NEWS

Plasminogen Activator Proteins Tested as Prognostic Markers

Nancy J. Nelson

A controversial area in breast cancer treatment is the management of node-negative patients. It is known that 10 years after surgery and radiation about 30% of node-negative patients will relapse and 70% remain disease-free. The question is how to distinguish between these two groups so that chemotherapy can be given to those likely to relapse.

Go



View larger version (24K):
[in this window]
[in a new window]
 
 
A team of German investigators reporting at the annual meeting of the American Association for Cancer Research in San Francisco claims to have an answer. They believe that they can identify patients whose chance of recurrence is so small that they could forego chemotherapy. The molecules that allow them to do this are two prognostic/predictive markers, uPA, (urokinase-type plasminogen activator), and PAI-1 (plasminogen activator inhibitor-1).

In earlier work published in the British Journal of Cancer in 1999, the researchers, including Nadia Harbeck, M.D., and Manfred Schmitt, Ph.D., of the Technical University of Munich, and Fritz Janicke, M.D., of the University of Hamburg, found that 55% of the 125 node-negative patients they studied had low levels of both uPA and PAI-1 and a greater than 95% probability of disease-free survival after 5 years. In contrast, the patients with high levels of uPA and/or PAI-1 had less than a 65% probability of disease-free survival in the same time period.

Based on these data, a prospective multi-center trial for node-negative breast cancer patients supported by the German Research Association began in Germany in June 1993. In this study, the researchers addressed two issues: 1) Can the prognostic ability of uPA and PAI-1 be confirmed in a prospective multi-center study? 2) Do high levels of uPA and/or PAI-1 predict whether patients will respond to CMF (cyclophosphamide, methotrexate, and 5-fluorouracil) chemotherapy?

At the AACR meeting, Harbeck and Anita Prechtl, M.D., Technical University of Munich, presented an interim analysis of the 556 patients from this multi-center trial that showed the answer to the first question seems to be "yes," and to the second, "not yet." The data are not yet published.

Measuring Protein Levels

The German researchers performed an ELISA assay on the fresh or frozen tumor of each patients to determine the levels of the two proteins. The women with low levels of uPA (less than 3 ng/mg protein) and PAI-1 (less than 14 ng/mg protein) received no treatment. Those with either high uPA and/or high PAI-1 were randomized; half received no treatment, the other half received CMF.

Go



View larger version (17K):
[in this window]
[in a new window]
 
 
After 32 months, the interim results for the untreated patients showed 10 recurrences (out of 208) in women with low levels of both proteins and 23 recurrences (out of 166) in women with high levels of one or both of the markers. The 3-year disease-free survival was estimated to be 93.3% for those with low levels compared with 85.3% for those with high levels. The difference was statistically significant.

In the randomized high-risk patients, nine recurrences were seen among the 88 women treated with CMF, and 16 among the 94 untreated women. The probability of relapse was estimated to be reduced by 43.8% with CMF treatment; however, this reduction was not statistically significant.

The researchers concluded that they had indeed validated the prognostic power of uPA and PAI-1, that adjuvant chemotherapy may be avoided in the low-risk group because of their low risk of relapse (less than 10%), and that treatment with CMF in high-risk patients may possibly reduce risk of recurrence substantially—although the risk reduction is not yet statistically significant.

"It’s a carefully done study—done the right way. That’s impressive," said Peter Ravdin, M.D., Ph.D., of the University of Texas Health Science Center of San Antonio, commenting on the results. "It is a prospective study that definitely shows that uPA and PAI-1 are prognostic markers and shows the power of a well-standardized test to select low-risk patients with node-negative breast cancer."

Possible Criticisms

One problem with the clinical relevance of the study, however, is that the ELISA assay developed by American Diagnostica Inc., Greenwich, Conn., to detect the proteins depends on the availability of fresh or frozen tissue.

Sheila Taube, Ph.D., associate director of the Cancer Diagnosis Program at the National Cancer Institute, explained that this is a potential problem because of the small size of most node-negative tumors. Most of the tumor tissue in this country is fixed and embedded in parafin sections and used to evaluate factors such as tumor grade and hormone receptor status, leaving little or no fresh tissue available for the protein assay.



View larger version (117K):
[in this window]
[in a new window]
 
Dr. Sheila Taube

 
But the biggest criticism of the study is the short follow-up time. "At 3 years, the recurrence rate of the low-risk group is about 7%. Most people in the field want to see at least 5 years of follow-up and probably longer before we become really convinced that this is the case," said Gary Clark, Ph.D., of the Baylor Methodist Breast Center at Baylor College of Medicine, Houston. "I wish they had waited a couple of years before they presented the data."

And even if the results hold up for the 5 or 10 years of follow-up, JoAnne Zujewski, M.D., from NCI’s Division of Clinical Sciences, questioned one of the conclusions of the report—that low-risk patients should not get chemotherapy. "I wouldn’t have taken the conclusion that far at this time," she said.

"Let’s say your chance of being alive and disease-free in 10 years is 90%. If you knew you could increase your chance by 1% to 2% with chemotherapy, would you do it? Some people would."

Ravdin agreed. "The real rate of recurrence at 10 years for the low-risk group will probably be between 10% and 20%. Given the fact that adjuvant therapy can reduce risk by 50%, it’s not absolutely clear that low-risk patients shouldn’t get therapy. A think their claim is a little bit broad."

In fact, Ravdin published a survey of breast cancer survivors in a 1998 issue of the Journal of Clinical Oncology that documents the willingness of these patients to undergo chemotherapy, even with small survival gains—if their lives were extended for 3 to 6 months or their risk was reduced by only 0.5% to 1.0%.

Even though some people would accept the toxicities of chemotherapy, Zujewski and Taube think that it is very important to develop predictive markers so that patients are not overtreated.

It is estimated that at least 90% of node-negative breast cancer patients receive adjuvant therapy. Given that about 50% to 60% of breast cancer patients today present with node-negative disease, and 70% of them will not relapse without chemotherapy, the risk of overtreatment is a major issue for breast cancer management. And because better screening and detection of tumors may push the percentage of node-negative women even higher—to 70% to 80% in the near future, Janicke said—management of these patients is likely to be a major part of an oncologist’s practice.

Supporting Work

Supporting the conclusions of the German team are more than 10 years of work pointing to a key role played by the plasminogen activator system in tumor invasion and metastasis. Studies first published in 1988 showed that the activity of uPA is associated with the course of the disease in primary breast cancer patients. A serine protease, uPA is one of many enzymes involving in destroying the tissue the tumor passes through as it spreads.

"I have long been impressed by uPA family members," said Clark. "From a biological point of view, they are very, very attractive as both prognostic and predictive factors as well as targets of opportunity for novel therapies."

Daniel F. Hayes, M.D., of Georgetown University’s Lombardi Cancer Center, Washington, D.C., noted how few markers are used routinely in clinical care. "Five years ago, a panel convened by [the American Society of Clinical Oncology] was unable to determine whether any markers other than estrogen and progesterone receptor could actually be used to reliably guide patient care in a reproducible fashion," he said. Ravdin, however, thinks that three additional factors have been tested enough to have validity—HER2 (using the FISH assay) for identifying low-risk node-negative patients, S-phase, and tumor grade.

Currently, physicians rely on some combination of tumor size, grade, S-phase fraction, Ki-67, HER2, lymphovascular invasion, age, and hormone receptor status to decide to whom they will recommend chemotherapy. When the long-term results are in from the German trial, uPA and PAI-1 measurement may be one of the tools used by clinicians to assess whether a node-negative breast cancer patient would be likely to benefit from chemotherapy. "Except for S-phase, they are probably the most developed factors out there," said Clark.



             
Copyright © 2000 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement