June 19, 1998 LOS ANGELES, June, 16, 1998 -- A new molecular marker can be used to better predict tumor progression in men with prostate cancer, the second-leading cause of male cancer deaths in the United States. Researchers at the USC/Norris Comprehensive Cancer Center report the new findings from a study of 96 men with localized disease in the June 17 issue of the Journal of the National Cancer Institute. The team found that patients with tumors expressing abnormally low levels of a protein important in regulating cell division faced a significantly higher risk of disease recurrence and death than patients with tumors expressing high levels of the protein.
"Physicians may be able to use this tumor marker to identify prostate cancer patients most likely to harbor dangerous, life-threatening tumors," says Richard J. Cote, M.D., who led the study team. Cote is an associate professor of pathology and urology at the USC/Norris Cancer Center.
"In addition, the marker can help doctors make better decisions about treatment, ensuring that men most likely to develop metastatic disease undergo aggressive therapies. It will also help identify men who can avoid the most intensive and expensive treatments," he says. The American Cancer Society estimates that this year 184,500 American men will be diagnosed with prostate cancer and that some 42,000 men will die of the disease. With one of the highest incidences of all cancers, it is the second-leading cause of cancer deaths in men. Gauging how aggressive prostate tumors are -- and thus how aggressive treatment should be -- has created a quandary for physicians and men diagnosed with early prostate cancer.
In the last decade, the widespread use of the prostate specific antigen (PSA) test has allowed the detection of many more cases of early prostate cancer than previously possible. Yet, scientists believe that many of the localized tumors identified by the PSA screen are so slow-growing that men are more likely to die from other causes than from prostate cancer.
"The dilemma is to identify those cancers most likely to progress and kill the patient," Cote says. "We just haven't had the tools to do that in prostate cancer."
In the study, Cote and colleagues analyzed the prostate tumors of 96 men, aged 46 to 79, who underwent radical prostatectomy (with removal of pelvic lymph nodes) between 1982 and 1989. All tumors had invaded nearby tissue but had not spread to the lymph nodes. These patients fall into a clinical gray area. Although these types of tumors can be treated with surgery or radiation, as many as 50 percent of patients will develop recurrent disease within five years. Participants were followed for an average of 9.6 years after surgery.
Using monoclonal antibodies, the team assayed the tumor samples for the presence of the p27(Kip1) protein. p27 helps control the timing and rate of cell division and, when functional, can stall tumor growth. As part of the body's natural defense against cancer, the p27 protein is found in virtually all normal cells. In previous studies, low levels of p27 protein in tumor cells have been shown to predict disease progression in breast and colon cancer.
Researchers divided the 96 tumors into three groups, based on the percent of tumor cells in each sample expressing p27 protein. Fifty-three tumors had high levels of the protein, with more than 50 percent of tumor cells expressing p27; 31 tumors showed moderate levels (between 11 and 50 percent of tumor cells produced p27); and 12 samples showed low (less than 10 percent of cells) or undetectable levels of the protein.
Decreased p27 expression was strongly associated with an increased rate of tumor recurrence. Men with the lowest p27 expression had a more than three-fold increased risk of recurrence, and more than eight-fold increased risk of dying, when compared to patients with the highest p27 expression. Of the men in the high p27 group, 67 percent remained disease free after 9 years, compared to 47 percent in the moderate group and 17 percent in the low group. In addition, 92 percent of men in the high p27 expression group were still alive after 9 years, while only 79 percent of the moderate group and 49 percent of the low group survived at 9 years.
"Evaluation of p27 in prostate cancer may not only be of great medical importance, but may also have tremendous economic benefits as well," says study co-author Gary Lieskovsky, M.D., professor of urology at the USC/Norris Cancer Center. "It could help us determine those patients who need aggressive therapy versus those patients who may be best treated more conservatively."
Notably, scientists think that tumors lose expression of p27 through an increase in enzymes that degrade the p27 protein, and not because of a malfunction in the p27 gene, as is the case with some other common tumor markers like the p53 tumor suppressor gene. This points to the importance of looking at protein expression -- and not simply genetic analysis -- when evaluating cancer cells, Cote says. Cote's team is now investigating whether levels of p27 expression could play a role in tumor resistance to hormone treatment and chemotherapy.
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