By Dean A. Haycock

Special To BioWorld Today

Uncertainty surrounding the subject of breast cancer goes beyond conflicting recommendations of whether women in their 40s should or should not have annual mammograms. It extends in many cases to the results of prognostic tests used by physicians and patients to decide on the best treatment. These tests, which include determination of tumor size, grade, stage and hormone receptor status, often fail to provide a clear indication of what the best treatment will be.

Now three papers from separate labs in the February issue of Nature Medicine point toward new prognostic markers that could lead to better treatment for patients with breast and other cancers.

The markers are two proteins that regulate cell division, p27 and cyclin E. While genetic mutations of other cell cycle regulators are common in human cancers, mutations in p27 and cyclin E genes are rare. Levels of these regulators in cancer cells may be controlled not by turning their genes on and off, but by their degradation.

In each of the papers, researchers report that low cellular levels of p27 protein, a potential tumor suppressor, correlates with poor cancer survival rates. The combined results suggest that measurement of p27 in different cancers may provide a powerful new prognostic tool. It might also direct selected patients with the high-risk cancer p27 profile toward more aggressive therapy earlier in the course of their disease.

In the first paper, Peggy Porter, at the Fred Hutchinson Cancer Research Center, in Seattle, and her colleagues show that high levels of cyclin E and low levels of p27 are correlated with poor breast cancer survival rates. This profile was associated with a nine-fold greater risk of death. The opposite finding, high p27 and low cyclin E, are correlated with higher survival rates. The data appear in a paper titled "Expression of cell-cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients."

Cascade Oncogenics Inc., a Portland, Ore., biotechnology company developing cancer diagnostic products, helped fund this research.

Michele Pagano and his colleagues found similar results in patients with colorectal cancer. Pagano was at Mitotix Inc., in Cambridge, Mass., when he worked on the study reported in "Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas."

Pagano, who is now at the New York University Medical Center, and his coworkers found that colorectal carcinomas with low or absent p27 protein demonstrated an enhanced ability to specifically degrade p27. They found that patients with high levels of p27 survived on average more than twice as long (151 months vs. 69 months) as patients who lacked the protein. The authors concluded that the absence of p27 protein is a powerful negative prognostic marker in colorectal carcinomas. It could, they said, point to patients who might most benefit from adjuvant therapy.

Yet More Confirmation Of Theory

A simple, accurate test that might point the way to the best therapy for individual cancer patients was described in the third Nature Medicine paper, "Decreased levels of the cell-cycle inhibitor p27Kip1 protein: Prognostic implications in primary breast cancer." Senior author Joyce Slingerland, of the division of cancer biology research at Sunnybrook Health Science Center, in Toronto, and her co-authors used immunohistochemistry to demonstrate that p27 levels are reduced in primary breast cancers. These authors also show that low p27 is a predictor of reduced disease-free survival.

"The fact that the two other groups also found the same thing makes me quite excited that we may have here an easy-to-do test that could assist the patient and the medical oncologist in deciding what kind of treatment the patient should have," Slingerland said. She described the test as technically easy and inexpensive.

If so, this will benefit both cancer patients and Mitotix. The company owns an exclusive worldwide license to p27 for all diagnostic and anti-proliferative therapeutic applications. The license was obtained from the Memorial Sloan-Kettering Cancer Center and the Fred Hutchinson Cancer Research Center. Mitotix, which collaborates with the DuPont Merck Pharmaceutical Co., specializes in research based on the cell division cycle. The company is developing prognostic and therapeutic applications for p27 and other cell cycle regulators.

"The recent publications on p27 and cyclin E in Nature Medicine by Mitotix and other groups highlights the critical importance these and other cell cycle regulatory molecules play in various cancers," Muzammil Mansuri, vice president of drug discovery at Mitotix, said. His company now is looking for an appropriate diagnostic partner to help them develop this technology.

Meanwhile, Slingerland is planning to expand her study of breast cancer patients and others are planning to examine p27 protein levels in other cancers.

Pagano will examine p27 levels in lymphoma, leukemia and breast cancer. Already, in collaboration with Antonio Girdono, at the Jefferson University Cancer Center in Philadelphia, Pagano has submitted a paper for publication describing p27 levels in 108 cases of lung cancer.

Next: Correlating The Absence Of p27 With Therapy

"Again, we found a correlation between p27 expression and survival. The survival is quite poor in tumors with low expression of p27," Pagano said. The next important step is to correlate the absence of p27 with therapy.

"The fact that we have a prognostic marker is important but it would become much more important if we can plan the therapy because of it," Pagano said.

The research also points to new therapeutic targets. Slingerland compares p27 to a breaking mechanism that controls cell division.

"There is some 'flip-switch' somewhere that is turning on the degradation of this breaking mechanism" Slingerland said.

That makes the enzymes involved in the degradation of p27 viable therapeutic targets.

"By blocking them, you could elevate the levels of p27," Pagano said. *