In patients with urothelial cancer, genetic variations linked to response to platinum treatment

May 1, 2011

A gene signature comprising four different single-nucleotide polymorphisms associated with response to platinum-based therapy in patients with urothelial carcinoma has been identified by Irish and U.S. researchers.

Orlando, FL-A gene signature comprising four different single-nucleotide polymorphisms (SNPs) associated with response to platinum-based therapy in patients with urothelial carcinoma has been identified by Irish and U.S. researchers.

"Platinum compounds are regulated by genes involved in DNA detoxification and repair," said first author David J. Gallagher, MD, attending medical oncologist at Mater Hospital, Dublin, Ireland. "We were able to identify four common germline variants independently associated with response of urothelial cancer to platinum-based therapy that may be biologically and clinically relevant."

Platinum-based therapy is associated with improved outcomes in neoadjuvant and metastatic urothelial cancer. Based on studies of other cancers that show germline associations (ie, inherent DNA, not tumor tissue DNA) with platinum response, the investigators hypothesized that germline variation also identified genes that determine urothelial cancer response to platinum-based therapy, Dr. Gallagher explained at the Genitourinary Cancers Symposium in Orlando, FL.

A univariate analysis found six SNPs to be associated with response. A subsequent multivariate analysis adjusted for two clinical risk factors (presence of visceral metastases and Karnofsky performance status <80%) identified four SNPs that were significantly associated with response to platinum: IL1B, CCND1, PARD6B, and RS1520896.

Predictive model created

A predictive model was developed based on the four SNPs, the two clinical risk factors, and an SNP score between 0 and 8. The investigators looked at the percent of patients with complete response and partial response across the SNP score, and found that the model more accurately predicted response than clinical factors alone. This is a first step, and the model needs validation, Dr. Gallagher told meeting attendees.

"This study is part of an important theme at this meeting," said senior author Dean Bajorin, MD, professor of medicine at Memorial Sloan-Kettering and the Weill Medical College of Cornell University in New York. "Intrinsic genetic makeup may predict how patients respond to drugs. Our genetics are expressed in the tumor we develop. Historically, we have looked at somatic DNA in the tumor. Only recently, we have begun to study germline DNA, which is our inherent DNA."

At least four abstracts reported at this year's Genitourinary Cancers Symposium focused on germline DNA, he added.

"Our study found that response to platinum-based therapy was predicted by four SNPs from a total of 80 SNPs that we looked at. This suggests that more factors are at play [in response] than tumor characteristics," Dr. Bajorin said.

Studies are planned to look at other patient populations with urothelial cancer to determine whether these four SNPs hold up as predictive of response to cisplatin.

"Pharmacogenomics will play an increasing role in determining how drugs are used. Our ultimate goal is to select patients who are more likely to respond to a given therapy," Dr. Bajorin concluded.