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Circulating Tumor Cells: Toward Sophisticated Approaches in Managing Metastatic Breast Cancer

Circulating Tumor Cells: Toward Sophisticated Approaches in Managing Metastatic Breast Cancer

Important therapeutic innovations within the past several years have resulted in only modest survival benefits for women with metastatic breast cancer. In this setting, cancer remains incurable and treatment is mainly palliative, involving judiciously applied multiple endocrine, chemotherapeutic, or biologic therapies in an attempt to induce a series of remissions and, ultimately, adequate palliation. At present, we lack both a consensus management algorithm and an ideal treatment model of specific subsets of women.

Clinical decision-making still involves a number of patient and tumor characteristics.[1-2] Pretreatment prognostic (measures of tumor burden or hormonal receptor status) and predictive factors (eg, hormonal receptor and HER2/neu status) are considered in order to select a therapy most likely to benefit patients.[1-4] Anatomic staging continues to play a major role in guiding treatment decisions, but it has become increasingly clear that the unpredictable clinical behavior reflects the biologic heterogeneity of the disease. The fact that not all patient subgroups have benefited from therapeutic innovations might explain the modest improvements in survival.

Assessing Treatment Efficacy

Appropriate risk and biologic stratification in breast cancer will offer the unique opportunity for development of more effectively tailored targeted therapies. The current clinical practice of continuing therapy as long as toxicity is acceptable and there is no evidence of disease progression is a limiting factor in such strategies. Additional treatment endpoints for assessing cancer therapy in breast cancer are disease-free survival and overall survival.

The current approach of assessing treatment efficacy involves serial history-taking and physical examinations, radiologic studies, and serologic tumor markers, with change in tumor size being the most frequently used surrogate endpoint. Prior studies suggested that levels of classic serum markers (such as antibodies to epithelial MUC) are related to tumor burden. However the clinical utility of serum markers in predicting prognosis and monitoring treatment remains controversial.[5]

In this issue of ONCOLOGY, Drs. Saad and Abraham point out the importance of monitoring response to treatment. In the first part of their article, the authors review the limitations of traditional serologic tumor markers.

Traditional Tumor Markers

Cancer antigens (CA) 15-3 and 27.29 are well-characterized assays that allow the detection of circulating MUC1 antigen in peripheral blood and are used as surrogate markers for breast cancer. Carcinoembryonic antigen (CEA) levels are less commonly elevated than are levels of MUC1 assays, with CEA levels minimally complementary to MUC1 levels. These markers can be used in conjunction with diagnostic imaging, history, and physical examination. Present data are insufficient to recommend the use of these markers alone for monitoring response to treatment, but in the absence of readily measurable disease, an increasing marker may be used to indicate treatment failure. Since spurious early rises may occur, caution should be used when interpreting a rising marker level during the first 4 to 6 weeks of a new therapy.HER2 amplification, overexpression, and the presence of HER2 extracellular domain are generally associated with poorer prognosis.

Although the use of HER2 to determine prognosis is not recommended, high levels of tissue HER2 expression or HER2 gene amplification principally indicates the need for anti-HER2–based therapy.[6] HER2 amplification/overexpression is a poor prognostic factor in the absence of HER2-directed therapy, but since the introduction of trastuzumab (Herceptin), the prognosis of HER2-positive tumors is as good as that of HER2-negative tumors.[6] Monitoring HER2 extracellular domain concentrations can be used to monitor the effects of systemic treatment.

Role of Circulating Tumor Cells

Advances in technology have provided a powerful method to help identify new drug targets as well as potential diagnostic and prognostic markers for use in association with new molecular therapeutics. Our understanding of the pathophysiology of breast cancer has generated detailed information about the potential roles of specific biomolecular markers in this process. Radiologic response is subject to considerable technical limitations, such as intraobserver and interobserver variation and disadvantages in reproducibility of radiographic studies.[7]

The authors report their experience showing statistical correlation among PET/CT, tumor marker CA 27.29, and the circulating tumor cell (CTC) test with some unexplained discordance in metastatic breast cancer. As traditional approaches are confounded by inaccuracies and limitations, simpler, more effective means of assessing the effectiveness of therapy are needed, both to allow optimal treatment of individual patients and to serve as surrogate measures of activity for novel therapies. Beyond Swenerton score, several steps have been taken in determining predictive and prognostic factors. In their review, the authors focus on CTC testing as a new and promising tool for stratifying and monitoring patients with metastatic disease. In particular, they have provided a comprehensive overview of the significance of CTCs in predicting clinical outcome.

The American Society of Clinical Oncology (ASCO) 2007 guidelines update committee reflecting on this need expanded the scope of the guideline to incorporate a broader range of markers in breast cancer.[5] In addition, the impact of genomic technologies was considered in the update. Although molecular subtyping is still in its infancy and subgroups are not well defined, the use of multiparameter technologies in clinical practice has considerable potential. Estrogen and progesterone receptors should be measured on metastatic lesions to identify patients who are most likely to benefit from endocrine forms of therapy in the metastatic disease setting.

The ability to detect the presence of minimal residual disease in various body compartments such as the bone marrow, lymph nodes, and peripheral blood provides new opportunities. CTCs detected in patients with both localized and metastatic breast cancer are significantly associated with a worse outcome.[8-10] However, the ASCO panel recommended that evidence for routine use of CTCs in clinical practice is insufficient.[5]

CTCs vs Other Measures

It is worthwhile to briefly review this innovative approach with potential important implications in the management of metastatic breast cancer. Our group previously evaluated the prognostic significance of CTCs in comparison with commonly used measures of tumor burden and prognosis and subtype of disease.[11] This study confirmed that the detection of CTCs was somewhat related to tumor burden, as measured by Swenerton score and serum CA 27-29, but the detection of CTCs demonstrated a superior and independent prognostic value compared to all the other factors and indicating that CTCs more strongly reflect the biology of the disease. Furthermore, the detection rate and prognostic value of CTCs was not associated with the type of therapy or the disease phenotype.

Significantly, CTCs could predict prognosis in two types of patients with opposite biologic features: namely, patients with hormone receptor–positive disease (luminal-like) and those with disease derived from basal or myoepithelial cells, including triple-negative (basal-like) and HER2-overexpressing disease. Moreover, CTCs were associated with an increased hazard of death independent of the type of therapy, and these data could be of particular value in patients with hormone-dependent tumors treated with systemic hormonal therapies. These findings confirmed and further strengthened our previous observation that CTCs are a valuable and independent prognostic tool, indicating the need to incorporate CTC detection in more appropriate biologic staging beyond anatomic features.

Prognostic Implications

The prognostic implications of detecting CTCs before initiating therapy for breast cancer raise important questions about the biologic characteristics of these cells and the reasons for the reduced capacity of systemic treatment to arrest or eradicate the cancer. Building on this, further study suggests that comprehensive analysis of CTCs is likely to provide new insights into the biology of breast cancer and contribute to defining novel treatments and better prediction models. More importantly, efforts are underway to genotype and phenotype these cells, which should lead to further monitoring in the adjuvant and metastatic settings.[12] Stemline progenitor cells may also play a role and will need to be targeted in future approaches.

Unlike soluble circulating tumor markers such as assays that detect MUC1, the number of CTCs is not simply a reflection of tumor bulk. The detection of CTCs is feasible and reproducible, and their number might accurately predict prognosis and treatment efficacy in patients with advanced disease, thereby providing a tool for appropriate patient stratification.[13]

Since CTCs are still compared to serum tumor markers, there is an expectation that trials designed to encompass treatment changes after demonstration of persistent adverse features (persistently elevated CTCs) would result in improved outcomes. Nevertheless, this approach does not validate CTCs as a prognostic factor but only as a strategy for evaluating the time and sequence of different chemotherapies. In fact, the authors have emphasized that although the concept of CTCs is appealing, more evidence is required for its integration into clinical practice.

Conclusions

More accurate determination of treatment effectiveness might spare patients toxicity as a result of futile therapy and allow a change to a more effective regimen. The Southwest Oncology Group is conducting a trial (S0500) with CTCs measured at baseline and 1 month later to determine whether an early change in therapy is beneficial to patients with metastatic breast cancer. Future validation trials should focus on a fundamental shift in approaching the characterization and eradication of micrometastatic disease. Only by introducing this strategy will we be able to modify prognoses in metastatic and primary breast cancer.

The main article can be found here:

Role of Tumor Markers and Circulating Tumors Cells in the Management of Breast Cancer

References

References

1. Swenerton KD, Legha SS, Smith T, et al: Prognostic factors in metastatic breast cancer treated with combination chemotherapy. ­Cancer Res 39:1552-1562, 1979.

2. Hortobagyi GN, Smith TL, Legha SS, et al: Multivariate analysis of prognostic factors in metastatic breast cancer. J Clin Oncol 1:776-786, 1983.

3. Ravdin PM, Green S, Dorr TM, et al: Prognostic significance of progesterone receptor levels in estrogen receptor-positive patients with metastatic breast cancer treated with tamoxifen. J Clin Oncol 10:1284-1291, 1992.

4. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001.

5. Harris L, Fritsche H, Mennel R, et al: American Society of Clinical Oncology 2007 update of recommendations for the use of tumor markers in breast cancer. J Clin Oncol 25:5287-5312, 2007.

6. Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177-182, 1987.

7. Thiesse P, Ollivier L, Di Stefano-­Louineau D, et al: Response rate accuracy in oncology trials: Reasons for interobserver variability. Groupe Français d’Immunothérapie of the Fédération Nationale des Centres de Lutte Contre le Cancer. J Clin Oncol 15:3507-3514, 1997.

8. Cristofanilli M, Budd GT, Ellis MJ, et al: Circulating tumor cells, disease progression, and survival in metastatic breast cancer. N Engl J Med 351:781-791, 2004.

9. Cristofanilli M, Hayes DF, Budd GT, et al: Circulating tumor cells: A novel prognostic factor for newly diagnosed metastatic breast cancer. J Clin Oncol 23:1420-1430, 2005; erratum in: J Clin Oncol 23:4808, 2005.

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

11. Cristofanilli M, Broglio KR, Guarneri V, et al: Circulating tumor cells in metastatic breast cancer: Biologic staging beyond tumor burden. Clin Breast Cancer 7:471-479, 2007.

12. Reuben JM, Cristofanilli M: Circulating tumor cells in individualizing breast cancer therapy. In press.

13. Hayes DF, Cristofanilli M, Budd GT, et al: Circulating tumor cells at each follow-up time point during therapy of metastatic breast cancer patients predict progression-free and overall survival. Clin Cancer Res 12:4218-4224, 2006.
 
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