Background

Breast cancer is the most common malignant tumor that causes the death of women. It is a heterogeneous disease with molecular biological characteristics and is different in clinical and pathological characteristics. In 2000, Perou CM and team first classified breast cancer into 5 types according to cDNA gene chip technology, they are LUMINAL A, LUMINAL B; HER-2 overexpression; Basal cell-like breast cancer and normal breast-like breast cancer (Perou et al., 2000). Because of the cost and the feasibility of clinical operation, it is hard for gene map to become the routine method of clinical detection. Therefore, the three-negative breast cancer (TNBC) which is identified according to the immunohistochemical classification came into being.

1 Summary of TNBC

Bauer KR et al. put forward the concept of tri-negative breast cancer in 2007. As a subtype of breast cancer, TNBC has its unique clinical characteristics and the same characteristics in immunohistochemical staining: estrogen receptor ER, progesterone receptor PR, Human epidermal growth factor receptor HER-2 are negative (Bakha et al., 2007). The incidence of TNBC accounts for 15%~25% of all breast cancer, and the incidence in China is about 23.8% (Milioli et al., 2017).

1.1 Subtype of tri-negative breast cancer

In 2011, Lehmann and their team classified the TNBC into six subtypes by cluster analysis of gene chip data from TNBC patients. They were basal cell like type 1 (basal-like 1), basal cell like type 2 (basal-like 2), Immune regulatory subtype (immunomodula Tory, IM), mesenchymal type (mesenchymal, M), mesenchymal stem cell like subtype (mesenchymal stem-like, MSL) and androgen receptor subtype (luminal androgen receptor, LAR) (Lehmann et al., 2011). 75% of the TNBC showed BL subtype, while 54% of BL did not show in TNBC molecular typing. The relationship between basal-like breast cancer BLBC and TNBC was mostly crossed, but not completely overlapped (Badowskakozakiewicz et al., 2016; Hoadley et al., 2016).

1.2 Clinical features of triple negative breast cancer

TNBC has biological behavior and case characteristics which are different from other subtypes of breast cancer. Firstly the onset age of TNBC is relatively young and most of them are lymph node negative. What’s more, TNBC is a di

sease with high recurrence rate, short survival period and special metastasis pathway. Last but not least, the clinical stage is usually not late when it is first diagnose, but TNBC is easy to invade. Some studies have shown that the visceral metastasis rate of TNBC patients is higher than that of non-TNBC patients, and the lung and brain metastasis rate is also higher than that of non-TN patients. The rate of bone metastasis in BC patients was higher than that in non-TNBC patients. In the imaging examination represented by ultrasound and MR, some studies showed that the marginal burr like change and central necrosis rate of TNBC were lower than that of non-TNBC, showing the characteristics of partial benign tumor (Xie et al., 2018).

1.3 Pathological features of negative breast cancer

The tumor diameter of tri-negative breast cancer is larger than that of non-triple-negative breast cancer, and it is a kind of low-differentiated tumor. The cell proliferation activity, histological grade and mitotic count are significantly higher in tri-negative breast cancer than in non-triple-negative breast cancer patients (Dang et al., 2018). In TNBC, invasive ductal carcinoma was the main clinicopathologic classification, followed by medullary carcinoma. In addition, it is easy to invade the vascular and has a strong invasive ability and metastasis ability, which lead to the increase of recurrence rate.

2 Current Status of Treatment of Triple Negative Breast Cancer

2.1 Local treatment

Although TNBC has a high recurrence rate, surgery is still the first choice for local treatment (Grobmyer et al., 2017). Clinical trials have shown that comparing with mastectomy, breast conserving surgery have similar a local recurrence rates. Therefore, in TNBC, breast conserving surgery is the best procedure.

2.2 General treatment

Hormone receptor-positive breast cancer may have a good prognosis after endocrine therapy such as tamoxifen, aromatase inhibitor or ovariectomy. However, due to the lack of hormone receptor and HER-2 expression in triple negative breast cancer, endocrine therapy and targeted therapy are not the best treatment methods. At present, chemotherapy is the only effective treatment for TNBC. Although chemotherapy can benefit the survival of patients with triple negative breast cancer, the toxic reaction is heavy, some patients cannot tolerate, and once the patients develop chemotherapeutic drug resistance, the consequences are generally disastrous, and the tumor will quickly recur and metastasize (Wataru et al., 2018).

2.3 New research direction of tri-negative breast cancer

Due to the failure of traditional endocrine therapy and targeted therapy, triple negative breast cancer patients sometimes metastasize early, which seriously affects the physical and mental health of patients. In recent years, the main research directions of TNBC focus on three aspects: new targeted therapy, immunotherapy therapy and new endocrine therapy.

3 New Targeted Therapy

In order to reduce toxicity, reduce the risk of disease progression, and promote individualized treatment of triple negative breast cancer to improve the prognosis of patients, researchers have done a lot of research in the targeted treatment direction. At present, a variety of targeted drugs have entered the stage of clinical trials. And the research on targeted therapy of TNBC is divided into four categories.

3.1 Targeted therapy for DNA repair

The main research direction is that Poly-ADP-ribose polymerase (PARP), PAPR is a key enzyme involved in DNA repair. It can recognize the breakpoint of DNA single strand and initiate repair. Its inhibitor resulted in cell death by blocking the formation of adenosine ribose polymers (Ishitha et al., 2016). BRCA gene is a suppressor gene that can repair the broken DNA double strand by homologous recombination repair pathway. Some studies have shown that BRCA gene mutation was detected in 11.2% of TNBC patients. Blocking the repair of single strand DNA breakpoint by PARP inhibitor resulted in DNA single strand break, BRCA gene mutation could not initiate homologous recombination to repair DNA double strand, both existed in tumor cells which could produce synergistic lethal effect. Therefore, BRCA gene mutants are sensitive to PARP inhibitors and have a significant therapeutic effect.

Orapanil alone and combined with chemotherapeutic drugs obtained a high objective response rate in clinical trials, but the risk of a second primary tumor increased due to its mechanism of inhibiting DNA repair (Shaughnessy et al., 2011).

3.2 Targeted therapy related to tyrosine kinase inhibition

Tyrosine kinase inhibitor (TKIs) is a kind of drugs which can inhibit tyrosine kinase activity by inhibiting phosphorylation of protein tyrosine residues to block downstream signal transduction and then inhibit tumor growth and metastasis. Both epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR) have tyrosine kinase activity receptors, and control the proliferation, Invasion and metastasis of tumor cells by mediating many signal pathways (Chaudhuri et al., 2016).

Existing studies have shown that EGFR inhibitors alone are difficult to achieve the purpose of anti-tumor, and may be more suitable for use as a class of sensitizers. Bevacizumab, an inhibitor of VEFG, is the only drug associated with FDA. However, in 2011, FDA withdrew the indication of bevacizumab in breast cancer because several III phase clinical trials showed that its combined use of breast cancer therapy and chemotherapeutic drugs led to a significant increase in toxicity, but no significant improvement in DFS and OS (Ho-Yen et al., 2014).

3.3 PI3K-AKT-mTOR pathway inhibitor

PI3K/Akt/mTOR pathway plays an important role in the proliferation, vascular growth and metastasis of tumor cells. The pathway is activated in breast cancer. Its inhibitor can inhibit the growth of breast cancer and induce apoptosis of cancer cells. It is expected to be a new target for targeted therapy of TNBC (Banerji et al., 2012).

3.4 Serotonine protein kinase-related targeting drugs

PIM1 kinase is a serotonine protein kinase, and it has been shown that PIM1 kinase inhibitor can be used as a new target therapy for TNBC patients (Horiuchi et al., 2016). The expression of PIM1 in TNBC tissues is higher than that in normal breast tissues and receptor-positive breast cancer tissues, and PIM1 plays an important role in the growth and proliferation of MYC expressed TNBC cells (Fara et al., 2016).

The use of these monoclonal antibodies or inhibitors is of limited value, and only when combined with chemotherapeutic drugs or multiple targeted drugs can the objective response rate or survival be significantly improved. Continue to look for new markers of triple negative breast cancer, the goal is to improve the overall survival of patients, it is still the direction of treatment of triple negative breast cancer in the future.

4 Immunotherapy Therapy

Tumor immunotherapy is to control and kill tumor cells by stimulating or mobilizing the immune system of the body and enhancing the immunity of tumor microenvironment, which has high specificity and little damage to the normal tissues of the body. In recent ten years, new immunotherapy drugs have been emerging. At present, six kinds of drugs have been approved by FDA for the treatment of malignant tumors.

The most promising immunotherapeutic drug is the immune checkpoint inhibitor (ICPI). Immune checkpoint is a costimulatory molecule that inhibits signal pathway. In normal circumstances, it can inhibit the function of T cells, participate in negative regulation of immune system, and avoid the damage of autoimmune reaction to the body. But in tumor tissue, it may be used by tumor to form immune escape. The principle of immunological checkpoint inhibitor in the treatment of tumor is to remove the negative regulation of T cell activity by these costimulatory molecules and to enhance the cytotoxicity of T cell to tumor (Roberto et al., 2018).

The combination of chemotherapy and ICPI may have synergistic effect, which has been confirmed by many preclinical studies. These results show that immunotherapy may be effective in breast cancer and may be the best in patients with advanced TNBC.

The most studied targets of ICPI include cytotoxic T lymphocyte associated antigen 4 (CTLA-4), programmed death factor 1 (PD-1) and programmed death factor ligand 1 (PD-L1). PD-1 is an important immunosuppressive transmembrane protein expressed on the surface of T cells, mainly expressed on activated T cells. There are two ligands, PD-L1 and PD-L2. PD-1 is expressed in infiltrating CD8 T cells. Also expressed in other fine cells of the immune system, PD-1 ligand (PD-L1 or PD-L2) was up-regulated to block the anti-tumor immune response in tumor microenvironment, resulting in reduced proliferation of activated CD8 T cells.

Some data showed that the expression of PD-L1, PD-L1 in TNBC was significantly higher in about 19% of TNBC samples than in hormone-receptor-positive breast cancer.

4.1 Pembrolizumab (MK-3475)

At present, Pembrolizumab, a PD-1 antagonist, has been shown to be effective in many kinds of tumors. It can specifically inhibit the binding of PD-1 and PD-L1, PD-L2 and restore the function of T cells. Has been approved by the United States FDA for the treatment of melanoma, breast cancer research has also achieved some results. Experiments have shown that patients with metastatic TNBC benefit permanently from pembrolizumab treatment (Katz et al., 2018).

4.2 Atezolizumab (MPDL3280A)

MPDL3280A is a monoclonal antibody against PD-L1, which destroys the interaction between PD-L1 and PD-1 and restores the function of T cells. At present, the investigation have entered the stage of clinical trial, the preliminary study shows that MPDL3280A treatment in metastatic TNBC women is durable and safe (McNamara et al., 2014).

5 New Endocrine Therapy

Endocrine therapy is to inhibit the growth of tumor cells by regulating hormone levels and effects in vivo. Both ER and PR were negative in triple negative breast cancer patients, so traditional endocrine therapy was not effective for them.

5.1 Androgen receptor inhibitors

It showed that 10%~35% of patients with triple negative breast cancer expressed androgen receptor (AR). The overexpression of AR, which often indicated poor prognosis. Blocking the expression of AR was a feasible endocrine therapy for TNBC. Recent TBCRC011 phase II clinical trials showed that antiandrogen receptor inhibitors had a clinical benefit for 19% of patients compared with Carous (Gucalp et al., 2013; McNamara et al., 2014).

5.2 Others

Endocrine therapy for triple negative breast cancer also includes the treatment of gonadotropin releasing hormone and growth hormone releasing hormone. However, the current research progress of them is not enough.

6 Prospect

As a unique subtype of breast cancer, the treatment of triple negative breast cancer has not been able to meet the survival requirements of patients. Although a large number of related clinical trials have been carried out, no targeted treatment has been found. The current clinical treatment is still in the exploratory stage. Targeted therapy is still the most promising way to improve the survival of patients in the short term. Immunotherapy is expected to become an innovation in the field of triple negative breast cancer treatment after surgery, chemotherapy, radiotherapy and molecular targeted therapy. The research of new endocrine therapy is being carried out step by step. It is believed that the treatment level of triple negative breast cancer will make a great leap forward in the near future.

Authors’ contributions

JYZ wrote this manuscript. DWZ revised the manuscript. All authors read and approved the final manuscript.

Acknowledgements

This work was supported by the Heilongjiang scientific research project (grants 201810).

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