Background:
Metastatic disease is the most common cause of cancer-related death in patients with solid tumors. A considerable body of evidence indicates that tumor cells are shed from a primary tumor mass at the earliest stages of malignant progression. Some of these cells will travel via the peripheral blood to sites anatomically distant from the primary tumor and form metastases. As individual cells present in low numbers, such disseminated cells can be occult to standard methods of investigation such as microscopic examination of routinely stained cyto/histology slides. However, these cells are understood to be a source of eventual lethal metastases, the major cause of treatment failure in cancer patients. Detection and characterization of these cells is a promising method for both diagnosis and clinical management of cancer patients as well as monitoring treatment.
Previous Studies on Circulating Tumor Cells (CTCs):
Numerous studies have concluded that the presence of CTCs in the bone marrow (BM) is of prognostic significance in different types of solid tumors. The most extensive database on BM micrometastasis and prognosis exists for breast cancer, involving over 4000 patients. However, the use of BM examination for CTC detection is not yet part of routine clinical staging. This is predominantly because several other studies found no statistically significant relationship between CTC detection and prognosis. The most likely explanation of the discrepancy between these studies is the technical and methodological differences applied for CTC detection. Since the frequency of CTCs in BM of cancer patients can be as low as one tumor cell in a background of one million normal hematopoietic cells, the reliable detection and quantification of such rarely occurring cells challenges available analytical methods.
Another approach that we use for the detection of occult micrometastases is measuring CTCs in peripheral blood (PB). The reliable measurement of CTCs depends on both sample preparation protocol and detection technique, and hence research in this area must take both into account simultaneously in order to develop a reliable and clinically useful approach. There is good reason to be optimistic about the value of CTC detection. A recent clinical trial involving 177 metastatic breast cancer patients showed the number of CTCs in PB after immunomagnetic enrichment provided prognostically useful information regarding progression-free and overall survival in a subset of patients.
Health Relevance:
Breast cancer is the most common visceral malignancy affecting women, with 212,118 new cases estimated for 2005 in the United States. Breast cancer survival is determined primarily by stage of disease at diagnosis, with 92%, 73% and 13% overall survival at 5 years for localized, node positive and metastatic disease, respectively. In 2005 there will be an estimated 41,250 deaths as a result of breast cancer.
Current tumor staging parameters are only able to statistically predict the risk of recurrence for populations of patients without giving indications about the possible outcome for any one individual, which, after complete surgical excision of localized disease, is primarily influenced by the presence of unidentified disseminated circulating tumor cells. It has been estimated that most breast cancer metastases are initiated early, when the primary tumor is less than 0.2 cm3 in volume and clinically classified as local disease. In fact, breast cancer cells are detected in the bone marrow of 33% of breast cancer patients with node negative disease. Identification of patients at higher risk for relapse is essential so that more aggressive therapy tailored according to the patient’s needs can be initiated.
Another potential application of CTC detection from PB is the early diagnosis of cancer. At some ill-understood point during primary tumor growth, invasive sub-populations of the primary tumor cells gain access to the circulation. While the literature supports the concept that many tumor cells shed from a primary tumor are immediately destroyed in the circulation and most shed cells do not in fact result in metastasis, detection of such shedding may provide an early clue as to the presence of malignancy . With ancillary use of appropriate tissue and/or organ specific markers, CTC screening could be an early indicator of metastasis-capable malignancy.