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Page 4 of 24 Peyvandi et al. J Cancer Metastasis Treat 2019;5:44 I http://dx.doi.org/10.20517/2394-4722.2019.16

dormant, they eventually formed metastasis. This experimental observation supports the notion that DTC/
DCC can remain dormant for prolonged periods before resuming growth to form macroscopic metastases.
As current adjuvant treatment in breast cancer seems to have reached a plateau in term of survival benefits,
understanding how DTC and micro-metastases adapt to the distant environment, survive and eventually
resume growth to form macroscopic metastases may identify new therapeutic opportunities [1,8,78] .

In both the linear and parallel tumor progression models, the genomic instability of tumor cells is the
basis of the evolutive process. The variability emerging among tumor cells within the same tumor tissue
[79]
is referred to as intratumoral heterogeneity and is also found within metastases . This heterogeneity may
also be responsible to the presence of tumor cells with low and high tumorigenic potentials, the latter being
[80]
CSCs or cancer initiating cells (CICs) . Moreover, it is believed that heterogeneity also exists inside the
CSC population itself. In such a scenario, metastasis progression and resistance to anti-tumor treatment
[59]
are thought to be due to clonal evolution and selection much alike Darwinian evolution . Intratumoral
[81]
heterogeneity may also contribute to tumor dormancy or escape from it. Marusyk et al. have used the
MDA-MB-468 tumor cell model in vivo to show that a IL-11 expressing tumor population is able to drive
non-cell-autonomous tumor growth from dormant tumor cells. This indicates that re-establishment of
certain heterogeneity is necessary for tumor growth after seeding or treatment. In line with this observation,
[82]
Aceto et al. have reported that, CTC clusters have higher ability to seed metastasis compared to single
[83]
[84]
CTC, involving at least in part altered DNA methylation . Furthermore, Kmieciak et al. showed that the
heterogeneity of breast cancer cells in the levels of IFN-γ receptor α expression could determine a selective
+
dormancy. Tumor cells expressing high levels of IFN-γ receptor α are eliminated by CD8 T cells, while
tumor cells with low expression levels do not die and remain dormant in the presence of IFN-γ producing
+
CD8 T cells. Thus, tumor heterogeneity contributes to tumor dormancy by providing cells with different
genetic and biological features.

METASTATIC BREAST CANCER DORMANCY
As mentioned before, breast cancer metastasis occurs with a bimodal distribution with two peaks: a first
one 1-2 years and a second one at 4-5 years after surgery, followed by a tailed extension up to 15 years [17,85,86] .
These observations are inconsistent with a model of continuous growth kinetics and rather suggestive of
discontinuous growth, thereby implying a period of dormancy [16,17,85-87] . Clinical observations also revealed
that timing of appearance of metastasis has a similar profile for the different breast cancer subtypes,
suggesting that after primary tumor removal, DTC from distinct subsets evolve following similar patterns
+
but with different dominances (i.e., TNBC and HER2 cancers tend to relapse at the early peak, compared to
+
+
ER /PR cancer which tend to relapse at the second peak or later [85,86,88,89] . These observations also suggest that
relapses occurring at peaks may follow inducible and reproducible patterns based on defined mechanisms,
[90]
for example tumor surgery , while relapses occurring in between or in the tailed extension may be
due to unpredictable or random events, such as genetic mutations, epigenetic modifications or unrelated
inflammatory events [65,67,68,91,92] . Accordingly, these clinical observations were modelled mathematically by
considering known basic hazard rates and unknown variables [93,94] . Dormant disseminated cancer cells and
[95]
micrometastases have been reported in breast cancer patients and in experimental animal models [77,96-98] .
Although dormancy is a common phenomenon in breast cancer, the underlying biological mechanisms
remain ill characterized. Dormancy might be functionally considered as a transitional, metastable step of
cell adaptation to a novel external stress, in particular a “foreign” soil. DTC lacking survival capabilities
would rapidly die, while those that have acquired the latter would immediately grow to form macroscopic
metastases without latency [Figure 1]. Mechanistically, three forms of cancer dormancy have been
described and many genes and molecules involved identified [99-102] : cellular dormancy, microenvironmental
(angiogenic) dormancy and immunological dormancy. These three forms of dormancy are not mutually
exclusive and it is likely that clinical dormancy is owed by their combination and interrelation.