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Page 2 of 14 Di Raimo et al. J Cancer Metastasis Treat 2018;4:54 I http://dx.doi.org/10.20517/2394-4722.2018.50
[6,9]
ological and biological characteristics, reflects different clinical outcomes and therapeutic strategies . Es-
trogen and progesterone receptors (ER and PR) in addition to the human epidermal growth factor receptor
2 (HER-2) and the proliferation index (Ki-67) represent the most clinically used predictive biological mark-
ers [10,11] . Nowadays, it has been amply demonstrated how their expression is correlated with both BC intrin-
sic subtypes classification and the relative prognosis [6,12] . Concisely, the canonical molecular classification,
firstly established by Perou in 2000, divided breast cancers in two principal subfamilies, ER- positive and
+
+
-
-
ER-negative [6,12,13] . In the first subfamily are included the LUMINAL A (ER PR HER2 Ki67) and LUMINAL
+
+
B (ER PR Her2 Ki67 ) subgroups that represent the most common subtypes among BC. Despite the high-
+/-
+/-
est incidence, luminal A has the best survival rate and is recurrence-free, while luminal B, due to their het-
erogeneity, presents a worse outcome together with an high risk of relapse, thus additional chemotherapy
and anti-HER2 drugs treatment are needed [14,15] . The ER- subfamily includes two principal subgroups. The
first subtype, called HER2 OVER-EXPRESSED (ER-PR-Her2 Ki67 ), is correlated with poor prognosis and
+
+
a higher risk of early relapse. Hopefully, it has been demonstrated that anti-HER2 drugs treatment brings
[6]
an increment on survival and patients respond positively to chemo and neoadjuvant therapy . The second
ER- subgroup, the so-called BASAL LIKE, that represents 15% of BC, is characterized by an expression
patterns including lack or low expression of ER, PR and HER2 in addition to a high expression of basal
markers and Ki67. In the 60%-90% of cases, basal-like BC is TRIPLE NEGATIVE BC (TNBC), due to the
[16]
absence of the principal three biological marker expressions . TNBC represents a very heterogeneous sub-
group comprised of further six subclasses, such as basal-like BL1 and BL2, mesenchymal-like, mesenchy-
mal stem-like, luminal-androgen receptor expression, immunomodulatory and an unstable type subclass-
[17]
es . In general, the TNBC subgroup exhibits, in addition to a high proliferation rate, an increase in basal/
[14]
myoepithelial cells-related cytokeratins (CKs) and epidermal growth factor receptor (EGFR) expression .
Furthermore, even if its heterogeneity is correlated with different prognosis and severity levels, the high
percentage of TNBC patients present the worse clinical outcome, a shorter relapse-free period and a strong
possibility to develop bone, lung, brain and liver metastasis [18,19] . Actually, it is clearly demonstrated that
there is a strict correlation between the survival of women with BC and the incidence of distant metasta-
ses [20,21] . The migration of tumor cells from the primary tumor into the blood stream and their subsequent
dissemination to secondary locations throughout the body represents the sine qua non condition that acts
[22]
as a trigger for the entire metastatic process . Nowadays, circulating tumor cells (CTCs) represent an im-
portant prognostic biomarker in early BC disease and their presence is directly correlated with the patient’s
response to therapy and with poor prognosis in case of recurrence in radically resected BC or in metastatic
disease [23-26] . Nevertheless, determination and utility of CTCs, in the common clinical practice, are still
[27]
object of discussion . Therefore, after a little excursion on CTCs characteristics and behavior during the
metastatic process, the aim of this review is to make a point on clinical utility and validity of CTCs for a
prospective therapeutic scenario.

CTCs AND THEIR PLASTICITY IN THE METASTATIC PROCESS
It is estimated that, at least in 90% of cases, metastases in distant organs represent an obstacle to the thera-
py and the primary cause of death in BC patients [23,28] . In the presence of metastatic cancers, chemotherapy
is less effective on tumor cells and, as estimated by the American Cancer Society, only 22% of patients pres-
ent a 5-year survival rate (www.cancer.org). Metastasis can be described as a complex dynamic multi-step
process that begins with the intravasation of primary tumor-derived cells into blood or lymphatic vessels
and goes on with the arrest, adhesion and extravasation of CTCs bringing to the colonization of distant
organs [22,29,30] . Whenever these cells penetrate into the bone marrow, acquiring a status of dormancy, they
are defined as “Disseminated Tumor Cells” (DTCs) [31,32] . Since their first detection in 1869 by Ashworth,
several studies and clinical trials have demonstrated and confirmed, over the years, the strict correlation
between detection and monitoring of CTCs in peripheral blood and metastatic BC (MBC), in terms of dis-
ease progression, prediction of treatment efficacy and overall-survival [33-43] . This concept has also been rati-
fied in the eighth edition of the AJCC Cancer Staging Manual, in which circulating CTCs and bone mar-