December 31, 2008 – The only Food and Drug Administration–approved test for detecting circulating breast cancer cells apparently does not pick up normal-like breast cancer, 1 of the subtypes of breast cancer, according to a report in the January 7 issue of the Journal of the National Cancer Institute.
The CellSearch circulating tumor cell test (Veridex, San Diego, California) is used to detect circulating cancer cells in patients with metastatic disease (prostate, colorectal, and breast) before and during treatment and allows clinicians to monitor treatment effectiveness, said Anieta Sieuwerts, PhD, from the Erasmus Medical Center, in Rotterdam, the Netherlands, in an interview with Medscape Oncology.
Thus, in patients whose breast cancer includes the normal-like subtype, the test will not indicate whether or not treatment is working effectively against this type of breast cancer. The normal-like subtype is not as common as the basal subtype or as well-known as the HER2-positive subtype. However, it generally has "aggressive features," said Dr. Sieuwerts.
Dr. Sieuwerts believes this discovery is important but was not alarmist about the test's deficiency. "The test has proven its usefulness in breast, colon, and prostate cancer, and the test may not be useful for only a minority of metastatic breast cancer patients," she said.
Normal-Like Subtype Bypassed by Technique
There are 5 subtypes of breast cancer that have been identified by their gene-expression patterns. The subtypes — basal, HER2-positive, luminal A and B, and normal-like — vary in their natural history and response to therapy. In the new study, the Dutch researchers investigated whether the 5 subtypes were identified by CellSearch, which uses antibodies against the cell surface–expressed epithelial cell-adhesion molecule (EpCAM) to isolate circulating tumor cells.
Specifically, they wanted to see whether the assay could isolate cells of breast cancer cell lines whose subtype is known and that had been added to human blood from a healthy volunteer. The investigators tested cells from a total of 34 cell lines that represented a mix of the 5 breast cancer subtypes (15 luminal, 9 normal-like, 5 basal-like, and 5 HER2-positive). The assay did not detect the 9 normal-like breast cancer cells but did detect the other subtypes.
The reason that the test misses the normal-like subtype is that "these [normal-like] cells lack the expression of EpCAM, the target used to catch the circulating tumor cells from the blood — the assumption was that all subtypes would be captured by the anti-EpCAM antibody," said Dr. Sieuwerts. EpCAM is integral to the CellSearch test.
Dr. Sieuwerts and her colleagues are working to identify and validate markers that would capture the normal-like subtype.
Next Steps
"New tests that include antibodies that specifically recognize normal-like breast tumor cells are needed," said Dr. Sieuwerts. The first step in that process is to find a marker that captures normal-like breast cancer.
"Once such a marker has been identified and thoroughly validated in a clinical setting, the introduction of this marker in the CellSearch test would be relatively easy," she added.
Dr. Sieuwerts acknowledged that clinicians may not be highly familiar with the normal-like breast cancer subtype. "This subtype lacks the more distinct characteristics that are associated with the other subtypes, eg, estrogen-receptor expression for the luminal subtypes, HER2 expression for the ERBB2 subtype, and expression of specific cytokeratins for the basal tumors, which in addition lack the expression of estrogen and progesterone receptors, and HER2 [triple-negative breast cancer]," she observed.
However, in their report, the Dutch researchers indicate that the normal-like cells can, for example, be identified by their ubiquitous expression of the markers TWIST1 and caveolin-1.
"Thus, the normal-like breast cancer cell subtype is an important target for the development of individualized therapy and should not be overlooked when assessing circulating tumor cells," write the report authors.
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