CTC Testing Offers Current Value and Future Promise in MBC

Massimo Cristofanilli, MD

Director, Jefferson Breast Care Center

Sidney Kimmel Cancer Center

Jefferson University Hospitals

Circulating tumor cell (CTC) enumeration is a strong prognostic factor in metastatic breast cancer (MBC) and predicts treatment failure. I use the CellSearch test as a complementary test for staging of the disease and re-evaluation of therapy efficacy.

Multiple studies have shown that ≥5 CTCs/7.5 mL of blood, counted using the CellSearch system and evaluated before starting systemic treatment, is associated with poor outcome in patients with MBC. As has been demonstrated, CTC enumeration allows a more accurate assessment and monitoring of breast cancer and, in some cases, helps us reduce the number of imaging studies.¹

Clinical Utility Explored

Patients are very interested in the value of this test and in learning about the growing literature available.Two recently published papers provide interesting data and perspectives on the use of CTC enumeration and molecular analysis in patients with advanced breast cancer.

A paper from Giuliano and colleagues2 is a retrospective study performed using a dataset of more than 500 patients in which CTCs were used as clinical tests. The analysis confirms the prognostic value of baseline CTCs, but also clearly shows that the group with worse outcomes generally will progress by developing new metastatic sites (Figure 1).

As we know, metastatic breast cancer is an incurable condition, and patients ultimately succumb to their disease because of widespread progression.

Figure 1. Association of Baseline CTCs With Metastatic Spread²

SThe baseline CTC count correlates with rates of development of new metastatic sites (A) and new lesions (B) in the first progression of disease among the overall population (N = 492) of patients analyzed in a retrospective study. The development of new metastatic sites by the first PD after baseline (C) also correlates with CTC count. CTC indicates circulating tumor cell; PD, progression of disease.

The ability to identify these patients upfront can allow a more aggressive approach in cases with a lack of detectable CTCs and a more conservative one, along with a close monitoring approach, in other patients (Figure 2).

Another implication of recent CTC research is evidence that current chemotherapy regimens are mainly able to affect disease proliferation—but not metastatic spreading—and have somewhat limited value in patients with detectable and persistent CTCs.

Figure 2. Association of Baseline CTCs With Visceral Disease Spread²

CTC count correlated with types of the first PD occurring after baseline in 149 patients with disease initially confined to nonvisceral organs (A). The marker also was predictive of the time to visceral disease (B) and overall survival (C) among 186 patients without visceral metastases.

Molecular CTC Tests Needed

This hypothesis provides an understanding of the reasons for the failure of improving survival in patients with persistent CTCs by simply changing the chemotherapy regimen, as Smerage and colleagues³ describe in their report on a large clinical trial designed to explore ways in which oncologists can use CTC enumeration to help manage patients with MBC.There is an increasing need for molecular analysis of CTCs to better identify molecular drivers of advanced disease and potential therapeutic targeting. One example of the potential benefits of such analysis is evident in a recent report⁴ that delineated the presence of TP53, a suppressor gene mutated in a variety of solid tumors, including breast cancer. TP53 mutations in breast cancer are associated with more aggressive disease with resistance to DNA-damaging agents.

Fernandez and colleagues4 used a combination of CTC enrichment and isolation methods to obtain a population of pure cancer cells from patients’ peripheral blood for genomic analysis. The genomic analysis in two patients with CTCs revealed TP53 mutations along with cells with wild-type allele, suggesting a heterogeneous population.

The other objective was to compare the CTCs data with next-generation sequencing (NGS) of metastatic lesions to determine the ability to detect similar mutations. Interestingly, the study clearly showed that CTCs and NGS identify the same variant TP53 R110 fs*13.

The variable detection on CTCs is actually a more realistic representation of the dynamic changes occurring in cancer cells. We certainly cannot expect that cancer cells in the peripheral blood recapitulate exactly the ones in the established metastatic lesions with regard to phenotypic and, in some respect, genotypic characteristics. The integration of data from tissue and blood (ie, liquid biopsy) for accurate representation of disease biology is the next challenge in the evaluation and management of MBC.

References

1. Budd GT, Cristofanilli M, Ellis MJ, et al. Circulating tumor cells versus imaging—predicting overall survival in metastatic breast cancer. Clin Cancer Res. 2006;12(21):6403-6409.
2. Giuliano M, Giordano A, Jackson S, et al. Circulating tumor cells as early predictors of metastatic spread in breast cancer patients with limited metastatic dissemination. Breast Cancer Res. 2014;16(5):440. doi:10.1186/s13058-014-0440-8.
3. Smerage JB, Barlow WE, Hortobagyi GN, et al. Circulating tumor cells and response to chemotherapy in metastatic breast cancer: SWOG S0500 [published online June 2, 2014]. J Clin Oncol. 2014;32(31):3483-3489.
4. Fernandez SV, Bingham C, Fittipaldi P, et al. TP53 mutations detected in circulating tumor cells present in the blood of metastatic triple negative breast cancer patients. Breast Cancer Res. 2014;16(5):445. doi:10.1186/s13058-014-0445-3.