Circulating Tumor Cells in Metastatic Breast Cancer: Are We Afraid of the Truth?

Get Permission

Massimo Cristofanilli, MD, FACP

The discovery of the liquid phase of solid tumors is an important step forward in understanding the metastatic process and the complexity of the disease. We should not be afraid of embracing this information for routine patient care, disease stratification, and clinical research.

—Massimo Cristofanilli, MD, FACP

All truths are easy to understand once they are discovered; the point is to
discover them.”

—Galileo Galilei


There are several “truths” in breast oncology that have been discovered over the years, become widely understood, and changed the way we practice. Prospective randomized studies have shown that breast-conserving therapy is associated with similar outcome compared with mastectomy.1 A more conservative surgical approach with the axillary nodes has similar impact on outcome.2 Adjuvant systemic combination therapy improves survival in primary breast cancer,3 and the inclusion of endocrine and biologic therapies is recommended in hormone receptor–positive and HER2-positive disease.4,5

In metastatic breast cancer, targeted therapies have improved progression-free survival and in some cases overall survival in defined subtypes of disease.6,7 Both single-agent and combination-regimen systemic chemotherapy have been evaluated in prospective studies showing evidence of palliative effect.8 These studies suggested some limitations in our systemic treatments and the need for investigations to better understand the metastatic process in order to develop more effective approaches.9

‘Liquid Phase’ of Solid Tumors

The detection of circulating tumor cells in the peripheral blood of patients with metastatic breast cancer demonstrated that solid tumors have a “liquid phase” that should always be evaluated and measured in these patients.10 Large prospective studies and retrospective analyses have confirmed that baseline detection of ≥ 5 circulating tumor cells/7.5 mL whole blood in patients with metastatic breast cancer has a definitive prognostic and predictive value irrespective of line of therapy and disease subtype.11,12

A recent study by Smerage et al, reviewed in this issue of The ASCO Post, further confirms these findings but also adds important new information with implications for patient management.12 The detection of ≥ 5 circulating tumor cells can be used to classify metastatic breast cancer in two biologically different diseases; because the prognostic value is independent of known disease subtype, this means that circulating tumor cell detection introduces a new dimension (liquid phase).

Furthermore, the use of systemic chemotherapy as “early” second-line therapy for patients with persistent circulating tumor cells shortly after initiation of systemic treatment is not beneficial and possibly detrimental. In other terms, these patients should be more carefully evaluated for possible use of targeted therapies because “empiric” choices are unlikely to be effective.

Another important consideration is the use of standard anatomic imaging to assess “tumor shrinkage” as a surrogate for therapeutic benefit.13,14 This approach does not consider the liquid phase of the disease and therefore is imperfect by definition. Chemotherapy as a debulking modality can reduce tumor size without affecting circulating tumor cells, translating to a nonmeaningful response13—that is, patients may be exposed to unnecessary toxicity and prolonged treatment without the expected benefit. What are the additional implications of not using this information? Should we consider developing response evaluation criteria in solid tumors (RECIST) version 2?

Clinical Trial Considerations

We regard prospective randomized studies as the “holy grail” for assessing the impact of any new therapeutic intervention and potentially proceeding to regulatory approval if a benefit is demonstrated in progression-free and overall survival. We certainly cannot predict if the randomization process will equally distribute among study groups patients with ≥ 5 circulating tumor cells, but it appears unlikely.

As an example, consider the prospective pivotal phase III open-label multicenter trial (NCT00388726, EMBRACE) that resulted in the approval of eribulin (Halaven) in HER2-negative metastatic breast cancer.15 The study enrolled 762 patients who received at least two prior chemotherapy regimens for their advanced disease, including anthracyclines and taxanes. Patients were randomly assigned to receive eribulin vs physician’s choice (standard arm). The chemotherapies used in the standard arm included but were not limited to vinorelbine, gemcitabine, capecitabine, taxanes, and anthracyclines.

The median overall survival of the eribulin group (399 days/13.1 months) compared with the standard group (324 days/10.6 months) improved by 75 days/2.5 months (hazard ratio = 0.809, 95% confidence interval = 0.660–0.991, P = .041). The Smerage et al study does not specify the drugs used as “early“ second-line therapies, but they likely reflected physician choice and possibly were similar to those used in the EMBRACE study.

What difference in overall survival would have been observed if we were to select a single specific regimen after persistent elevated circulating tumor cells? It is only possible to speculate about indirect comparisons without a confirmation, but it is conceivable that use of a variety of different regimens can dilute any potential (limited) benefit of chemotherapy in metastatic breast cancer.

In conclusion, the discovery of the liquid phase of solid tumors is an important step forward in understanding the metastatic process and the complexity of the disease. We should not be afraid of embracing this information for routine patient care, disease stratification, and clinical research. ■

Disclosure: Dr. Cristofanilli is on the scientific advisory board of Cynvenio.


1. Veronesi U, Cascinelli N, Mariani L, et al: Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 347:1227-1232, 2002.

2. Giuliano AE, Hunt KK, Ballman KV, et al: Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: A randomized clinical trial. JAMA 305:569-575, 2011.

3. Bonadonna G, Brusamolino E, Valagussa P, et al: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 294:405-410, 1976.

4. Burstein HJ, Temin S, Anderson H, et al: Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update. J Clin Oncol. May 27, 2014 (early release online).

5. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684, 2005.

6. Giordano SH, Temin S, Kirshner JJ, et al: Systemic therapy for patients with advanced human epidermal growth factor receptor 2-positive breast cancer: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 32:2078-2099, 2014.

7. Baselga J, Campone M, Piccart M, et al: Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520-529, 2012.

8. Cardoso F, Harbeck N, Fallowfield L, et al: Locally recurrent or metastatic breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 23(suppl 7):vii11-vii19, 2012.

9. Velasco-Velázquez M, Jiao X, De La Fuente M, et al: CCR5 antagonist blocks metastasis of basal breast cancer cells. Cancer Res 72:3839-3850, 2012.

10. 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.

11. Bidard FC, Peeters D, Fehm T, et al: Clinical validity of circulating tumour cells in patients with metastatic breast cancer: A pooled analysis of European studies. Lancet Oncol 15:406-414, 2014.

12. Smerage JB, Barlow WE, Hortobagyi GN, et al: Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500. J Clin Oncol. June 2, 2014 (early release online).

13. Therasse P, Arbuck SG, Eisenhauer EA, et al: New guidelines to evaluate the response to treatment in solid tumours. J Natl Cancer Inst 92:205-216, 2000.

14. 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.

15. Cortes J, O’Shaughnessy J, Loesch D, et al: Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): A phase 3 open-label randomised study. Lancet 377:914-923, 2011.


Dr. Cristofanilli is Professor of Medical Oncology, Deputy Director of Translational Research, and Director of the Jefferson Breast Cancer Center, Thomas Jefferson University, Philadelphia.

Related Articles

Early Change in Chemotherapy Based on Elevated Circulating Tumor Cells Does Not Improve Outcome in Metastatic Breast Cancer

Elevated circulating tumor cells are associated with poor prognosis in metastatic breast cancer. In a phase III trial (Southwest Oncology Group [SWOG] S0500) reported in Journal of Clinical Oncology, Jeffrey B. Smerage, MD, PhD, Clinical Associate Professor in Medical Oncology at the University of...