Novel Immunoassay Predicts Risk of Breast Cancer Metastasis

A novel diagnostic test that identifies sites where breast tumors are able to metastasize was used to predict risk of distant metastasis in ER+/HER2− breast cancer independently of IHC4 score and classical pathologic features.

Primary breast cancers are able to metastasize when three types of cells are present together in the same site: an endothelial cell, a perivascular macrophage, and a tumor cell that produces high levels of Mena, a protein that enhances a cancer cell’s ability to spread. Tumor cells can enter blood vessels at sites where these three cells are in contact. Such a site is referred to as a tumor microenvironment of metastasis, or TMEM.

Investigators at the Albert Einstein College of Medicine (New York, NY, USA) recently developed a test that uses a triple immunostain, which contains antibodies to the three cell types that make up a TMEM. They used this test to evaluate breast tumor specimens from 259 women who later developed a distant metastasis (the cases) and on specimens from women who were alive and had not developed a distant metastasis (the controls). Case patients and control subjects were matched (1:1) on age at and calendar year of primary diagnosis. Results for the TMEM assay were compared to those obtained by the IHC4 method.

IHC4 measures the levels of four key proteins (ER, PR, HER2 and Ki-67) in addition to classical clinical and pathological variables (for example, age, nodal status, tumor size, and grade) and calculates a risk score for distant recurrence using an algorithm. Quantitative assessments of ER, PR, and Ki-67 are needed for the IHC4 test. The test uses formalin-fixed paraffin-embedded samples.

Results showed that TMEM score was significantly associated with increased risk of distant metastasis in estrogen receptor (ER)+/human epidermal growth factor receptor (HER2)− tumors, whereas IHC4 score had only a borderline positive association. Furthermore, the association for TMEM score persisted after adjustment for the IHC4 score. The area under the curve for TMEM, adjusted for clinical variables, was 0.78. Neither TMEM score nor IHC4 score was independently associated with metastatic risk overall or in the triple negative or HER2+ breast tumor subgroups.

“Currently marketed tests assess risk for breast cancer metastasis by looking for changes in gene expression or in levels of proteins associated with growth of tumor cells,” said senior author Dr. Joan Jones, professor of pathology, anatomy, and epidemiology at the Albert Einstein College of Medicine. “But those changes do not reflect the mechanism by which individual tumor cells invade blood vessels, a necessary step for metastasis. By contrast, our test is based on what Einstein researchers learned from intravital imaging, which reveals biological processes deep within the tissues of a living animal. Using this technology, they determined how breast cancer tumor cells spread in rodents.”

The study was published in the August 8, 2014, online edition of the Journal of the National Cancer Institute.

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