Mutational Analysis Leads Search for New Treatments for Bladder Cancer

Debra Wood, RN

April 2011, Vol 2, No 2 - Genitourinary Cancers Symposium

Orlando, FL—Novel therapies are desperately needed for bladder cancer, a common malignancy with a poor prognosis for advanced disease, said Matthew I. Milowsky, MD, medical oncologist at Memorial Sloan-Kettering Cancer Center (MSKCC), New York City, at the 2011 Genitour inary Cancers Symposium.

“Bladder cancer is an absolutely devastating disease, and the molecular characterization of these tumors is exciting,” Dr Milowsky said.

Understanding of genetic mutations associated with bladder cancer will lead to targeted therapies, already used in other cancer types. “If we are able to understand the molecular alterations that occur, then we can use multiple therapies targeting those alterations,” he said. “We are not there yet, but we are getting close.”

A number of genes associated with bladder cancer are known to harbor mutations, according to Dr Milowsky. Low-grade, genomically stable lesions are characterized by upfront alterations in fibroblast growth factor 3 (FGFR3) and the HRAS gene, whereas high-grade, invasive tumors are characterized upfront by alterations in tumor suppressors, such as p53, Rb, and PTEN genes, with a subgroup of tumors having mutations and overexpression of FGFR3.

FGFR3 mutations are present in approximately 15% of invasive bladder tumors, and overexpression occurs in approximately 40% of invasive tumors.

The MSKCC Bladder Cancer Oncogenome Project uses mutational profiling, structural variation, and methylation events to identify known driver alterations for guiding treatment or trial selection and to identify genetic drivers in patients in whom no known driver alteration has been identified.

The team profiled select mutations from 137 high-grade bladder cancer specimens. They found FGFR3 mutations in 16 samples, BRAFmutations in 2 of the tumors, PIK3CA mutations in 17 specimens and Tp53mutations in 19 samples. Dr Milowsky said it was possible to identify morphologies using microscopy and sort out patients with FGFR3mutations for clinical trials, and he foresees a time when a physician can perform a core biopsy, subject it to a biomarker analysis, and use an agent to target the molecular alterations.

Novel agents are being investigated for genitourinary cancer targeting FGFR3, PIK3CA, and BRAF, and have shown promising activity in other diseases. For example, TKI258 (dovitinib lactate) is a potent inhibitor of fibroblast growth factor, vascular endothelial growth factor, and platelet-derived growth factor receptor tyrosine kinases, which is now in clinical trials for urothelial carcinoma. Other agents targeting the epidermal growth factor receptor/HER2 pathway are ap proved for other cancers.