Circulating Tumor Cells, Disease Progression, and Survival in Metastatic Breast Cancer

Abstract & Commentary

Synopsis: The levels of circulating tumor cells at baseline and at the first follow-up visit after the initiation of therapy were the most significant predictors of progression-free and overall survival in women with metastatic breast cancer.

Source: Cristofanilli M, et al. N Engl J Med. 2004; 351:781-791.

In a prospective, multicenter study, Cristofanilli and colleagues tested 177 patients with clinically detectable metastatic breast cancer for levels of circulating tumor cells both before and after the initiation of various forms of therapy. The response to therapy was followed using standard clinical detection, but blood samples were also collected to determine the burden of tumor cells in the circulation. Cristofanilli et al found that the levels of circulating tumor cells at baseline and at the first follow-up visit were the most significant predictors of progression-free and overall survival. Christofanilli et al note that this study was made possible by technological advances affording detection of circulating tumor cells. In this study, they used a newly developed approach called CellSearch System by Veridex. The system is based on enumeration of epithelial cells, which are separated from the blood by antibody-coated magnetic beads and identified using fluorescent-labeled antibodies against cytokeratin.

All but 10 of the 177 patients had a minimal follow-up time of 38.7 weeks. Circulating epithelial cells were rare in healthy women and in patients with benign breast disease. The levels of circulating tumor cells at baseline and at the first visit after the initiation of therapy predicted outcome better than estrogen-receptor status, progesterone-receptor status, HER2/neu status, or type of therapy. Tumor burden at the first follow-up visit was somewhat more predictive of outcome than tumor burden before treatment. Indeed, for those receiving adjuvant hormonal intervention, circulating tumor cell count was only predictive for outcome after treatment and not before.

Comment by Sarah L. Berga, MD

The main hypothesis guiding this study is both simple in concept and exciting in potential. The investigators asked whether the number of cancer cells detected in the blood before and after therapy correlated with tumor behavior and survival in patients with known metastatic breast cancer. A key barrier to testing this hypothesis was surmounted by the development of a robust technique to both identify and quantify tumor cells in the circulation. Since the study results rest so directly on technique, the study is in part a validation of this technique for detecting breast cancer cells in the circulation. Since there is no readily available gold standard for detecting breast cancer cells in the circulation, the manufacturers of the new approach had to depend in part on clinical outcomes for validation. Thus, the investigators of necessity had to simultaneously testing both a biological hypothesis and a new technological development.

Assuming that there study results are valid and replicable, where do the results made possible by this new technique put us? If the technique is highly sensitive and specific, then we potentially have a new method for refining the stage of the patient’s breast cancer prior to initial therapy. Having this information might lead to important prognostic information. Such a technique might even allow us to predict tumor aggressiveness or its return after an apparent remission. We also might be able to say with greater accuracy which patients do and do not need adjuvant therapy, what type of adjuvant therapy would be best for a given breast cancer, or when to switch to another type of adjuvant therapy because the initial one chosen is not working. In short, this new technique might allow us to act upon the notion that all breast cancers (and their hosts) are not the same. Given the many side effects of adjuvant therapy, having some way to individualize is truly exciting. The most far-reaching possibility, however, would be that such a technique could be used for advance detection of cancers, breast or otherwise, by a simple screening blood test. The widespread availability of a reliable and cost-effective screening technique would clearly be a welcome addition to our diagnostic armamentarium for those at high risk for breast or ovarian cancer, including those who carry BRCA1 and BRCA2 mutations. Realizing these clinical dreams hinges, in part, on whether tumor cells in the circulation adequately reflect the primary tumor across time and following intervention. Either way, though, this technique may help us to learn more about the multiple determinants of tumor behavior in vivo.

Dr. Berga is James Robert McCord Professor and Chair, Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, GA.