Abstract
Triple- negative breast cancer (TNBC) is a subtype of breast cancer that does not express the estrogen and progesterone receptors and HER2 protein. This type of cancer represents an important clinical challenge because it does not respond to endocrine therapy or anti- HER2 drugs. In this case, the mainstay treatment is the chemotherapy. The basic principles of diagnosis and management of triple-negative breast cancer are similar to those of breast cancer in general, but the key in managing TNBC remains to find new treatment targets that can potentially improve the outcome of the disease.
Introduction
Breast cancer is one of the most frequent cancer in women and one of the leading cause of death among this category of patients. Triple negative breast cancers represent approximative 10- 20% of all breast cancers diagnosed worldwide (18)
It is well known the importance of the hormone receptors to the biology of the breast cancer and that the human breast cancers are dependent of estrogen and progesterone for growth. This effect is mediated via hormone receptors (estrogen- ER and progesterone- PR receptors). These receptors are usually overexpressed in breast cancers. Thus, new therapies that could interact with the hormone biology were analyzed for finding better treatment and it came clear that endocrine therapy would become an important tool for managing breast cancer. Nowadays, all guidelines recommend that testing for ER and PR should be performed in all invasive breast cancers and the result should select patients that can benefit from endocrine therapy.
Immunohistochemistry (IHC) is the main method used to characterize the percentage of positive cells and the intensity of staining within the cells in all tissues. It is the method of choice for determining the hormone receptors status in breast cancers. There are many scoring systems that can be used to predict the response to therapy and the first system was based on counting the percentage of the positive cells. Thus, according to International Breast Cancer Study Group scheme which represents the basis of the St Gallen treatment guidelines, breast cancer is divided into 3 groups: nonresponsive (0 %), responsive uncertain (1-9%) and responsive (10%). The threshold of 1% positive cells represents the option for endocrine therapy (2).
Human epidermal growth factor receptor 2 (HER 2) gene, initially called HER2/neu or ERBB2 encodes a transmembrane receptor HER2, which belongs to the epidermal growth factor receptors family (EGFR). These receptors are important in growth, differentiation and possible angiogenesis. (9) Knowing the HER2 status of a breast tumor is important because thus we know if HER2 plays a role in cancer and, if so, these patients can benefit from therapies that target HER2. The HER2 status can be identified by IHC and fluorescence in situ hybridization (FISH). IHC evaluates overexpression of the receptor protein at the surface of the cells, while FISH evaluates the status of the HER2 gene in the nucleus. (2). IHC reactions for HER-2 are: 0 and 1+ scores are negative, 2+ is weakly positive and 3+ is positive. For a positive HER-2 result further evaluation is unnecessary for invasive cancers. Weakly positive or equivocal or 2+ cases should be tested for gene amplification by FISH. (2)
In this review triple-negative will be referred to cancers that have ≤1% expression of ER and PR as determined by IHC, and that are either 0-1+ by IHC for HER2, or 2+ and FISH negative, according to ASCO/CAP guidelines 2013 (5)
A logic assumption would be that TNBC and the basal- like tumors are the same. The basal-like tumors represent 8-37% of all breast cancer (3). They are associated with high histological and nuclear grade with high mitotic and proliferative indices. These tumors have an aggressive clinical behavior and tend to metastasize to the brain and lungs. Basal-like tumors do not express ER, PR and HER2 and thus they are referred as triple negative. They also express myoepithelial markers (CK5, CK14, CK17 and laminin) and P- cadherin and EGFR. (3,16) These cancers are associated with mutations of tumor protein 53 gene and microarray and IHC analyses demonstrated that basal-like cancers constitute approximately ¾ of a BRCA1 gene- related breast cancers. (3)
It is important to note that the terms triple negative and basal-like are not the completely the same. The triple negative refers to the IHC classification of the breast cancers without the ER, PR and HER2 expression and the basal-like subtype is expressed via gene expression microarray analysis (4) There is approximative 80% overlap between triple-negative and intrinsic basal-like subtype. Triple-negative also includes some special histological types such as medullary and adenoid cystic carcinoma with low risks of distant recurrence (6).
TNBC express other markers than the basal ones and can be classified as normal breast-like, molecular apocrine or claudin- low subtype by gene expression profiling (8). Besides, there are other histological types of breast cancers that do not show the basal-like pattern and they express a triple negative phenotype (pleomorphic lobular carcinomas, apocrine carcinomas a.s.o.) (8) A small number of triple-negative tumors express luminal markers, such as androgen receptors, and have a lower proliferative activity (7). Other markers of TNBC that are potentially targetable are HER1/ EGFR, c- Kit expression, p53 mutations, poly ADP-ribose polymerase 1. (16)
These biological subgroups mix and currently they cannot be combined into a unique model of triple-negative breast cancer biology.
General characteristics of TNBC
TNBC is characterized by several clinicopathologic features. The majority of TN tumors have a ductal origin, but other phenotypes like metaplastic, adenoid cystic, atypical or typical medullary, can be present. (16)
The onset at a younger age (<50 years), the higher tumor grade, the greater likelihood of BRCA1 expression, the greater the tumor size, all suggest an aggressive pattern of TNBC. They are more prevalent in African- American women and there is a high association with obesity or metabolic syndrome (12,17). Other risk factors implied in the disease are younger age at menarche, high parity, full-term pregnancy at a younger age or shorter duration of breastfeeding. (16)
TNBC are considered interval cancers (they are discovered/detected within the 12 months after a mammographic screening in which findings are considered normal). This is highly suggestive for the rapid progression of the disease and the similarity of the tumor tissue to the normal one. (12) Other facts that suggest the aggressive pattern of TNBC is that the top of the recurrence is between the first and the third years and most of the deaths appear within the 5 years post treatment. Also, patients with TNBC have a shorter survival rate after the appearance of the first metastatic tumor, compared with patients with non-TNBC (8)
There is a weak association between the tumor size and the node involvement, in other words, even size small tumors have a high frequency of lymph node involvement (12).
TNBC is more likely to metastasize in central nervous system, lung and liver. (17, 12)
There is a shorter median time from the identification of a metastatic tumor to death in TN tumors compared to non-TN (12,16).
The prognosis of the disease is inferior compared to non-TNBC. The specific cancer survival, the likelihood of distant recurrence and death are all worse in the TNBC. (16).
Treatment
Because TNBC does not respond to endocrine or HER2 therapy, the mainstay systemic treatment is represented by chemotherapy. A characteristic of these tumors is their chemosensitivity, although they are generally associated with a poor outcome. The basic treatment is a combination of anthracyclines and taxanes (10,11,12). Their efficacy was proven even in metastatic disease (12). However, there are some limitations of these regimens in metastatic disease: these drugs are usually used in adjuvant therapy, the disease- free interval is short and the maximum anthracyclines doses have cardiotoxicity, thus questioning the chemosensitivity to these drugs (12).
Two neoadjuvant studies analyzed the relation between chemosensitivity and outcome in breast cancers.(14,15) In both studies patients with a pathologic complete response had a good prognosis regardless of subtype. The women with higher risk of recurrence were those with a residual response after neoadjuvant therapy. What it is important to remember is that there are patients with TNBC who are well treated with common chemotherapy, this subtype requires more research and more effective therapies capable of dealing with the disease (14,15). The response to chemotherapy in TNBC is higher compared to the luminal A or B, but this subtype has a shorter disease-free interval and overall survival. (13)
In TNBC with BRCA1 mutations, there are some studies that suggest the adding of the platinum salt agents in chemotherapy. Their mechanism of action is that they cause DNA cross-link stand breaks and they can be effective in cells with BRCA mutants because of their dysfunction in repair mechanism (10,11,13). The recommendations for BRCA testing should be offered to all patients with TNBC under 40 (10).
Other targeted against TNBC, such as antiangiogenic agents, EGFR inhibitors, PARP inhibitors, are now taken into considerations and scientific efforts are made to discover better and better solutions.
The antiangiogenic agents, such as Bevacizumab (Avastin) are analyzed in approaching TNBC. High VEGF 2 expression has been observed in the subgroup of TNBC. (17) Bevacizumab is a monoclonal antibody that targets all forms of vascular endothelial growth factor (VEGF) that was approved by the FDA as first-line treatment for metastatic breast cancer (12). The TNBC patients showed a clear advantage in terms of response rates and time to progression with the addition of the Bevacizumab (12). Now, there are studies that analyze the use of Bevacizumab in adjuvant and neoadjuvant chemotherapy in only TNBC (12). Other small-molecule kinase inhibitors, including sunitinib and sorafenib, have been developed as potential antiangiogenic agents and are under investigation for the treatment of TNBC. (17, 12)
EGFR inhibitors, such as Cetuximab (Erbitux) are under investigation for the treatment of TNBC.(12,16). They are associated with adverse effects such as fatigue, diarrhea and vomiting, neutropenia and thrombocytopenia. (16).
Assessment the role of the BRCA 1 in breast cancer and identifying the metabolic pathways has led to the progression of new therapeutic options. We need to discover better biological characterization of TNBC in order to develop specific therapies for each subgroup.
Conclusions
In conclusion, TNBC represents a clinical challenge because of its unique characteristics, from the perspective of molecular, biological and clinical features, prognosis and therapeutic options. The importance of chemotherapy in dealing with the disease has led to new clinical trials that investigate new strategies in understanding and treatment of the challenging TNBC.