Mar. 31, 2009 Researchers at NewYork-Presbyterian Hospital/Weill Cornell Medical Center have identified a new marker for breast cancer metastasis called TMEM, for Tumor Microenvironment of Metastasis. As reported in the March 24 online edition of the journal Clinical Cancer Research, density of TMEM was associated with the development of distant organ metastasis via the bloodstream — the most common cause of death from breast cancer.
The National Cancer Institute (NCI)–funded translational study could lead to the first test to predict the likelihood of breast cancer metastasis via the bloodstream — a development that could change the way breast cancer is treated.
An estimated 40 percent of breast cancer patients relapse and develop metastatic disease. About 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 Dr. Joan G. Jones, 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.
"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," adds first author Dr. Brian D. Robinson, resident in Anatomic Pathology at NewYork-Presbyterian Hospital/Weill Cornell Medical Center.
The Weill Cornell investigators set out to build on previous research by co-author Dr. John S. Condeelis of the Albert Einstein College of Medicine. 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, Drs. Jones and Robinson developed a triple immunostain for human breast cancer samples that simultaneously labels the three cell types that together they named TMEM (Tumor Microenvironment of Metastasis).
In a case-control study, they 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 only localized disease (i.e., invasive ductal carcinoma limited to the breast or with regional lymph node metastasis only). All patients were female and underwent primary resection of their breast cancer at NewYork-Presbyterian Hospital/Weill Cornell Medical Center between 1992 and 2003.
They found that TMEM density was more than double in the group of patients who developed systemic metastases compared with the patients with only localized breast cancer (median of 105 vs. 50, respectively). Offering further evidence in support of the TMEM concept, they found that in well-differentiated tumors, where the outcome is generally good, the TMEM count was low.
Notably, 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," says Dr. Jones.
The researchers say the next step will be to validate the findings in a larger sample group. Also on the agenda is identifying a threshold TMEM density for metastasis risk, and streamlining the process for measuring TMEM.
Breast cancer is the most prevalent malignant disease of women in the developed world, apart from non-melanoma skin cancers, with approximately one in eight women in the United States being diagnosed with breast cancer at some time in their lives. While an estimated 10 percent to 15 percent 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. To decrease the risk for the emergence of metastatic tumors, approximately 80 percent of breast cancer patients are treated with adjuvant chemotherapy. The clinical benefit is a 3 percent to 10 percent increase in 15-year survival, depending upon the age of the patient at diagnosis.
Study co-authors include Drs. Gabriel L. Sica and Yi-Fang Liu of NewYork-Presbyterian/Weill Cornell; Dr. Thomas E. Rohan of the Department of Epidemiology and Population Health at Albert Einstein College of Medicine; Dr. Frank B. Gertler of the Department of Biology, Koch Institute for Integrative Cancer Biology at Massachusetts Institute of Technology; and Dr. John S. 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.
The study was funded by the Integrative Cancer Biology Program (ICBP) of the National Cancer Institute (NCI).
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