzed large-scale genomic data from patients treated in routine clinical practice.

Study findings analyzing the efficacy of combination therapy with anticancer drugs (EV+P) in patients with metastatic urothelial carcinoma. Patients with high NECTIN4 gene expression had longer overall survival and a higher objective response rate than those with low expression. Considering tumor mutational burden (TMB) alongside NECTIN4 expression was found to help predict treatment efficacy. Image provided by the research team.

Metastatic urothelial carcinoma is cancer that has spread to other organs from the bladder, ureters, or other parts of the urinary tract. It is difficult to treat, with a five-year survival rate of only about 10%. For more than 40 years, platinum-based chemotherapy was the mainstay of first-line treatment, but a new combination therapy has recently become the standard of care.

The new treatment combines enfortumab vedotin (EV), an antibody-drug conjugate (ADC), with the immunotherapy drug pembrolizumab (P). EV delivers a cancer drug by targeting a specific protein on the surface of cancer cells, while pembrolizumab helps immune cells attack cancer cells. Although the combination has improved outcomes compared with existing cancer treatments, patients respond differently, making it important to find ways to predict treatment effectiveness in advance.

Higher NECTIN4 Expression Linked to Longer Survival and Tumor Shrinkage

The research team analyzed genomic data from patients treated in routine clinical practice that were held by Tempus AI, a U.S. healthcare artificial intelligence (AI) company. The results showed that patients with higher NECTIN4 gene expression in their cancer tissue before treatment had longer survival after combination therapy with EV and pembrolizumab and were more likely to respond to treatment, with their tumors shrinking.

NECTIN4 is the protein targeted by EV. The more of this protein cancer cells produce, the more targets the drug may be able to act on.

The team also found that analyzing tumor mutational burden alongside NECTIN4 expression can provide additional information for predicting treatment response. Tumor mutational burden refers to the amount of genetic mutations accumulated in cancer cells. In general, a greater number of mutations can give immune cells more clues to distinguish cancer cells, potentially affecting response to immunotherapy.

Jo Byeori, Research Assistant Professor at the Institute of Genomic Medicine, Seoul National University College of Medicine. Courtesy of Seoul National University.

A key feature of the study is that it used patient data collected in routine clinical practice rather than in a clinical trial. By analyzing treatment outcomes and genomic information from a diverse group of patients, the researchers identified molecular markers that could help predict the effectiveness of the new standard treatment.

NECTIN4 gene expression and tumor mutational burden can be assessed using existing genomic tests, so they may eventually help guide treatment strategies without the need for additional testing. However, separate prospective clinical validation is needed before they can be used to select patients in routine clinical practice.

“This study demonstrates the potential to predict the effectiveness of EV+P based on the molecular characteristics of a tumor before treatment,” said Jo Byeori, a research assistant professor at the Institute of Genomic Medicine, Seoul National University College of Medicine. “Prospective validation in the future could help inform personalized treatment strategies for individual patients.”

The findings were published in the international journal European Urology.

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