Molecular-Based Treatment for Bladder Cancer

By Gopa Iyer, MD , John Sfakianos, MD , and David Solit, MD
Friday, May 23, 2014

More than 70,000 cases of bladder cancer are diagnosed each year in the United States. While the majority of them are superficial in nature and can be managed with cystoscopic resection, up to one-third of patients present with muscle-invasive disease, which mandates treatment with cystectomy and perioperative cisplatin-based chemotherapy.(1)

Unfortunately, bladder cancer is a disease of the elderly, a population that harbors multiple medical co-morbidities. As many as half of patients with muscle-invasive disease are not suitable candidates for cisplatin chemotherapy.(2) Additionally, even with the application of this standard-of-care treatment, a significant number of patients are at high risk for metastatic recurrence of disease.

Currently, in the metastatic setting, cure with chemotherapeutic regimens is extremely rare.

Genomic Analysis

Over the last 20 years, no Food and Drug Administration–approved treatment for bladder cancer has been developed, underscoring our limited understanding of the fundamental biologic changes that drive tumorigenesis, invasiveness, and metastatic spread. However, multiple large-scale efforts at defining the hallmark genetic alterations within bladder cancer have been underway for the past five years.(3),(4),(5)

Notably, bladder cancer has been observed to harbor one of the highest rates of somatic alterations across cancer types, similar in number to those for melanoma and lung cancer.

Recently, as part of The Cancer Genome Atlas (TCGA) project, researchers performed a comprehensive, multi-platform genomic analysis of a panel of muscle-invasive high-grade bladder tumors, incorporating whole exome sequencing and whole transcriptome sequencing as well as methylation and phospho-proteomic profiling.(6)

Complex Changes

While these studies have revealed a complex complement of mutations and structural alterations within bladder cancer, recurrent genetic changes were also identified, many of which are targetable by small-molecule inhibitors being evaluated in other cancers.

Improved characterization of the crucial alterations within bladder cancer — upregulation of mitogenic signaling pathways, dysregulation of genes that control the cell cycle, derangements of modifiers of chromatin remodeling, or disruption of canonical DNA repair pathways — should lead to a better understanding of this genetically complex disease and subsequently open new avenues for treatment.

This information will ideally provide the treating physician with predictive biomarkers of response to both standard cytotoxics as well as targeted therapies, thereby allowing for prospective selection of patients most likely to respond to a given treatment.

A New Era of Targeted Therapies

At Memorial Sloan Kettering, we are sequencing every patient with metastatic bladder cancer to define the complement of targetable alterations within tumors. We are using a CLIA-certified next-generation exon capture and sequencing assay that screens over 300 oncogenes and tumor suppressor genes across tumor types.(7)

Additionally, we are performing whole exome sequencing of patients who achieve durable, significant responses to targeted therapies, in an effort to identify unique predictive biomarkers of response that can steer future trials of such agents.

Ultimately, the goal of all of these efforts is to usher in a new era of targeted therapies so that cures in bladder cancer will no longer be rare, but an expected outcome.