Once the diagnosis of breast cancer has been established through various investigations, next step is staging the breast cancer and planning an appropriate treatment strategy. Triple negative receptor status plays an important role in deciding the treatment for breast cancer.
What is Triple Negative Breast Cancer
Normally, breast cancer cells have specialized proteins on/in their surface, called receptors. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) are most common receptors detected on breast cancer cells, which can promote the growth of these cells.
Conversely, the drugs that inhibit these receptors are utilized to retard the growth of these cancer cells. TNBC cells do not have any of these receptors, that is, negative for ER, PR, and HER2. These breast cancers grow and spread more rapidly than receptor-positive breast cancers and do not respond to treatment generally employed for receptor-positive breast cancers, that is, hormonal or trastuzumab-based therapies.
Breast cancer is the most common cancer in women worldwide and is responsible for most cancer-related death in women. TNBC is the most aggressive subtype of breast accounting for about 15–20% of all cases of breast cancer but comparatively higher percentage of death related to breast cancer.
TNBC tends to grow and spread quickly to distant body parts, especially visceral organ (as opposed to normal breast cancers that most commonly spread to bones), making them more difficult to treat.
TNBC is not a single entity and includes many heterogenous cancer types. Based on gene expression profiling and preferred treatment approach TNBCs are divided into four subtypes: basal-like 1 (BL1), basal-like 2 (BL2), luminal androgen receptor (LAR) and mesenchymal (M) type.
These subtypes may occur individually or concurrently making it more difficult to treat TNBCs with a single targeted treatment in every patient. Thus, identification of biomarker involved in the TNBC is vital for selection of an appropriate treatment strategy.
Triple Negative Breast Cancer Treatment
The treatment of TNBC depends on many factors including the overall stage assigned to the disease, the subtype/biomarkers of TNBC involved, and the patient’s overall health & personal preferences. Based on the results obtained from various clinical research studies carried out so far, the following are preferred treatment approaches for TNBC according to the extent of disease spread:
|Disease type||Preferred Treatment|
|Limited Disease||TNBC that is limited to a specific site is generally treated with surgery (breast-conserving surgery or mastectomy) followed by radiation therapy as first-line treatment.
Depending on the risk of recurrence, chemotherapy and/or targeted therapy may also be employed after surgery. Immunotherapy with immune checkpoint inhibitors may also be employed as per physician discretion.
|Advanced/ Metastatic disease||TNBC that has spread to nearby lymph nodes or to distant body parts is generally treated with chemotherapy and/or targeted therapy as the first-line treatment because complete removal of cancerous tissue cannot be achieved with surgery.
Further, surgery and/or radiation therapy can be employed for palliation of the symptoms like pain and obstruction of blood vessels.
In most cases, TNBC spread to distant body parts within 3 years of diagnosis rendering the systemic therapy the mainstay of TNBC treatment.
The most commonly employed systemic neoadjuvant chemotherapy include anthracycline- and taxane-based chemotherapy. Addition of carboplatin to standard chemotherapeutic regimen has been reported to improve the outcome in TNBC patients and is generally recommended.
Poly (ADP-ribose) polymerases (PARPs) inhibitors are considered the first-line systemic therapy for BRCA-positive TNBC. Addition of PARP inhibitor to standard neo-adjuvant chemotherapy has been reported to improve outcome in TNBC patients with a mutation in the BRCA gene (10%-20% of all TNBC cases).
Similarly, many other targeted therapies have been tested in various clinical research studies and have shown better outcome in TNBC patients with specific genetic abnormality. The following table lists potential targeted therapy for the four TNBC subtypes with characteristic genetic alterations:
|TNBC subtype||Common genetic abnormality||Potential targeted therapy|
|BL1||Cell cycle genes
DNA damage repair genes
|PARP inhibitors (e.g. olaparib, talazoparib, veliparib, rucaparib, and niraparib)
Cyclin dependent kinase (CDK) inhibitors (e.g. dinaciclib, palbociclib, abemaciclib, and LEE011)
|BL2||Growth factor signaling (epidermal growth factor [EGF], IGF1, MET, Wnt/b-catenin pathways)
Growth factor receptors (EGFR, IGF1R, MET, EPHA2)
Glycolysis and gluconeogenesis
|Mammalian target of rapamycin (mTOR) inhibitors (e.g. everolimus, temsirolimus, ridaforolimus, and zotarolimus)
Growth factor inhibitors (e.g. Alofanib, Lucitanib)
A combination of EGFR tyrosine kinase inhibitors (TKIs) (e.g. erlotinib and lapatinib) and the monoclonal antibodies (e.g. cetuximab and panitumumab)
|LAR||Luminal gene expression; Androgen receptor gene||Anti-androgens (e.g. enzalutamide, bicalutamide, and dehydroepiandrosterone [DHEA]), Histone deacetylase (HDAC) inhibitors (e.g. Panobinostat, Entinostat, vorinostat, and Valproic Acid), Heat shock protein-90 (Hsp90) inhibitors (e.g. Ganetespib and Onalespib), Src inhibitors (e.g. Dasatinib and Saracatinib), Phosphoinositide 3-kinase (PI3K) inhibitors (e.g. taselisib, buparsilib)|
|M||Epithelial-mesenchymal transition (EMT)
Cell motility and differentiation
Regulation of cancer stem cells
Growth factor signaling
|Drugs targeting pathways involved in EMT: Notch, Wnt/β-catenin, Hedge-hog, and TGF-β signaling pathways|
Apart from above mentioned targeted drugs, a novel treatment approach of combined inhibition of ataxia telangiectasia and rad3-related (ATR) kinase and Wee1-like protein kinase (WEE1) has been shown to be effective in a preclinical study.
Another recent preclinical study has demonstrated that Folate Receptor alpha (FRα) is overexpressed in many aggressive BL1/2 TNBC tumors and in post-neoadjuvant chemotherapy-residual disease associated with a high risk of relapse. Thus, FRα can be targeted with an anti-FRα antibody (MOv18-IgG1) conjugated with an Src inhibitor.
This approach presents a new strategy to treat patients with high-risk disease and who are not getting benefitted with currently available targeted agents. Validation in clinical trials is a pre-requisite for these proposed novel therapeutic approaches before these approaches can be included in the clinical practice.
With the progress in the understanding of the disease and ongoing clinical trials testing multiple drug combinations, the treatment for advanced TNBC is rapidly evolving.