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Precision medicine for urothelial bladder cancer: update on tumour genomics and immunotherapy
Kenneth M Felsenstein1,2,3,4, Dan Theodorescu1,2,5
1Department of Surgery (Urology), University of Colorado, 12631 E. 17th Avenue, Aurora, Colorado, 80045, USA.
Abstract:
Effective management of advanced urothelial bladder cancer is challenging. New discoveries that improve our understanding of molecular bladder cancer subtypes have revealed numerous potentially targetable genomic alterations and demonstrated the efficacy of treatments that harness the immune system. These findings have begun to change paradigms of bladder cancer therapy. For example, DNA repair pathway mutations in genes such as ERCC2, FANCC, ATM, RB1, and others can predict responses to neoadjuvant platinum-based chemotherapies and to targeted therapies on the basis of mutation status. Furthermore, an increasing number of pan-cancer clinical trials (commonly referred to as basket or umbrella trials) are enrolling patients on the basis of molecular and genetic predictors of response. These studies promise to provide improved insight into the true utility of personalized medicine in the treatment of bladder cancer and many other cancer types. Finally, therapies that modulate immune responses have shown great benefit in many cancer types. Several immune checkpoint inhibitors that target programmed cell death protein 1 (PD1), its ligand PDL1, and cytotoxic T lymphocyte-associated protein 4 (CTLA4) have already been approved for use in bladder cancer, representing the most important change to the urological oncologist's tool-kit in over a decade. These advances also provide opportunities for personalization of bladder cancer therapy.
Insights
Advances in understanding molecular bladder cancer subtypes are revolutionizing treatment. Genomic alterations and immunotherapies, including immune checkpoint inhibitors, offer personalized medicine approaches for advanced urothelial carcinoma.
Area of Science:
- Oncology
- Genitourinary Cancer
- Molecular Medicine
Background:
- Advanced urothelial bladder cancer management remains a significant clinical challenge.
- Recent breakthroughs have elucidated molecular subtypes of bladder cancer, identifying actionable genomic alterations.
- The efficacy of immunotherapies has been established across various cancer types.
Purpose of the Study:
- To review recent advances in understanding molecular bladder cancer subtypes.
- To discuss the impact of genomic alterations and immunotherapies on bladder cancer treatment paradigms.
- To highlight the role of personalized medicine in managing advanced urothelial carcinoma.
Main Methods:
- Review of current literature on molecular bladder cancer subtypes and targeted therapies.
- Analysis of clinical trial data for genomic alterations and immune checkpoint inhibitors.
- Discussion of approved immunotherapies targeting programmed cell death protein 1 (PD1), PDL1, and cytotoxic T lymphocyte-associated protein 4 (CTLA4).
Main Results:
- Mutations in DNA repair genes (e.g., ERCC2, ATM, RB1) predict response to platinum-based chemotherapies and targeted agents.
- Pan-cancer trials are increasingly enrolling patients based on molecular predictors, advancing personalized medicine.
- Approved immune checkpoint inhibitors (anti-PD1, anti-PDL1, anti-CTLA4) represent a major therapeutic advance in bladder cancer.
Conclusions:
- Understanding molecular bladder cancer subtypes enables personalized treatment strategies.
- Targeted therapies based on genomic alterations and immunotherapies are transforming bladder cancer care.
- Personalized medicine holds significant promise for improving outcomes in advanced urothelial carcinoma.
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