Hope seen for early test to detect breast cancer

Harvard researchers at Children's Hospital Boston have developed a simple urine test that appears to detect breast cancer early and accurately track tumor growth.

The findings are still preliminary, but if further research supports them, the test could be a major advance in the effort to catch breast cancer before it turns deadly. The Boston scientists are searching for similar markers in urine for other cancers.

Earlier this year, a team at the National Cancer Institute reported that other tumors, including prostate cancer, may also be detectable with urine tests. That would be more convenient and inexpensive than the scans, blood tests, and biopsies commonly used to screen for and diagnose cancers. Scientists say a screening test that found cancer without needle jabs, intrusive scopes, surgery, or exposing patients to radiation would be widely used, improving the odds that tumors would be seen before they spread to other organs, when they are most treatable and least dangerous.

Breast tumors are typically found with a mammogram, a type of X-ray, or when they become large enough to be felt by a woman or her doctor. By then, they may have spread. Further, almost half of women do not get annual mammograms. The result is that 37 percent of breast cancers are diagnosed after they have spread, according to the American Cancer Society.

The society estimates that 215,000 new breast cancer cases will be reported this year in the United States and that about 40,000 women will die of the disease.

Children's Hospital researchers evaluated their new test, which identifies the presence of an enzyme called ADAM 12, in experiments using urine samples from 71 women known to have breast cancer, from early to late stages. The test successfully identified 67, or 94 percent, of the cases. In a control population of 46 women without cancer, there were seven false positive results, or 15 percent. In these seven women, the amounts of the telltale enzyme were very low, the researchers said. The findings have been accepted for publication in the Journal of Biological Chemistry.

''Our data demonstrate for the first time that ADAM 12 can be detected in the urine of breast cancer patients," biochemist Marsha Moses, Roopali Roy, and their co-workers wrote in the paper. ''Increased urinary levels of this protein correlate with breast cancer progression."

If the results can be repeated in a larger group of patients, the urine test would offer the first noninvasive way to detect breast cancer early, monitor a tumor as it expands, and perhaps keep track of how well treatment is working.

The Harvard research team focused on urine as a place to seek early evidence of cancer, Moses said, because ''I wanted something that was noninvasive," a simple, painless, and reliable test that accurately warns when tumor growth is getting underway.

Her goal is to offer a test kit that doctors can use routinely in their offices and in hospital laboratories. Eventually, she hoped that the test can be done at home. She said that a test could be available within a few years.

''This is important and exciting work," said Dr. Catherine Park, a cancer specialist at the University of California, San Francisco, because it may link an enzyme that plays a role in the growth of a tumor with a detectable measure of how fast the tumor is expanding. She added that it remained to be seen whether the urine test would be accurate enough to provide a ''black-and-white answer."

Dr. Sudhir Srivastava, chief of biomarkers research at the National Cancer Institute, said that until more research is done, ADAM 12 must be considered ''a putative marker, those that are just at the discovery stage and need to be validated with proper studies."

Noting the small number of patients studied by the Children's Hospital researchers, he added, ''At this point it looks promising, but it's not ready for prime time." He also said it was surprising that a cancer biomarker would be found in urine. The kidneys and liver tend to remove such enzymes and molecules. A biomarker is a chemical signal.

Srivastava's program is spending $23 million this year to find cancer biomarkers, including those in urine. National Cancer Institute colleagues reported in February in the Journal of Clinical Oncology evidence that prostate cancer is also detectable with urine tests. The team, working with the Children's Hospital and Harvard scientists, found two biomarkers in urine that seemed to predict the return of cancer in patients who had undergone treatment for prostate cancer.

The urine test for breast cancer seems to identify patients with tumors and also warns of a tumor's severity, distinguishing among patients in varying stages of cancer.

Moses said her experiments show that when the amount of ADAM 12 in urine spikes sharply, the tumor may be entering a more dangerous growth phase. As a breast tumor gets bigger, and begins sending its deadly ''seeds" to lymph nodes and various organs, the enzyme level increases. Moses said the warning's accuracy may improve if ADAM 12 can be combined with other biomarkers in the urine that her lab is studying.

The ADAM 12 enzyme ''is a member of a family of enzymes that were only recently discovered," Moses said. ''Some of them are associated with cancer, but in general their functions are not well established."

ADAM 12 is suspected of playing a role in remodeling a structure called the extracellular matrix, a cagelike environment in which each cell lives. It helps the cell see and feel its neighbors, helps anchor the cell in place, and facilitates the flow of chemical signals, food, and waste into and out of the cell. This structure is apparently constantly changing to meet the cell's needs, and levels of ADAM 12 may increase, Moses said, when the enzyme is active in changing the extracellular matrix, perhaps to allow the expanding tumor to push through surrounding tissues, or to draw in new blood vessels it needs for growth.

Moses said one of her coauthors, Ulla Wewer of the University of Copenhagen in Denmark, ''found that it [ADAM 12] is in breast cancer tissue, so she associated it with breast cancer. But we're now looking to see if it's associated with other tumors, too."

If it is, then ADAM 12 and other enzymes linked to the extracellular matrix might become useful biomarkers to detect and monitor a variety of dangerous tumors. Preliminary results from urine samples taken from thousands of cancer patients with various types of tumors suggest such enzyme tests could be useful in detecting these cancers, the Children's Hospital researchers said.

Children's Hospital has applied for patents and is negotiating to license its test to a biotechnology company.

Moses's co-workers in this research included David Zurakowski and Susan Pories, at Harvard Medical School.