HAMBURG, germanyElevated 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
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
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.