GENETICS OF SMALL CELL BLADDER CANCER

ORLANDO, Florida ― Small cell bladder carcinoma (SCBC) is a rare, aggressive subtype of bladder cancer that is generally diagnosed at an advanced stage, with up to 65% of patients having metastases at, or soon after, diagnosis. Although the standard therapy remains cisplatin and etoposide, response to chemotherapy is poor.

However, an extensive multiplatform molecular analysis has identified biomarkers that may help explain SCBC's resistance to standard chemotherapy and the aggressive course of the disease.

In addition, next-generation sequencing (NGS) and Sanger sequencing helped reveal cell surface receptors and downstream molecules that may be candidates for therapeutic strategies.

The data were presented here at Genitourinary Cancers Symposium (GUCS) 2015.

"We utilized a multimodality approach to identify subsets of small cell bladder cancer," study author David Arguello, MD, a research scientist at Caris Life Sciences, the sponsor of the study, told Medscape Medical News.

Owing to the rarity of the disease, which accounts for only 0.5% to 1.0% of bladder malignancies, the team had only 19 samples to use for their assays. Molecularly, SCBC is similar to small cell lung cancer, which also responds poorly to chemotherapy.

Using a multiplatform profiling system, the researchers evaluated 19 SCBC specimens to identify potential targets and therapeutic options for this malignancy. Protein expression was assessed by immunohistochemistry (IHC), and gene amplification was determined using fluorescent in situ hybridization or chromogenic in situ hybridization.

Sequencing was then performed by either Sanger sequencing or NGS, with NGS evaluating up to 47 genes at a depth of 1500x.

Similarly to what has been found in small cell lung cancer, TP53 was the most common mutation (90.0%) in the small cell bladder cancer samples. "So even though we are looking at a different organ system, it behaves in a similar fashion," Dr Arguello told Medscape Medical News.

"We were also looking at various mutations that may have significance in targeting," he continued. "Just like its cousin urothelial carcinoma, the PIK3CA pathway is impacted in this disease. It looks like there are a small subset of patients who have mutations that are related to the PIK3CA pathway, such as PTENand FBXW7. Many of these are tumorigenic and could be potential drivers of this disease."

Aberrations that were identified by NGS included TP53 (90%), cMET (20%), RB1 (11.1%), FBXW7 (10%), and PTEN (10%). Sanger sequencing also detected mutations in KRAS (1/1 [100%]) and PIK3CA (1/3, 33.3%).

Potential Therapies Revealed

IHC testing revealed clues as to why much of the standard treatments are not effective in this disease. The high expression of the multidrug resistance protein 1 (MRP1), which is associated with resistance to various chemotherapies, was present in all five of the specimens tested for this protein.

In addition, high expression of RRM1, TUBB3, and TS imply resistance to agents such as gemcitabine, paclitaxel, and fluorouracil, Dr Arguello commented.

PD-L1, the ligand to PD-1, was not expressed in any of the six samples assayed. The absence of PD-L1 expression suggests that immunotherapy may not be as beneficial in the population, he pointed out.

"Using IHC, we also tried to identify those patients who are most likely to respond to conventional chemotherapeutics," Dr Arguello said. "For example, there is a subset who may be able to benefit from treatments like temozolomide, which is not usually used in this disease."

Temozolomide (Temodar, Merck Sharp & Dohme Corp) is currently approved in the United States for the treatment of glioblastoma multiforme and melanoma. "Based on our cohort of SCBC patients, we found that a significant number of patients had low or absent MGMT protein expression [15/18, 83.3%], which indicates a potential ― and I emphasize potential ― benefit with temozolomide, an agent typically associated with CNS cancers," explained Dr Arguello.

For background, he noted, the association between improved temozolomide response/survival and low/absent MGMT has been established in gliomas using methodologies such as immunohistochemistry and pyrosequencing.

Outside of CNS cancers, a case has been reported of a colorectal cancer patient with low/no MGMT protein expression who responded to temozolomide. "Although we do not have clinical evidence of temozolomide response in SCBC, this may be worth further exploration," he said.

High protein expression of TOP2A and TOPO1 indicates that anthracyclines and camptothecins may play a role in disease management.

There were also mutations in cMet, but the significance of those is still under investigation, explained Dr Arguello. EGFR amplification was also detected in 1 of 4 (25%) specimens, and clinical trials testing efficacy of EGFR inhibition may be worthwhile.

Larger analyses of this aggressive disease are warranted. "We are developing a very large panel that will look at about 598 genes, and hopefully we will be able to find more aberrations, which will be able to guide future clinical trials," he said.

The study was funded by Caris Life Sciences. First author Jue Wang, MD, has disclosed no relevant financial relationships. Dr Arguello and two coauthors are employees of Caris.

Genitourinary Cancers Symposium (GUCS) 2015. Abstract 338. Presented February 27, 2015.