New method finds microscopic breast cancer metastases that are overlooked by standard pathological analysis

A team of MUSC physicians is developing a genetic screening method that may be 10 to 100 times more sensitive than routine pathological analysis of lymph nodes for microscopic evidence of breast cancer. If further testing proves that the method can identify women in whom breast cancer most likely will recur, it could help cancer treatment specialists decide whether or not to institute aggressive anti-cancer therapy on affected patients.

If further tests prove successful, the new method may enable cancer specialists to more easily identify women in whom breast cancer will likely occur. In those cases, specialists could begin aggressive anti-cancer therapy earlier and possibly improve the patients’ chances for success.

MUSC’s team, led by David Cole, M.D., assistant professor of surgery, uses a polymerase chain reaction (PCR) probe that signals the presence or absence of up to four genes associated with breast cancer. Cole went to Chicago this week to present MUSC’s findings at the 1997 Clinical Congress of the American College of Surgeons. Cole’s associates on the research team are Mark Lockett, M.D., Paul Baron, M.D., Paul O’Brien, M.D., Bruce Elliott, M.D., Jacob Robison, M.D., and John Metcalf, M.D.

When the PCR probe finds any one of the suspect genes in DNA from lymph nodes taken from a woman who has had a lumpectomy or a mastectomy for breast cancer, “we would consider that evidence that the lymph node has at least some form of cancer cell that shouldn’t be there,” Cole said.

PCR analysis amplifies genes to the point where they can be detected in a highly accurate manner. “The current thinking is if you have one cancer cell in a million normal lymph node cells, a PCR probe would be able to pick that up,” Cole said. “That is on the level of 10 to 100 times more sensitive than routine histologic staining done by a pathologist.”

The MUSC researchers compared the PCR probe against pathologic histochemical staining analysis. They found that 48 percent of the lymph tissue that was pathologically categorized as negative for cancer actually had one of the four cancer-related genes. A total of 29 women out of 45 were considered to be negative for micrometastases based on routine pathological tests of their lymph nodes. Fourteen of the 29, however, exhibited evidence of micrometastases on PCR analysis.

The results of the PCR probe changed the way the tumor was clinically staged in all 14 women. The researchers converted seven tumors from stage I to stage IIA, and seven were upstaged from IIA to IIB.

Cole cautioned that the study was a feasibility investigation of the PCR probe analysis. “This is a preliminary panel of genes that we tested only to establish that the method would be effective and potentially sensitive,” he said.

The probe still must be refined to select the best genetic markers of breast cancer. “There are many genes out there that have been associated with breast cancer,” Cole added. “We have to find the ones that will provide the most efficient way of screening for micrometastases.”

The results of the probe also must have a bearing on the management of women with breast cancer. “If the probe picks up micrometastases that never develop into actual breast cancer, it will not be relevant clinically,” Cole said. “We need to test the probe in a large enough cohort of patients over three to five years to learn whether it can predict cancer recurrence.”

If the probe is able to do so, it may be used to select women who should receive aggressive therapy. “We have become more aggressive in the last five or 10 years in terms of treatment of breast cancer with extremely high doses of chemotherapy and bone marrow transplantation,” Cole said. “The first thing to establish with the probe is that it is the most sensitive methodology for screening for micrometastases. Then if your most sensitive method is negative, that means a patient does not have occult metastases and maybe we can back off on using these aggressive therapies.”

The new screening probe also may change the course of treatment for women whose lymph nodes had been pathologically classified as negative for breast cancer metastases. “A young woman who was node negative on pathologic analysis but node positive by PCR probably would be the one you would push into more aggressive chemotherapy,” Cole said.

Aside from its apparent diagnostic benefits, according to Cole, PCR has two more advantages: the technology is widely available and it can be done without exorbitant costs. “We are trying to take PCR that everyone is familiar with, utilize genes that have been defined, and put both components together,” Cole said. “In this manner we have better ability to screen women for hidden breast cancer cells and make more intelligent decisions about their treatment.”