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The first prospective assessment of the role of CTCs in early breast cancer patients was published in 2006 by
[35]
Xenidis et al. , suggesting that detection of peripheral blood CK-19 mRNA-positive cells in eBC patients
were associated with early clinical relapse (P = 0.00001) and disease-related death (P = 0.008). Since then,
several big randomized prospective trials preplanned a CTCs analysis with the aim to better evaluate the
prognostic and predictive value of CTCs detection in early breast cancer patients.

The main evidences supporting the prognostic value of CTCs detection in the earlier setting of breast
[36]
cancer were provided by the translational research program of the phase 3 SUCCESS-A trial . Pre- and
post-adjuvant treatment blood samples from 2026 patients were evaluated and the presence of CTCs was
associated with poor DFS (P < 0.0001), DDFS (P < 0.001), breast cancer-specific survival (P = 0.008), and
OS (P = 0.0002). Similar correlations were demonstrated by several other trials, across different subtypes
and clinical features [37-41] . Interestingly, the large sized cohort allowed both correlation of CTCs and clinical
characteristics (such as node-positivity), and to show an additional negative influence on DFS and OS in
case of persistence of CTCs after therapy.

From the same group, a more recent analysis of correlation between CTC counts at the 2-year visit after
treatment and outcome provided evidences about follow-up CTCs detection. The presence of CTCs at
2 years after chemotherapy significantly predicted both shorter OS (HR = 4.24, 95%CI: 2.32-7.73; log-rank
test, P < 0.001) and shorter DFS (HR = 2.37, 95%CI: 1.57-3.58; log-rank test, P < 0.001) in the univariate
[42]
analyses. Of note, a subgroup analysis was not able to show a correlation in HER-2 positive breast cancer .
The importance of follow-up CTCs detection was more recently assessed in a per-protocol secondary
[43]
analysis of a double-blinded phase III trial, whose important results were published by Sparano et al.
in 2018. Among 353 estrogen receptor positive eBC patients without any evidence of recurrence between
4.5 years and 7.5 years after primary surgery, a positive CTC assay result was associated with a 13.1-fold
higher risk of recurrence (hazard ratio point estimate, 13.1; 95%CI: 4.7-36.3), reinforcing the value of
CTCs detection during follow-up and the possible future implication in the decisional process on adjuvant
endocrine therapy duration of treatment. In the CTCs analysis of REMAGUS 02 trial, Pierga et al. found
[37]
that circulating tumor cell detection before and/or after neoadjuvant chemotherapy was significantly
associated with early metastatic relapse (P = 0.013; median follow-up, 18 months). An updated analysis of
[44]
this cohort from Bidard et al. confirmed the results with higher statistical significance. However, neither
CTC detection before or after neoadjuvant chemotherapy nor changes in CTC count during neoadjuvant
chemotherapy was predictive of pathologic complete response.

Patient and treatment selection for neoadjuvant therapy has gained greater momentum in breast
cancer since a correlation between tumor response and long-term outcome was observed. However, in
contrast with the metastatic setting, the utility of the CTC number change to monitor the efficacy of
neoadjuvant treatment has not been demonstrated. In the sub-study of the NeoALTTO phase III trial,
a numerically lower pCR rate was observed in patients with detectable CTCs, although no statistically
significant association was found . A lack of correlation was highlighted also in the CTCs analyses of
[45]
the inflammatory breast cancer (IBC) patients enrolled in both BEVERLY 1 and 2 trials, even though the
association of achieved pCR and negative baseline CTCs identified a very good prognosis subgroup of
HER2+ IBC (95% 3-years DFS) [39,40] .

In summary, notwithstanding the potential of CTCs in monitoring treatment response, there is still no
solid evidence about their role in driving the treatment intensity as, on the other hand, has been recently
[46]
suggested in the metastatic setting .

Despite the growing evidence with regards to the potential clinical relevance of pre-treatment detection,
several investigations have called into question the value of CTC count after neoadjuvant treatment.