Tumor-Associated Proteases Predict Outcome in Node-Negative Patients

HAMBURG, germany—Elevated levels of two related tumor-associated proteases correlated with an increased risk of recurrence after definitive surgical treatment for node-negative breast cancer, German investigators reported at the San Antonio Breast Cancer Symposium.

Patients who had elevated levels of either urokinase-type plasminogen activator (uPA) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1), had a significantly higher incidence of recurrence without adjuvant chemotherapy. The results corroborate results of other studies and make a strong case for using assays of the proteases to identify high-risk patients who might benefit from more aggressive therapy, said Christoph Thomssen, MD, an oncologist at the University of Hamburg.

“Two prospective studies by our own group have produced similar results regarding the prognostic significance of uPA and PAI-1,” Dr. Thomssen said. “In addition, almost 50 groups all over the world have reported similar results. No conflicting data have been reported. A meta-analysis of the studies is being prepared. We conclude that uPA and PAI-1 are ready to be transferred into clinical practice.”

Dr. Thomssen reported findings from an ongoing study of risk factors for recurrence in 689 node-negative breast cancer patients. Data have been collected and analyzed for 556 patients who have a median follow-up of 32 months.

The study follows an earlier investigation whereby Dr. Thomssen and colleagues demonstrated the ability to distinguish high- and low-risk pa-tients on the basis of the patients’ levels of uPA and PAI-1. The earlier study also permitted the investigators to evaluate different levels of the two proteases and their prognostic accuracy.

Findings from the previous study led the German clinical researchers to use cutoff points of 3 ng/mg protein for uPA and 14 ng/mg protein for PAI-1 to define normal and abnormal levels in the ongoing investigation.

The ongoing multicenter study involves pre- and postmenopausal women who have breast tumors of 1 to 5 cm in size. Of the 556 patients evaluated thus far, 241 have low levels of uPA and PAI-1, and 315 have elevated levels of one or both proteases.

Patients with low levels of uPA and PAI-1 have been assigned to observation because of a presumed low risk of recurrence, Dr. Thomssen said. Those patients who have elevated levels of either protease are randomly assigned to observation or to adjuvant CMF chemotherapy.

In the presumed high-risk group, 133 patients have refused randomization and have been excluded from analysis. Dr. Thomssen reported data on 208 evaluable patients in the low-risk group and 166 untreated patients in the high-risk group. To date, 10 of 208 low-risk patients have had breast cancer recurrence, compared with 23 of 166 untreated high-risk patients (P = .009). In a multivariate analysis, only tumor grade and baseline levels of the two proteases emerged as significant predictors of recurrence.

Tumor grading proved ineffective as a means of stratifying patients into high- and low-risk groups, Dr. Thomssen said. Grading categorized 70% of patients as low risk and 30% as high risk. “Use of tumor grading to categorize patients as high or low risk would lead to overtreatment in about 60% of patients,” he said. “In contrast, uPA and PAI-1 grouped 55% of patients as low risk and 45% as high risk, which would have resulted in substantially less overtreatment (50%).”

Effect of Treatment

A further comparison of treated and untreated high-risk patients showed that treatment reduced the risk of recurrence by 44%, he said. “The effect of treatment has been diluted by the high number of patients who shifted their options in favor of treatment with CMF, so, at this point, the effect of adjuvant chemotherapy on recurrence is not statistically significant,” Dr. Thomssen said. “Enrollment was completed earlier this year, and we expect to see a statistic-ally significant difference with longer follow-up.”

The findings provide confirmatory evidence of the strong and independent prognostic significance of uPA and PAI-1 in node-negative breast cancer patients, he concluded.

“More than 50% of node-negative patients express low uPA and PAI-1 in the primary tumor, and they can be identified as having less than a 10% risk of relapse within 3 years,” Dr. Thomssen said. “In these patients, adjuvant chemotherapy might be avoided. In contrast, patients who have high levels of uPA or PAI-1 in the primary tumor have a substantial risk of relapse and probably would benefit from adjuvant CMF therapy, which has reduced the risk of relapse by 43.9% in this study so far.”