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established prognostic cut-off used in the metastatic setting of 5 CTCs detected in 7.5 ml of blood through
the CellSearch, discretionary cut-off of either 1 CTCs, 5 CTCs or both have been used. However, since
[36]
the number of CTCs appeared to be directly correlated with the prognosis and considering the lower
number of CTCs presents in the earlier stages, the lowest cut-off (1 CTCs) has been empirically adopted by
most of the investigators.

CONCLUSION AND FUTURE DIRECTIONS
Improving the management of early disease patients represents one of the most pressing challenges in
breast cancer care. Thus, in order to enhance the chances of early diagnosis, early detection of recurrence
and personalized treatment, several liquid biopsy tools have been deployed in this setting in the last 20 years.
Among them, CTCs and ctDNA detection and characterization have played a fundamental role, showing a
potential prognostic and predictive value in numerous prospective trials.

As a matter of fact, the sensitivity and specificity of the current methods are still suboptimal to candidate
ctDNA detection as a tool of early diagnosis. In this context, the assessment of epigenetic alterations (e.g.,
methylomes analysis) has shown promising preliminary results, demonstrating the potential utility of
[19]
ctDNA methylation profiles as a basis for non-invasive, sensitive and accurate early tumor detection .

Despite the highlighted current analytical and technical limitations of ctDNA detection in early setting,
encouraging results are shown by investigations addressing the potential prognostic role of ctDNA
detection after primary treatment [27,31] , which suggest considering the detection as a good indicator of MRD.
Furthermore, the molecular characterization of ctDNA could act as a versatile, dynamic and not invasive
tool of disease characterization that might lead clinicians in the process of treatment choice, anticipating or,
[46]
in a foreseeable future, even partially replacing the tissue biopsy .
Combined analysis of ctDNA and CTCs could improve the prognostic value and clinical utility. In fact,
under certain circumstances, even with undetectable amount of ctDNA, CTCs can be isolated from the
circulation. Indeed, in a cohort of 196 TNBC patients that received a blood draw after NAT (results recently
published by Radovich et al. ), the combination of ctDNA and CTCs provided additional information
[29]
to identify patients with worse prognosis, such that the sensitivity to detect recurrences within 24 months
went from 79% with ctDNA detection alone to 90% when combined.

These results suggest that these methods have, at least in part, a complementary sensitivity and that the
combined use could improve the performances. Another successful combinatorial approach is represented
by the PCR-based NGS assay called CancerSEEK, that provided high performance in diagnosis and
[16]
assessment of primary tumor combining ctDNA detection with different circulating protein biomarkers .

However, although the findings provided by several investigations currently suggest a potential clinical
impact of ctDNA mutation tracking, clinical utility is still far from being demonstrated, as the highlighted
lead time among several studies has not yet been translated in a ctDNA based eBC management that has
prospectively shown a significant increase of overall survival.

CTC detection in early-stage breast cancer is associated with prognostic information in patients with
locally advanced or high-risk primary breast cancer at different time points in their treatment history [42,47,50] .
In particular, the number of CTCs detected before any treatment has been associated with prognosis in
several investigations [37,40,44,73,74] , suggesting a potential role of CTCs in stratifying patients for neoadjuvant
treatment selection. Furthermore, large data analysis including patients with early low-risk luminal breast
cancer seem to indicate that CTCs detection could serve as a predictive biomarker for loco regional
radiotherapy (XRT) . In that respect, there is currently a plan for a prospective trial to test de-escalating or
[75]