Breast cancer is the most common non cutaneous cancer in U.S. women, with an estimated 63,960
cases of in situ disease and 266,120 cases of invasive disease in 2018.
Prognosis and selection of therapy may be influenced by the following clinical and pathology
features (based on conventional histology and immunohistochemistry):
- Menopausal status of the patient , Stage of the disease , Grade of the primary tumor
,Estrogen receptor (ER) and progesterone receptor (PR) status of the tumor.
- Human epidermal growth factor type 2 receptor (HER2/neu) overexpression and/or
- Histologic type: Breast cancer is classified into a variety of histologic types, some of
which have prognostic importance. Favorable histologic types include mucinous,
medullary, and tubular carcinomas
The use of molecular profiling in breast cancer includes the following:
- ER and PR status testing , HER2/neu receptor status testing.
- Gene profile testing by microarray assay or reverse transcription-polymerase chain
reaction (e.g., MammaPrint, Oncotype DX).
On the basis of ER, PR, and HER2/neu results, breast cancer is classified as one of the
Hormone receptor positive , HER2/neu positive and Triple negative (ER, PR, and HER2/neu
ER, PR, and HER2 status are important in determining prognosis and in predicting response to
endocrine and HER2-directed therapy.
Metastatic Triple-negative breast cancer (TNBC) is a diagnosis of exclusion, defined by the
lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal
growth factor receptor 2 (HER2) .
TNBC tends to occur in younger, often premenopausal patients, African Americans, and in
association with hereditary syndromes, most commonly germline BRCA1 mutations.
It constitutes up to 15% of all breast cancers but accounts for > 25% of breast
cancer-related deaths as it has an inherent predisposition for rapid dissemination and
visceral metastases with limited improvements in overall survival and inferior clinical
outcomes It is characterized by higher incidence of brain metastases and rapid progression
from the onset of metastasis to death Having aggressive biology more than other breast types
due to high risk of early relapse between the first and third years after diagnosis ,
metastases are rarely preceded by local recurrence and most deaths occur in the first 5 years
Based on 3,247 gene expression profiles from 21 breast cancer data sets, we discovered six
TNBC subtypes including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal
(M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype.
Due to the palliative intent of treatment as in MBC it is critical that an individualized
approach is taken that incorporates patient, disease, and treatment-related factors,
including an individual oncologist treatment preference.
Emerging clinical trials of targeted agents offer glimpses of hope, including the use of poly
ADP ribose polymerase inhibitors(PARP I) in TNBCs with DNA repair defects, antiandrogen
therapy in patients who are androgen receptor positive, and phosphatidylinositol 3-kinase
inhibitors (PI3K) which may sensitize BRCA-proficient TNBCs to poly ADP ribose polymerase
inhibition Moreover, a subset of TNBCs seems to be immunogenic, with high levels of
tumor-infiltrating lymphocytes, providing a strong rationale for ongoing efforts to explore
the role of immunotherapies.
There have been several head-to-head chemotherapy trials performed within the metastatic
setting, and much of what is applied in clinical practice is extrapolated from chemotherapy
trials in the adjuvant setting, with taxanes and anthracyclines incorporated early on in the
patient's treatment course.
Angiogenesis is essential for the development of malignancies and plays a central role in the
early stages of growth, invasion, and metastatic spread of breast cancer (BC), thus
representing a reasonable therapeutic target. This evidence is a solid biological rationale
for the use of therapeutic agents able to interfere with the VEGF (vaso endothelial growth
factor ) function.
The recombinant monoclonal antibody bevacizumab is currently the most widely used and
developed antiangiogenic drug in the treatment of breast cancer(BC) , able to recognize all
the isoforms of VEGFA, preventing its binding to the cellular receptor, and inhibiting the
angiogenic and proliferative signal. In vivo studies showed that bevacizumab inhibits both
proliferation and migration of endothelial cells induced by VEGFA; besides in some models of
human BC, the treatment with bevacizumab was associated to a reduction in microvascular
density According to the Folkman model, bevacizumab would lead to the normalization of the
tumor vasculature, resulting in a restoration of cancer cells susceptibility to chemotherapy.
This theory is currently accompanied by the newer "action and reaction" model.
The humanized, anti-VEGF monoclonal antibody bevacizumab has been shown to increase
progression-free survival (PFS) and/ or overall survival (OS) in metastatic breast cancer
(MBC), response rate RR .
Taxanes as part of chemotherapy have been studied as having an inhibitory action on the
proliferation of endothelial progenitor cells, with an antiangiogenic effect at lower doses
than those needed to inhibit the proliferation of cancer cells. The resulting hypoxia induces
cancer cells to a kind of "reaction" through the autocrine production of proangiogenic agents
several evidences of their benefits on clinical outcomes, such as OS, time to progression
(TTP), and over all response rate ( ORR.) Even if conventional taxanes demonstrated to be
more active in endocrine receptor-negative tumors and are indicated in the first-line
treatment of TNBC