If cancer doctors had a crystal ball, they could peer into and know whether or not a particular patient's cancer will spread, it would take the guesswork out of choosing which treatment option is best.

For now, the next-best thing may be the discovery of a new breast cancer marker associated with metastasis that may lead to the development of a tissue test to predict the likelihood of metastasis via the bloodstream.

In a small, case-control study, researchers at NewYork-Presbyterian Hospital/Weill Cornell Medical Center (New York) have linked the density of the new marker, called Tumor Microenvironment of Metastasis (TMEM), with the development of distant organ metastasis via the bloodstream. According to the authors, that is the most common cause of death from breast cancer. They also noted that about 40% of breast cancer patients relapse and develop metastatic disease and that roughly 40,000 women die of metastatic breast cancer every year.

"Currently, anyone with a breast cancer diagnosis fears the worst that the cancer will spread and threaten their lives. A tissue test for metastatic risk could alleviate those worries, and prevent toxic and costly measures like radiation and chemotherapy," says senior author Joan Jones, MD, professor of clinical pathology and laboratory medicine at Weill Cornell Medical College and director of Anatomic Pathology at NewYork-Presbyterian Hospital/ Weill Cornell Medical Center.

In the study, investigators performed a retrospective analysis of tissue samples from 30 patients with invasive ductal carcinoma of the breast who developed systemic, distant-organ metastases. These samples were compared to matched controls that had breast cancer that did not spread. The samples were compared by size of the tumor, differentiation of the tumor (how it looks under a microscope compared to normal breast tissue), and other factors, Jones told Medical Device Daily. All patients were female and underwent primary resection of their breast cancer at NewYork-Presbyterian Hospital/Weill Cornell Medical Center between 1992 and 2003.

The researchers found that TMEM density was more than double in the group of patients who developed systematic metastases compared with the patients with only localized breast cancer. Also, they found that in well-differentiated tumors, where the outcome is generally good, the TMEM count was low.

"If patients can be better classified as either low risk or high risk for metastasis, therapies can be custom tailored to patients, preventing over-treatment or under-treatment of the disease," said first author Brian Robinson, MD, resident in Anatomic Pathology at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.

The Integrative Cancer Biology Program of the National Cancer Institute funded the study. Because the analysis was done on a very select group of patients, Jones said the findings would have to be validated in a larger sample group before the test could be rolled out.

"What we need to do next, before we could make this a more generally applicable test, is we need to do a population study ... using a much broader range of subjects," Jones said. "So we're trying to get funding to do that and get a bunch more people a few hundred, lets say so we can see if what we observed in these select patient samples [can be made] more general."

The Weill Cornell investigators set out to build on previous research by co-author John Condeelis, PhD, of the Albert Einstein College of Medicine (Bronx, New York). Working in animal models, he identified a link between blood-borne or systemic metastasis and a three-part association between invasive carcinoma cells, perivascular white blood cells (macrophages) and the endothelial cells that line vessel walls. To confirm this finding in humans, Jones and Robinson developed a triple immunostain for human breast cancer samples that simultaneously labels the three cell types that together they named TMEM.

"What made us try this in the human samples is what had been observed in some of the animal models of breast cancer," Jones said.

In some of the animal models scientists have been able to actually look at the tumor in the live animal and watch cells move in the vessels.

Jones admitted that the fact that this test did seem to work in the case-control study was somewhat surprising to her.

"This is a very novel way for a pathologist like me to look at tissue," she told MDD. "It's not intuitive, it is kind of a new concept."

Jones said that before she and her colleagues did the case-control study, they had analyzed "a bunch of breast cancers" and stained them and looked for these TMEM structures and counted them. In those tumors where the outcome was moderate or poor, the researchers counted a higher number of the TMEMs. "That encouraged us to think, well maybe this means something,'" she said.

Likewise, in the case-control study, the cancers that metastasized had a higher number of TMEMs than the cancers that did not spread. "It did seem to have some reflection of that tumor's ability to get into blood vessels," Jones said.

Notably, Jones said TMEM density was associated with the development of distant-organ metastasis, independent of lymph node status and tumor grade.

"Traditionally, the likelihood of breast cancer metastasis is estimated based on tumor size, tumor differentiation how similar or dissimilar the tumor is compared to normal breast tissue and whether it has spread to the lymph nodes. While these are useful measures, TMEM density directly reflects the blood-borne mechanism of metastasis, and therefore may prove to be more specific and directly relevant," Jones said.

In addition to validating the findings in a larger sample group, the researchers say they need to identify a threshold TMEM density for metastasis risk, and streamline the process for measuring TMEM.

While an estimated 10% to 15% of patients have an aggressive form of the disease that metastasizes within three years after initial diagnosis, metastasis can take 10 years or longer to occur, the authors noted. To decrease the risk for the emergence of metastatic tumors, roughly 80% of breast cancer patients are treated with adjuvant chemotherapy. The clinical benefit is a 3% to 10% increase in 15-year survival, depending upon the age of the patient at diagnosis, according to the study authors.

"A lot of patients are getting chemotherapy because there could be some chance that they're going to metastasize, but they don't really know what that risk is," Jones said.

Study co-authors include Gabriel Sica, MD, PhD, and Yi-Fang Liu, MD, of NewYork-Presbyterian/Weill Cornell; Thomas Rohan, MD, PhD, of the Department of Epidemiology and Population Health at Albert Einstein College of Medicine; Frank Gertler, PhD, of the Department of Biology, Koch Institute for Integrative Cancer Biology at Massachusetts Institute of Technology (Cambridge); and Condeelis of the Department of Anatomy & Structural Biology, Program in Tumor Microenvironment and Metastasis, Albert Einstein Cancer Center at the Albert Einstein College of Medicine.

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