Triple-negative breast cancer (TNBC) is defined as breast cancer that is negative for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, and accounts for approximately 15% to 20% of all breast cancer pathology types. Triple-negative breast cancers are more malignant and have a higher probability of developing visceral metastases such as brain, lung and liver, and a lower probability of bone metastases compared to non-triple-negative breast cancers; together with their lack of appropriate drug treatment targets, patients often have a poorer prognosis and higher mortality.
Triple-negative breast cancers often do not benefit from endocrine therapy and anti-HER2-targeted therapy for breast cancer because patients lack ER, PR and HER2 expression. Chemotherapy is currently the more recommended treatment for triple-negative breast cancer, but there is no targeted standard treatment regimen.
As precision medicine thinking continues, many new chemotherapeutic agents are emerging and other drug targets continue to be explored, offering new hope for the treatment of recurrent and metastatic triple-negative breast cancer. Here’s a look at systemic treatments for recurrent and metastatic triple-negative breast cancer.
Chemotherapy for recurrent and metastatic triple-negative breast cancer
Preferred chemotherapy regimens for recurrent and metastatic triple-negative breast cancer generally include single-agent sequential chemotherapy or combination chemotherapy. Combination chemotherapy usually has better objective remission rates and progression-free survival times than single-agent sequential chemotherapy, although combination chemotherapy is more toxic, patients may be tapered or discontinued midway, and patient survival benefit is limited. In contrast, sequential use of single agents is associated with relatively less toxic effects, and the likelihood of drug dose reduction or discontinuation during dosing is reduced.
In general, physicians choose combination chemotherapy for patients who need rapid tumor shrinkage or symptomatic remission, and single-agent sequential chemotherapy for patients for whom tolerability and quality of life are priorities. Notably, the sensitivity of individuals with triple-negative breast cancer to conventional chemotherapy varies widely.
Commonly used single agents
- Anthracyclines, such as doxorubicin, epirubicin, pirarubicin, and doxorubicin liposomes;
- Paclitaxel, such as paclitaxel, docetaxel, and albumin-bound paclitaxel. Albumin-bound paclitaxel can replace paclitaxel or docetaxel due to clinical need (e.g., to reduce allergic reactions). The weekly dose of albumin-bound paclitaxel should not exceed 125 mg/m² when replacing weekly paclitaxel or docetaxel;
- Anti-metabolites, such as capecitabine and gemcitabine;
- Non-paclitaxel microtubule formation inhibitors, such as vincristine (Vinorelbine) and eribulin (Eribulin).
Other effective single agents include cyclophosphamide, cisplatin, etoposide, vincristine analogs, mitoxantrone, and fluorouracil.
Commonly used combination chemotherapy regimens
- Cyclophosphamide, doxorubicin, and fluorouracil (FAC/CAF) regimens;
- Fluorouracil, epirubicin, and cyclophosphamide (FEC) regimens;
- Cyclophosphamide, epirubicin, and fluorouracil (CTF) regimens;
- Doxorubicin, cyclophosphamide (AC) regimens;
- epirubicin, cyclophosphamide (EC) regimen;
- Doxorubicin combined with docetaxel or paclitaxel (AT) regimens;
- Cyclophosphamide, methotrexate (Meth) and fluorouracil (CMF) regimens;
- docetaxel in combination with capecitabine regimen;
- Gicitabine in combination with paclitaxel regimen.
For triple-negative breast cancer, doctors typically choose a gemcitabine plus carboplatin (Carboplatin) or cisplatin (Cisplatin) regimen for their patients.
Length of chemotherapy
The standard drug therapy is to apply 1 regimen until disease progression before switching, but because of the lack of evidence of differences in overall survival (OS), whether to use long-term chemotherapy or short-term chemotherapy followed by discontinuation or maintenance therapy still needs to be weighed against efficacy, adverse drug effects, and patient quality of life.
Comparative analysis of several chemotherapy regimens
- Anthracyclines and paclitaxel remain the basic therapeutic agents for triple-negative breast cancer, and several large-scale international multicenter clinical trials have confirmed the superiority of paclitaxel combined with or sequential anthracyclines compared with conventional anthracycline combination chemotherapy regimens for triple-negative breast cancer.
- In recent years, many studies have begun to explore the role of platinum in triple-negative breast cancer. Studies have shown no significant difference in the efficacy of platinum alone compared with docetaxel, which is commonly used in clinical practice, in treating triple-negative breast cancer in the overall population. A study of first-line treatment of advanced triple-negative breast cancer compared docetaxel in combination with cisplatin to docetaxel in combination with capecitabine. The results showed greater disease progression-free survival (PFS) and overall survival benefit with docetaxel combined with platinum-containing regimens compared with combined non-platinum regimens.
- In the area of chemoresistance in triple-negative breast cancer, it has been found that neoadjuvant chemotherapy with paclitaxel (i.e., chemotherapy administered before surgery) can enrich triple-negative breast cancer patients with TEKT4 mutations, which can cause paclitaxel resistance by reducing microtubule stability and resisting the microtubule-stabilizing effects of paclitaxel. Therefore, TEKT4 mutant triple-negative breast cancers may be sensitive to microtubule depolymerizing agents such as vincristine.
Endocrine therapy for recurrent and metastatic triple-negative breast cancer
Breast cancer is a hormone-dependent tumor, and tumor cell growth is regulated by multiple hormones in the body. For most breast cancer patients with positive estrogen and progesterone receptors, estrogen and progesterone are closely related to the development of tumors. Inhibition of tumor cell growth can be achieved by reducing estrogen and progesterone levels in the body or inhibiting the effects of estrogen and progesterone through endocrine therapy.
Patients with triple-negative breast cancer are ER and PR negative, so traditional endocrine therapy is usually ineffective for these patients.
However, available findings have confirmed that 10% to 35% of patients with triple-negative breast cancer express androgen receptors. The use of androgen receptor inhibitors [such as bicalutamide or enzalutamide] in patients with androgen receptor-positive triple-negative breast cancer can be of clinical benefit.
Targeted therapy for recurrent and metastatic triple-negative breast cancer
Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors
PARP inhibitors promote apoptosis in tumor cells by inhibiting tumor cell repair of damaged DNA; PARP inhibitors also enhance the efficacy of radiotherapy and chemotherapy with alkylating agents and platinum-based drugs.
The “Achilles heel” of hereditary breast cancer is a mutation in the breast cancer susceptibility genes 1 and 2 (BRCA1/2), which PARP inhibitors exploit to attack and limit the ability of breast cancer cells to repair damaged DNA and eventually leads to apoptosis of cancer cells. Thus, breast cancer patients with BRCA1/2 mutations are particularly sensitive to PARP inhibitors, and the combination of platinum and PARP inhibitors improves the efficacy of BRCA1/2 mutated breast cancer.
The PARP inhibitors that have been developed include iniparib (Iniparib, BSI-201), olaparib (Olaparib, AZD-228), and veriparib (Veliparib, ABT-888).
Results from both phase II and phase III clinical studies on PARP inhibitors have shown that chemotherapy combined with PARP inhibitors improves the clinical benefit rate and prolongs survival in patients with advanced metastatic triple-negative breast cancer compared with chemotherapy agents alone. PARP inhibitors have emerged in the treatment of patients with triple-negative breast cancer. However, some studies have also shown that PARP inhibitors do not provide the desired benefit to patients.
The question of the potential benefit of PARP inhibitors remains to be further evaluated.
Epidermal growth factor receptor inhibitors
The epidermal growth factor receptor is highly expressed in triple-negative breast cancer, and this high expression may make it a therapeutic target in triple-negative breast cancer.
There are two main classes of epidermal growth factor receptor inhibitors in clinical use: tyrosine kinase inhibitors, represented by drugs such as gefitinib (Gefitinib), and monoclonal antibodies, represented by drugs such as cetuximab (Cetuximab).
Phase II randomized clinical studies have confirmed that cetuximab can benefit patients with metastatic triple-negative breast cancer, but the impact on overall patient survival is inconclusive and needs further study.
Anti-angiogenesis
For example, bevacizumab, a recombinant humanized monoclonal antibody, binds to and blocks the biological activity of human vascular endothelial growth factor (VEGF), thereby inhibiting tumor neovascularization and blocking nutrient delivery to the tumor.
The efficacy of bevacizumab in patients with recurrent and metastatic triple-negative breast cancer was reported early.
The results of clinical studies confirm the efficacy of bevacizumab in patients with advanced triple-negative breast cancer, and its combination with rescue chemotherapy (i.e., chemotherapy given after failure of conventional chemotherapy or tumor recurrence and metastasis) may benefit patients with triple-negative breast cancer.
Targeted therapy based on molecular typing of triple-negative breast cancer
Precise treatment of breast cancer cannot be achieved without molecular typing of the tumor, and genetic analysis has led to the classification of triple-negative breast cancer into six subtypes: basal cell-like 1 (BL1), basal cell-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem cell (MSL), and androgen-dependent (LAR). There are also four subtypes: basal cell-like immunosuppressive (BLIS), basal cell-like immune activating (BLIA), mesenchymal (M), and androgen-dependent (LAR).
Some studies have confirmed that androgen-dependent triple-negative breast cancers are often associated with activation of the PI3K pathway, and that the combination of androgen receptor blockers and PI3K inhibitors may provide better efficacy; whereas in immunomodulatory triple-negative breast cancers, as immunosuppressive genes such as PD-1, PD-L1  nbsp;and CTLA-4 are highly expressed, inhibitors of immune checkpoints (which help tumor cells escape the surveillance of immune cells) may have promising applications.
Summary
Patients with triple-negative breast cancer ER, PR, HER2 are all negative, and traditional endocrine therapy and anti HER2-targeted therapy are usually ineffective. Chemotherapy is still the more recommended treatment for triple-negative breast cancer. Physicians will choose single-agent sequential chemotherapy or combination chemotherapy, depending on the individual patient’s condition.
Because 10% to 35% of patients with triple-negative breast cancer express androgen receptors, androgen receptor-positive triple-negative breast cancer patients may be considered for androgen receptor inhibitors.
Molecularly targeted therapies for triple-negative breast cancer, PARP, epidermal growth factor, and VEGF have emerged as new targets, and a variety of specific inhibitors may be developed in the future, with the expectation of bringing more benefits to triple-negative breast cancer patients.