Detection and Significance of Circulating Tumor Cells in Patients with Metastatic Breast Cancer

Abstract & Commentary

By William B. Ershler, MD

Synopsis: In this review of 195 patients with metastatic breast cancer, detection of 5 or more circulating cancer cells in 7.5 mL of whole blood correlated with reduced overall survival. Furthermore, the presence of extensive bone metastases, as detected by PET/CT, was shown to be associated with increased circulating tumor cells (CTC).

Source: De Giorgi U, et al. Circulating tumor cells and bone metastases as detected by FDG-PET/CT in patients with metastatic breast cancer. Ann Oncology. 2010;21:33-39.

Several studies have suggested a prognostic and predictive role for circulating and disseminated tumor cells in patients with breast cancer. It has been postulated that the circulating tumor cell (CTC) number will become a useful tumor marker, valuable both in prognosis, as well as measurement of effective treatment.1,2 However, implementation of this assay into clinical routine has been cumbersome. CTCs are infrequent enough that they are recognized only by using a combination of surface and intracellular markers and, just recently, a number of technical advances have made their reliable detection possible. It has become apparent that, unlike other tumor markers, the number of CTCs does not necessarily correlate with the total tumor burden.3,4 For example, in one recent study, there was only limited correlation between CTC levels and radiographic measurement of tumor load.5

PET (2-[fluorine-18]fluoro-2-deoxy-D-glucose-positron emission tomography) is more sensitive than conventional imaging in the detection of breast cancer metastases and, together with computerized tomography (CT), there is greater anatomical precision with regard to metastatic disease.6,7 Thus, if there is any correlation between CTC and the extent or distribution of metastatic disease, it would seem logical that this might be best determined by PET/CT rather than other imaging techniques. Accordingly, De Georgi et al at M.D. Anderson in Houston evaluated the relationship between the detection and prognostic significance of CTCs and sites of metastases detected by PET/CT in patients with metastatic breast cancer (MBC). Between May 2004 and January 2008, 195 patients with relapsed/progressive MBC underwent whole-body FDG-PET/CT and provided blood samples for assessment of CTC count.

Higher CTC numbers were detected in patients with bone metastases relative to those with no bone lesions (mean 65.7 vs. 3.3, p = 0.0122) and in patients with multiple bone metastases relative to those with one or two bone lesions (mean 77.7 vs. 2.6, p < 0.001). CTCs predicted overall survival (OS) in 108 patients with multiple sites of metastases, including bone (p = 0.0008), but not in 58 without bone metastases (p = 0.4111) and in 29 with bone involvement only (p = 0.3552). Of 16 patients with human epidermal growth factor receptor 2 (HER-2)-positive tumors who were treated with trastuzumab-based regimens, 15 patients had < 5 CTCs at progression. In multivariate analysis, CTCs, not bone metastases, remained a significant predictor of OS.

Commentary

In this retrospective analysis of 195 patients with metastatic breast cancer, the presence of extensive bone involvement, as detected by PET/CT, was shown to be associated with increased CTC numbers. The study clearly indicated a difference in frequency and number of CTC in those with bone metastases compared to those with metastatic disease at other sites. Even though it is curious that those with bone metastases alone (i.e., without metastases at other sites) did not have significantly more CTC than those without bone metastases, it is clear that patients with extensive bone metastases were most likely to have high CTC numbers and, in fact, poorest overall survival.

It is notable that 15 of 16 patients with HER2-positive tumors, who were treated with trastuzumab-based regimens, had < 5 CTCs at the time of progression, suggesting that trastuzumab might be affecting tumor-cell circulation. This finding may have important biological implications, and warrants prompt confirmation.

Clinical oncologists are becoming aware of the importance of detecting CTC in patients with breast cancer. In addition to providing insights into the biology of breast cancer metastases, it is now clear that CTC numbers provide significant, independent prognostic information. This report provides evidence for a strong correlation of CTC and extensive bone involvement. Yet, how this information becomes applied to the management of breast cancer, in the adjuvant or metastatic setting, remains in the realm of clinical investigation.

References

1. Amadori A, et al. Circulating and disseminated tumor cells in the clinical management of breast cancer patients: Unanswered questions. Oncology. 2009;76: 375-386.

2. Mostert B, et al. Circulating tumor cells (CTCs): Detection methods and their clinical relevance in breast cancer. Cancer Treat Rev. 2009;35:463-474.

3. Gaforio JJ, et al. Detection of breast cancer cells in the peripheral blood is positively correlated with estrogen-receptor status and predicts for poor prognosis. Int J Cancer. 2003;107:984-990.

4. Cristofanilli M, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med. 2004;351:781-791.

5. Budd GT, et al. Circulating tumor cells versus imaging — predicting overall survival in metastatic breast cancer. Clin Cancer Res. 2006;12:6403-6409.

6. Hodgson NC, Gulenchyn KY. Is there a role for positron emission tomography in breast cancer staging? J Clin Oncol. 2008;26:712-720.

7. Cohade C, Wahl RL. Applications of positron emission tomography/computed tomography image fusion in clinical positron emission tomography-clinical use, interpretation methods, diagnostic improvements. Semin Nucl Med. 2003;33:228-237.