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Page 2 of 24 Peyvandi et al. J Cancer Metastasis Treat 2019;5:44 I http://dx.doi.org/10.20517/2394-4722.2019.16

in particular lung, liver, bone or brain, leading to organ destruction and failure, resistance to therapy and
[1,2]
[3]
cachexia . Metastasis formation is believed to be a highly inefficient process . The main rate limiting step
[4,5]
in the metastatic process appears to be the ability of tumor cells to adapt to the new environment . During
this adaptation step at the metastatic site, cells have to establish bidirectional paracrine communication
with a new tissue different from the primary site, acquire novel survival capacities and escape immune
destruction. While cell autonomous processes, such as genetic evolution and epigenetic modifications, altered
gene expression and metabolic adaptation, are essential to the metastatic process, the microenvironments
[5-8]
of the primary tumor and of the metastatic site are equally critical determinants of metastasis formation .
Tumor angiogenesis, the remodeling of the extracellular matrix, the activation of local resident cells and
the recruitment of inflammatory cells provide essential contributions to the metastatic process, including in
breast cancer [9-11] . At diagnosis, only a minority of cancers have already formed clinically overt metastases
[12]
(i.e., stage IV) . Those that progress to metastatic disease can do with strikingly different kinetic. For
example, lung and colorectal cancers mostly relapse within 1-3 years after diagnosis and the 5-year survival
rates for these cancers are about 20% and 60%, respectively [13,14] . Conversely, in prostate cancer relapses occur
[15]
late, with over 90% of the patients still alive 15 years after initial diagnosis . In breast cancer, relapses occur
with a peculiar bimodal distribution: a first peak appears generally 1-2 years and a second peak 4-5 years
after surgery, followed by a tailed extension up to 15 years [16,17] .

BREAST CANCER SUBTYPES AND ADJUVANT THERAPIES
Breast cancer is the most common cancer diagnosed among women. In spite of improved management
[18]
over the past 30 years, it remains the leading cause of cancer-related mortality for women world-wide .
Therapy and prognosis are largely determined by the biological and molecular characteristics of the
primary tumor and its size and spreading at time of diagnosis [19,20] . There are three main clinically relevant
+
+
biological subtypes: Oestrogen/Progesterone receptor positive breast cancer (ER /PR ), HER2 amplified
- [21-23]
-
+
-
(HER2 ) breast cancer and Triple Negative Breast Cancer (TNBC; i.e., ER, PR, HER2) . Based on gene
+
expression signatures four main molecular subtypes have been reported: Luminal A and B, HER2 , and
+
+
basal-like, which overlap largely, but not fully with the ER /PR+; HER2 and TNBC biological subtypes,
respectively [24,25] . Both biological and molecular classifications have prognostic and predictive (therapeutic)
+
relevance [19,20,24,25] : ER tumors are treated with adjuvant anti-estrogen therapies (e.g., tamoxifen) while
+
HER2 tumors are treated with HER2 inhibitors (e.g., trastuzumab), in addition to radiotherapy and
chemotherapy, if necessary [19,26] . TNBC, has no molecular target useful for targeted therapy yet and adjuvant
radio- and chemotherapies are still the standards of care [22,27] . The rational for administering adjuvant
therapy after surgery is to eradicate disseminated tumor cells (DTC) or micro-metastases to decrease the
+
risk of relapse. A large body of evidence from adjuvant studies suggest that ER breast cancer benefits less
-
[28]
from chemotherapy compared to ER breast cancer . This is particularly true for the luminal A molecular
+
subtype of ER breast cancer, which has a low rate of proliferation. Luminal A tumors have lower rates of
+
pathologic complete response to chemotherapy compared to the highly proliferative ER luminal B breast
cancer subset, as demonstrated with neo-adjuvant anthracycline/taxane-based chemotherapy [29,30] . For
+
HER2 breast cancer the introduction of HER2 inhibitors as adjuvant therapy, in combination with taxane-
based chemotherapy, has vastly decreased the risk of metastatic progression and greatly improved survival
in this cancer subtype [23,31] . TNBC is highly proliferative and respond better to chemotherapy compared to
[33]
ER cancers [22,32] . Today no established targeted therapy exists for TNBC . Interestingly, a fraction of TNBC
+
are rich in tumor infiltrating lymphocytes and this infiltration has been associated with improved disease-
free survival and overall survival OS, suggesting that immune cells may contribute to therapy success and
implying the possibility of applying check-point inhibitors-based immunotherapies for these patients [10,22] .
In spite of an approx 30%-35% decrease in mortality over the past 35 years due to combined systematic early
detection and improved adjuvant therapies, there are still about 20%-25% of breast cancer patients, all stages
combined, that will eventually succumb to their disease due to formation of therapy resistant metastases.