BioWorld International Correspondent
LONDON - A new analysis of the genetic abnormalities in breast cancer cells that already have spread around the body by the time of surgery could explain why chemotherapy is often unsuccessful in preventing recurrence of breast cancer.
A German team of researchers that carried out the study say the finding has important implications for those designing drugs aimed at eliminating such cells.
Christoph Klein, head of the Micrometastasis Laboratory of the Institute for Immunology at the Ludwig-Maximilians University in Munich, Germany, told BioWorld International: "This work shows that we need to characterize the target cells of adjuvant therapy for breast cancer in a much more detailed way than previously. Pharmaceutical companies working on drug development need to validate the expression of the molecules that their new compounds are targeting, to ensure that these are expressed by these cells, because you cannot extrapolate from the primary tumor."
When Klein and his colleagues analyzed the genomes of cells found in the bone marrow, but which were derived from the primary tumor in the breast, they found they had fewer chromosomal aberrations than cells from the primary tumor itself. "We were very surprised by this finding," Klein said. "We think this means that the cells disseminate very early on in the development of the primary tumor and that subsequent changes in their genome are very slow, possibly because they are in the completely different microenvironment of the bone marrow."
Despite their surprise at the data, the researchers believe that the observations fit well with the clinical picture of breast cancer, where women sometimes develop distant metastases many years after having surgery that completely removes the primary tumor. Such relapse can occur up to 25 years later, although the average time between surgery and development of clinically obvious metastases is between four and six years.
Klein and his colleagues describe their studies in a paper in the June 9, 2003, Proceedings of the National Academy of Sciences titled "From latent disseminated cells to overt metastasis: Genetic analysis of systemic breast cancer progression."
The team used an established assay to distinguish cells of epithelial origin, from breast, lung or colon tissue, for example, from those of mesenchymal origin, such as blood, bone marrow and lymph nodes. The test relies on detecting a molecule called cytokeratin, which is expressed only by epithelial cells.
Using this method, studies over the past 15 years have shown that cells that have detached from primary breast tumors can be detected in bone marrow, although they are very rare. For example, it is usual to find only one or two such cells in about a million cells from the bone marrow, and then in only about every third patient tested. Researchers also have shown that those patients in whom it is possible to find such cells have a worse prognosis, in general, than those in whom the cells could not be found.
Klein and his collaborators, who include teams from Heidelberg, Augsburg, Frankfurt and Oberaudorf, all in Germany, analyzed the genomes of the cells that they were able to find in the bone marrow, and compared the chromosomal aberrations with cells from each patient's primary tumor. They found that tumor cells in the bone marrow had relatively few chromosomal aberrations. Some even appeared to have no chromosomal aberrations at all, on initial inspection, although use of a high-resolution technique showed that some of these had similar deletions of parts of chromosomes, identical to those in the primary tumor.
"We believe this is a very important finding," Klein said. "We think it could help us to explain why adjuvant therapies often fail. If these disseminated tumor cells are in a completely different stage of development, they will express different genes and different proteins, they might be dormant, and they may not react in the same way to the drug being administered to the patient, which may have been tested in culture on cells from primary tumors."
He and his colleagues are planning a multicenter trial in which they will analyze and compare the genomes and gene expression of cells from patients' primary tumors and disseminated cells.
"We hope that our future study will allow us to characterize the target cells for adjuvant therapies," Klein said, "giving us the information that pharmaceutical companies will need if they are to design drugs directed at targets on the disseminated cells."
Klein added that it will probably be necessary to carry out similar studies on many different types of cancer, particularly those, like breast cancer, that have long latency periods. "The situation might be different for, say, pancreatic cancer, where patients tend to die rapidly after diagnosis," he said.