3. CTCs for prediction of prognosis

Cancer cells may leave the primary tumor and enter blood circulation long before the disease becomes clinically detectable and are considered a potential source of metastatic spread. Accordingly, numerous studies reported that early BC patients with detectable CTCs have significantly worse clinical outcomes than CTC-negative patients (Table 1). Among these, the largest data set was provided by the German SUCCESS trial (EUDRA-CT No. 2005-000490-21, NCT02181101). Briefly, blood samples from over 2000 average-to-high risk non-metastatic BC patients before chemotherapy and nearly 1500 patients after chemotherapy were examined [8]. Patients with CTCs at baseline had significantly shorter disease-free and overall survival. Further, the trial explored the relationship between CTC counts and prognosis in order to determine the optimal cut-off (i.e., no CTCs vs. ≥ 1; 0–1 vs. ≥ 2; 0–4 vs. ≥ 5 CTCs in 30 ml blood). A statistically significant impact on the clinical outcome was demonstrated for all cutoffs while patients with ≥5 CTCs had the highest relapse risk. Results from the SUCCESS trial are in accordance with smaller studies with longer follow-up [11, 14].

BC can be treated successfully despite the presence of minimal residual disease in the blood. In high-risk patients, the strong prognostic value of CTCs underlines the necessity to establish new treatment strategies for this particular patient group. Further, CTCs predicted clinical outcomes in women with triple-negative and luminal (i.e., hormone-receptor positive, including luminal B HER2-positive subtype) tumors, but no association was found in case of patients with HER2-positive, hormone receptor-negative disease [7]. This observation is in contrast with the previous study by Ignatiadis et al. who reported that CTCs were highly predictive of clinical outcomes in the triple-negative and HER2-subtype but not in luminal tumors [10, 15]. Similar findings were reported by others [13, 16, 17]. Possibly, the relatively short follow-up may contribute to these partly contradictory results since none of the abovementioned trials reported a follow-up longer than 100 months. Longer follow-up might be necessary to fully understand the relevance of CTCs in patients with luminal tumors who are more at risk for a

n.s.: not significant; BCSS: breast cancer-specific survival; DDFS: distant disease-free survival; DFS: disease-free survival;

Patients Method CTC

Franken [11] 404 Stage I–III CellSearch 76 (19%) 48 DDFS,

Lucci [3] 302 Stage I–III CellSearch 73 (24%) 35 DFS, OS

2026 Stage I–III, node-positive or high risk node-negative, all pts. received

Molloy [9] 733 Stage I–II qRT-PCR

444 Stage I–III, all pts. received adjuvant chemotherapy

95 Neoadjuvant trial, Stage II–III,

OS: overall survival; MFS: metastasis-free survival.

at diagnosis or high-risk

including data from five centers, some previously published as [3, 8, 11, 14].

167 Stage I–III RT-PCR

166 Stage I–IIIa RT-PCR

ineligible for breast conserving surgery

Table 1. The prognostic relevance of CTC presence in patients with non-metastatic BC.

chemotherapy

3173 Stage I–III CellSearch 641 (20%) 63 DFS, DDFS,

(CK19, p1B, EGP-2, PS2, MmGI)

RT-PCR (CK19)

(CK19, cerbB-2)

(CK20)

positivity n (%)

The Clinical Relevance of Circulating Tumor Cells in Early Breast Cancer

Follow up (median, months)

http://dx.doi.org/10.5772/intechopen.76117

58 (8%) 91 MFS, BCSS

181 (41%) 54 DFS, OS

n.a. n.a. None

37 (22%) 100 MFS, OS

CellSearch 22 (23%) 70 DDFS, OS

CellSearch 435 (21%) 36 DFS, DDFS,

Prognostic significance 49

BCSS, OS

BCSS, OS

BCSS

late relapse compared to women with more aggressive subtypes [18].

Author Number of patients

Janni pooled analysis [7]\*

Rack, SUCCESS trial [8]

Ignatiadis [10]

Kuniyoshi [12]

Hwang [13]

\*

REMAGUS02 trial [14]

Janni et al. performed a large, multicenter pooled analysis of the available trials and confirmed CTC presence in early BC as an independent predictor of shorter disease-free, overall, breast cancer-specific, and distant disease-free survival [7]. Interestingly, CTC positivity was not associated with survival in low-risk, small node-negative tumors, suggesting that early-stage


n.s.: not significant; BCSS: breast cancer-specific survival; DDFS: distant disease-free survival; DFS: disease-free survival; OS: overall survival; MFS: metastasis-free survival.

\* including data from five centers, some previously published as [3, 8, 11, 14].

BC and state the urgency for further research in this field to definitely translate this marker

Several studies observed the presence of CTCs in patients with no clinically detected metastatic lesion [2, 3]. Illie et al. revealed association of CTC presence with early carcinogenesis and risk of cancer [4]. However, the use of CTC presence as a screening tool to diagnose early breast cancer (EBC) is challenged by the low sensitivity of current CTC detection methods. Current CTC detection platforms such as the FDA-approved CellSearch™ system can only detect CTCs in about 70% of patients with metastatic breast cancer [5]. One of the solutions to improve sensitivity may be the previous performance of leukapheresis. Compared to 20–30% of CTC detection by the CellSearch™ system in early breast cancer, the combination of leukapheresis and the CellSearch™ system has revealed to be able to identify CTCs in 90% of patients with early breast cancer [6]. Respectively, rise of sensitivity due to enrichment techniques may pave the way to use CTCs for early breast cancer screening or diagnosis. An ongoing trial is currently enrolling patients who do not have a prior history of invasive breast carcinoma or clinically apparent metastatic disease to investigate the potential role of CTCs as

Cancer cells may leave the primary tumor and enter blood circulation long before the disease becomes clinically detectable and are considered a potential source of metastatic spread. Accordingly, numerous studies reported that early BC patients with detectable CTCs have significantly worse clinical outcomes than CTC-negative patients (Table 1). Among these, the largest data set was provided by the German SUCCESS trial (EUDRA-CT No. 2005-000490-21, NCT02181101). Briefly, blood samples from over 2000 average-to-high risk non-metastatic BC patients before chemotherapy and nearly 1500 patients after chemotherapy were examined [8]. Patients with CTCs at baseline had significantly shorter disease-free and overall survival. Further, the trial explored the relationship between CTC counts and prognosis in order to determine the optimal cut-off (i.e., no CTCs vs. ≥ 1; 0–1 vs. ≥ 2; 0–4 vs. ≥ 5 CTCs in 30 ml blood). A statistically significant impact on the clinical outcome was demonstrated for all cutoffs while patients with ≥5 CTCs had the highest relapse risk. Results from the SUCCESS trial

Janni et al. performed a large, multicenter pooled analysis of the available trials and confirmed CTC presence in early BC as an independent predictor of shorter disease-free, overall, breast cancer-specific, and distant disease-free survival [7]. Interestingly, CTC positivity was not associated with survival in low-risk, small node-negative tumors, suggesting that early-stage

are in accordance with smaller studies with longer follow-up [11, 14].

from bench to bedside.

48 Breast Cancer and Surgery

2. CTCs as a screening tool

a screening tool (NCT01322750).

3. CTCs for prediction of prognosis

Table 1. The prognostic relevance of CTC presence in patients with non-metastatic BC.

BC can be treated successfully despite the presence of minimal residual disease in the blood. In high-risk patients, the strong prognostic value of CTCs underlines the necessity to establish new treatment strategies for this particular patient group. Further, CTCs predicted clinical outcomes in women with triple-negative and luminal (i.e., hormone-receptor positive, including luminal B HER2-positive subtype) tumors, but no association was found in case of patients with HER2-positive, hormone receptor-negative disease [7]. This observation is in contrast with the previous study by Ignatiadis et al. who reported that CTCs were highly predictive of clinical outcomes in the triple-negative and HER2-subtype but not in luminal tumors [10, 15]. Similar findings were reported by others [13, 16, 17]. Possibly, the relatively short follow-up may contribute to these partly contradictory results since none of the abovementioned trials reported a follow-up longer than 100 months. Longer follow-up might be necessary to fully understand the relevance of CTCs in patients with luminal tumors who are more at risk for a late relapse compared to women with more aggressive subtypes [18].
