LOS ANGELES, July 15, 1998 -- A new study from the University of Southern California concludes that a molecular test may indicate which patients with locally advanced bladder cancer will most likely recur and which will be cured following surgical treatment.
Reporting in the July 15 Journal of the National Cancer Institute, John P. Stein, M.D., Richard J. Cote, M.D., and colleagues at the USC/Norris Comprehensive Cancer Center show patients with tumors expressing low levels of the tumor suppressor protein p21 are more likely to recur and die from the disease than those with elevated p21 levels.
"Our findings should help us to determine which patients will most likely benefit from continuing treatment after surgery, and which patients could be spared its toxic side-effects," says Stein, an assistant professor of urology at USC School of Medicine.
The study marks the USC/Norris team's latest finding from the emerging field of molecular diagnostics. By focusing on the nature of genetic changes in cancer cells and how these changes relate to the clinical course of disease, scientists have begun to forge new tools that may be used to predict how an individual will respond to treatment.
Stein and Cote studied 242 men and women, aged 49 to 83, who had surgery to remove the bladder after being diagnosed with locally confined cancer. Participants were followed for an average of 8.5 years. Researchers analyzed bladder tumor tissue using antibodies specific to the p21 protein and also tested for alterations in the expression of the p53 tumor suppressor protein.
Scientists found that 36% of tumors were p21 negative and 64% p21 positive. Patients with p21-positive tumors survived disease-free significantly longer than those patients with p21-negative tumors. Those in the latter group had a higher risk of recurrence and poorer overall survival, independent of other predictors.
Approximately 50,000 people are diagnosed with bladder cancer each year.
In general, tumor suppressor genes and proteins regulate the cell division cycle, acting as brakes on tumor cell growth. The p21 protein interacts with other proteins, including other tumor suppressors such as p53, to control when and how the cell replicates. If p21 is not present, this critical growth check-point disappears, allowing the cell to divide in an uncontrolled fashion.
Earlier work has shown that bladder cancer patients with alterations in the p53 tumor suppressor gene are more likely to recur or progress to metastatic disease. In addition, p53 is known to be a primary regulator of p21, since genetic changes in p53 may lead to loss of p21 expression and function. This in turn leads to unregulated cell growth, and is thought to contribute to the aggressive behavior of some tumors.
Importantly, in this study, researchers found that some patients with dysfunctional p53 are able to maintain p21 expression. These patients show similar rates of recurrence and survival as patients with normal p53 and p21. "We reasoned that if p21 is expressed despite alterations in p53, then cell cycle control might be maintained and the tumors would be less likely to progress," says Cote, USC associate professor of pathology and urology. "Our hypothesis seems confirmed by this study."
The study also highlights the need for a greater understanding of how the tumor suppressor genes and proteins function, says Cote. "While p53 status of a tumor provides a strong indication about the risk of recurrence, this study shows that knowledge of both p53 and p21 status is a more powerful indicator of risk," he says.
According to Stein, the findings from the present study, as well as other studies characterizing the influence of molecular alterations on tumor behavior, will have important clinical implications. "Molecular markers will allow us to manage patients with a clearer idea of the benefits of treatment in that individual. This represents a great advantage to physicians and patients," Stein says.
To help move molecular diagnostics from the research lab to the clinic, Cote and Stein are leading a multi-center, randomized clinical trial using p53-status of tumor cells and other molecular markers like p21 to guide treatment decisions in bladder cancer patients -- one of the first of its kind.
In an editorial in the same issue of the journal, oncologists Randall Millikan and Christopher Logothetis of the M.D. Anderson Cancer Center in Houston, Texas, write that more research is necessary before p21 can be used to guide treatment in all patients. Yet, "By expanding the important observations of the investigators from the Kenneth Norris Jr. Comprehensive Cancer Center to specific populations, bladder cancer may soon join the rank of human cancers in which molecular characterization drives therapeutic intervention."
"Effect of p21(WAF1/CIP1) Expression on Tumor Progression in Bladder Cancer," by John P. Stein, David A. Ginsberg, Gary D. Grossfeld, Sunanda J. Chatterjee, David Esrig, Ming G. Dickinson, Susan Groshen, Clive R. Taylor, Peter A. Jones, Donald G. Skinner and Richard J. Cote. JNCI. Vol. 90, No.14, July 15, 1998.
To arrange an interview with John Stein or Richard J. Cote, please call Eva Emerson at 323-442-2830.
Journal
JNCI Journal of the National Cancer Institute