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improve patients’ health outcomes, quality of life or cost effectiveness. In addition, PFS and OS showed no
[180]
difference in outcome when patients were switched to an alternate regimen . Thus, the American Society
of Clinical Oncology guidelines affirm that the use of CTC count alone may be prognostic but not predic-
[184]
tive for monitoring response to treatment for metastatic breast cancer . Nevertheless, several clinical trials
based on the comparison in HER2/ER/PR expression profiles between patient’s biopsy, from primary tumor
or metastatic site, and CTCs, demonstrated a discrepancy between biopsies and circulating cells that could
[185]
+
-
have important therapeutic implications . In fact, it has been revealed in HER2 and ER BC patients the
+
presence, respectively, of HER2 and ER CTCs associated with an increased mortality risk, poor PFS and
-
-/+
+/-
low OS [186-188] . Therefore, knowing that the switch between HER2 or ER can occur after multiple courses
-
in patients under HER2 targeted or ER-endocrine therapies, the monitoring of CTCs becomes crucial [189,190] .
Obviously, these evidences suggest a potential mechanism of a patient’s specific therapy-resistance, which
[191]
is still unknown and under investigation in ongoing clinical trials . In conclusion, despite several issues
needing to be overcome, CTCs could be considered as a “real-time” liquid biopsy, able to provide important
molecular information about patient’s current disease and, hopefully, to suggest the suitable personalized
[138]
treatment regimen .
CONCLUSION
At present, personalized medicine represents one of the principal aims of medical research. For this rea-
son, even the improvement achieved in treatment options and the better clinical outcomes for BC patients,
conventional tissue biopsies are considered, up to date, a poor diagnostic procedure. The growing interest
in CTCs and their in progress validation as diagnostic and prognostic biomarker, could represent the tool
for achieving this wishes of “personalization”. In fact, despite the still outstanding issues already covered in
this review, CTCs could be crucial to the understanding of the complex BC heterogeneity, at the same time,
they could be considered as a screening tool. Furthermore, their proved implication in the metastatic pro-
cess and, most important, in chemoresistance, is stimulating the rapid development of new CTC isolation
and single cell analysis platform. In the future, it is expected that the improvement in CTCs knowledge
may pave the way to the discovery of new targets and to therapies that are more efficient.

DECLARATIONS
Authors’ contributions
Conception and elaboration of the work: Di Raimo T, Angelini F
Provided administrative, technical, and material support: Di Raimo T, Angelini F
Revisiting the work critically for important intellectual content: Di Raimo T, D’Andrea MR, Angelini F
Final approval of the version: Di Raimo T, De Santis E, Coppola L, D’Andrea MR, Angelini F

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.