A Review of Current treatment for Triple-Negative Breast Cancer (TNBC)

 

Wahyuni1,2, Ajeng Diantini1*, Mohammad Ghozali3, I Sahidin4

1Department of Pharmacology and Clinical  Pharmacy, Faculty of Pharmacy,

Universitas Padjadjaran, Jatinangor, Indonesia.

2Department of Pharmacology, Faculty of Pharmacy, Universitas Halu Oleo, Kendari, Indonesia.

3Department of Biomedical Sciences, Faculty of Medicine, Universitas Padjadjaran, Jatinangor, Indonesia.

4Department of Pharmacognosy and Phytochemistry, Faculty of Pharmacy,

Universitas Halu Oleo, Kendari, Indonesia.

*Corresponding Author E-mail: ajeng.diantini@unpad.ac.id

 

ABSTRACT:

We reviewed about the Triple-negative breast cancer (TNBC) and its treatment. We collected credible data from scientific database such as google scholar and Pubmed from published literatures between 2015 to 2020. According the collected literature, TNBC is one of breast cancer type can be found in women with breast cancer. It estimated about 170.000 of TNBC cases worldwide. The ER-/PR-/HER2- TNBC is the character for TNBC, and it has the poorest prognosis among other breast cancer. The risk factor of TNBC is gender, age, breastfeeding status, and special race such as African-American and Hispanic. Besides, the BRCA-1 mutation is related to TNBC. The treatment of TNBC is including surgery and radiotherapy, chemotherapy, and targeted therapy. The surgery, including BCS (Breast-conserving surgery) or called as lumpectomy and mastectomy; chemotherapy agent sensitive to TBNC, including alkylator agents, anthracyclines, taxanes, platinum-based chemotherapy, vinca alkaloids, and antimetabolites; as well targeted therapy such as PARP1 and PARP2 inhibitor, CDK (Cyclin-dependent kinase) inhibitor, p%3 inhibitor, CHK1 inhibitor, androgen antagonist, DNMT1 (DNA Methyltransferase 1) inhibitor, Anti-EGFR, PI3K/AKT/mTOR inhibitor, and anti-VEGF. These treatments are used both in early and metastatic stage of TNBC, alone or in combination.

 

KEYWORDS: Breast cancer, Triple-negative breast cancer, Chemotherapy, Targeted therapy.

 

 


INTRODUCTION:

Breast is tissue located in the chest muscles, consisting of 2 types of tissue: glandular tissue and stromal/ supporting tissue. Glandular tissue is a part of the breast that produces milk, called lobules and channel milk, called ducts. On the other hand, stromal tissue consisted of fatty and fibrous connective tissue of the breast. Lymphatic tissue-immune system tissue is also composing up the breast1.

 

In 2018, breast cancer was the most diagnosed cancer (24.2%) and was ranked first in mortality because of cancer in women (15.0%). On the other hand, the incidences of breast cancer and mortality rate of breast cancer worldwide in both sexes were 11.6% and 6.6% respectively in 20182. Breast cancer is a compilation of malignancies in mammary glands, starting from the hyperproliferation of ductal, leading to the development of a benign tumor and the worst into metastatic carcinomas3,4. The triple-negative breast cancer (TNBC) is one breast cancer subtype that is mainly found in women.

 

The triple-negative breast cancer (TNBC) is breast cancer with a clinically lack expression of estrogen (ER), progesterone (PR), and HER-2 (human epidermal growth receptor-2). It is the poorest prognosis between all breast cancer, in which 15-20% of breast cancer is diagnosed as TNBC and contributed in approximately 170.000 cases worldwide. It is associated with high mortality, a lack of therapies, and increased incidence in young women. TNBC is developing mainly through the BRCA-1 related pathway and is a poor prognosis as well as biologically aggressive with a unique molecular profile5,6,7. TNBC is classified into four subtypes, which are Basal Like-1 (BL-1), basal-like -2 (BL-2), Mesenchymal (M), and Luminal androgen receptor (LAR)8. The risk factors of TNBC are young women (<45 years), older age in completing pregnancy, lack of breastfeeding or not breastfeeding, and African-American women, as well as Hispanic women. They are more likely to be diagnosed with TNBC than white women9,10. The OC (oral contraception) use > 1 year is associated with increased risk for TNBC (2.7x)11. Women with BRCA-1 mutation is related to TNBC5.

 

METHODS:

In this article, the required information was collected through literature review with keywords such as cancer, breast cancer, triple-negative breast cancer, treatment, surgery, chemotherapy, and targeted therapy in the credible scientific database, including Google Scholar and Pubmed from articles published in 2005 to 2020.

 

TREATMENT OF TNBC:

The standard therapy for TNBC is according to guidelines issued by the American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology (ESMO). The therapies for TNBC are shown in Table 112,13,14.

 

Table 1. Management Therapy for Triple Negative Breast Cancer14

Loco-regional

·   Breast-conserving surgery/ BCS (lumpectomy followed by radiation therapy)

·   Mastectomy

Early-stage

·   Chemotherapy with alkylator, anthracycline, and taxane

·   Capecitabine or carboplatin as neoadjuvant are considered

·   The platinum-based chemotherapy are considered to patients with a BRCA1/BRCA2 germline mutation

Metastatic stage

·   Taxanes, topoisomerase II inhibitor, platinum, vinca alkaloids, anti-tubulin, and antimetabolites are preferred as single agents

·   Immunotherapy is emphasized

 

Surgery:

Surgery is becoming an option in the early stage of triple-negative breast cancer (TNBC). The local recurrence rate post-surgery causes this is not high15. Patients with tumors> 2cm or patient wish are considered in performing surgery. Surgery is performed as lumpectomy or breast-conserving surgery (BCS) and mastectomy.

 

BCS or sometimes called lumpectomy, is surgery to remove cancer and some healthy tissue surrounding cancer, not but not the breast itself. The BCS is also called breast-sparing surgery, partial mastectomy, quadrantectomy, and segmental mastectomy. Meanwhile, mastectomy is a surgery that removes a whole breast that is performed in cancer in a large area of the breast that spread throughout the breast and contains pre-cancerous cells. The BCS is always followed by radiation therapy (RT) to minimize recurrence.  It is performed according to a few factors: a monocentric tumor with a smaller size, localized tumor, younger age, and patient compliance, needs, and expectation. Besides, it is affected by history and physical examination, breast imaging, and histological assessment. Radiation therapy (RT) must be performed post-surgery16,17. Despite to preserve the breast, the BCS also consider aesthetics. The aesthetic appearance post-BCS are affected by surgical technique and size and placement of incision in the lumpectomy cavity, and auxiliary dissection.  In incision, the lump location, type of incision, depth of mass cancer, and incision position must be considered19.

 

The BCS is contraindicated to pregnant women in the first or second trimester because RT follows the BCS. As well as patients with locally widespread disease, multicentric tumor, malignant, patients with BRCA-1/ BRCA-2 germline mutations, and already have thoracic wall radiation. It is also contraindicated to larger tumors in women with smaller breast and connective tissue-related diseases such as scleroderma and active SLE (systemic lupus erythematosus)16,17. BCS with radiation therapy established a better prognosis with a high rate of recurrence-free, disease-free, and survival rates than mastectomy18,19

 

Chemotherapy:

a.     Alkylator Agents:

The alkylating agents, including cyclophosphamide, ifosfamide, nitrosourea, dacarbazine, and temozolomide, are the oldest and most commonly used chemotherapy agents. This group acts by attacking the phosphate groups, amino thiols, and the imidazole group of biological macromolecules due to alkyl group-contained, thus form electrophilic groups from positive carbon ions. The mechanism of action of this drug is to form cross bonds directly with guanine base N2 radicals or N3 adenine from DNA molecules or the formation of cross bonds between DNA molecules and proteins, resulting in disrupting of DNA function and lead to cell death20,21.

 

Cyclophosphamide and ifosfamide are derivatives of nitrogen mustard based on structure, clinical use, and toxicity that affect DNA. Both of these drugs are active as metabolites. Both cyclophosphamide and ifosfamide, combined with taxanes and platinum-based chemotherapy, demonstrated efficacy and toxicity in TNBC treatment. Dacarbazine and temozolomide are also included as an alkylator, which acts by interfering with DNA replication through the methylation process in the guanine base. These agents can cross the blood-brain barrier and effective in treating intracranial metastases22,23,24.

 

b.    Anthracycline:

The anthracycline group is classified into the antitumor antibiotic group, which has an intercellular effect. Doxorubicin, daunorubicin, idarubicin, and epirubicin belong in this group. The mechanism of anthracycline is as topoisomerase II inhibitors, thereby causing the double-stranded DNA separation. Besides, inserting into DNA base pairs leads to changes in the structure of DNA, disrupting DNA, and RNA synthesis20. Mitoxantrone is an anthracycline group with the same antitumor activity as doxorubicin but has a better safety profile. The mechanism of mitoxantrone is similar to doxorubicin by interfering with the topoisomerase II inhibitors, but it produces fewer free radicals than doxorubicin20. Anthracyclin groups provide better efficacy in treating TNBC. They also exhibit significant efficacy in combination with taxane-anthracycline based chemotherapy in TNBC25,26.

 

c.     Taxanes:

Taxanes alkaloid, including paclitaxel and docetaxel, are active in the cell cycle's G2/M phase. This agent acts by binding to tubulin but does not interfere with tubulin formation in the vinca alkaloids. Taxanes alkaloid induces tubulin polymerization, resulting in unstable and malfunctioning microtubules, thus damaging cells. Also, the taxanes have antiangiogenetic activity, causing cancer cell death.. Taxanes are useful with good efficacy in any setting of TNBC treatment, including neoadjuvant, adjuvant, and metastatic. It also demonstrated a significant TNBC treatment result by combining with an anthracycline20,26,27.

 

d.    Platinum-based chemotherapy:

Platinum derivatives such as cisplatin, carboplatin, and oxaliplatin, are acting with platinum binds to DNA and form cross-linking DNA, both interstrand and intrastrand cross-link. Thus, it damages cells by disrupting the structure of DNA and prevent the bases from pairing up. These agents work during G1 and S phases20.

 

Figure 4. Platinum-based chemotherapy, (a) Cisplatin; (b) Carboplatin; (c) Oxaliplatin

 

Cisplatin is nephrotoxic, ototoxic and can cause peripheral neuropathy, nausea, and anemia. Carboplatin is less likely to damage the kidneys, ototoxic, and cause peripheral neuropathy, nausea, and vomiting compared to cisplatin20. Platinum-based chemotherapy (PBC) provides a better quality of life and survival compared to non-platinum-based chemotherapy (non-PBC) in TNBC treatment29. It also increased pathological complete response (PCR) rates in TNBC, with increase progression-free survival (PFS) in the neoadjuvant setting in early TNBC26,29.

 

e.     Vinca Alkaloids:

f.       

 

Figure 5. Vinca Alkaloids,

(a) Vincristine; (b) Vinblastine; (c) Vinorelbine

 

Vinca alkaloids such as vincristine, vinblastine, and vinorelbine are chemotherapy therapy derived from the Vinca plant. They inhibit mitosis in metaphase (M Phase) of the cell. Vinca alkaloids disrupt the balance between polymerization and depolymerization of microtubules, inhibit the formation of microtubules, and interfere with microtubules' dynamics. Thus causes mitosis to stop in metaphase; thereby, the cell replication is disrupted20. Vinorelbine combine with 5-fu induced apoptosis and autophagy of TNBC30. Vinorelbine, combined with platinum-based chemotherapy, showed tolerated effect and toxicity in metastatic TNBC pretreated with anthracycline or taxanes31.

 

g.     Antimetabolites:

Pyrimidine analogs (e.g., fluorouracil (5-FU), and capecitabine), cytidine analogs (e.g., cytarabine (ARA-C), gemcitabine), purines and purine antimetabolites (e.g., 6-mercaptopurine (6-MP), fludarabine, cladribine, and pentostatin), and antifolates (e.g., Methotrexate (MTX) and pemetrexed) belong to antimetabolites group20. However, only gemcitabine, capecitabine, and methotrexate are showing effect in TNBC combined with other chemotherapy agents32.

 

 

Figure 6. Antimetabolite, (a) Gemcitabine; (b) Capecitabine; (c) Metrotrexhate

 

Gemcitabine combined with platinum-based chemotherapy showed a sufficient effect, acceptable toxicity profile, and well-tolerated to patients. It also showed improved outcomes in metastatic TNBC33,34. Capecitabine is using as an adjuvant in standard chemotherapy of early-stage TNBC. It was improving disease-free survival (DFS) and overall survival (OS) of patients. Capecitabine combines with taxanes is prolonging the PFS (progression-free survival) with an acceptable safety profile35,36. On the other hand, high dose administration of methotrexate (MTX) increases anticancer activity in vitamin E derivates (α-tocopherol succinate)-treated TNBC patient. It showed significant improvement in OS and DFS combined with cyclophosphamide37,38.

 

Targeted Therapy:

a.     PARP1 and PARP2 inhibitor

BRCA-1/BRCA-2 is a tumor-suppressor gene playing a role in the DNA repair process, which repairs double-strand breaks of DNA through homologous recombination during S and G2 phases. BRCA-1 are involving RAD51 to double strain damage site, thereby providing the DNA repair. On the other hand, BRCA-2 involves RAD-51-mediated repair directly39,40. BRCA-1/BRCA-2 mutation is a germline mutation in which TNBC is more familiar with BRCA-1 mutation than BRCA-2 mutation41. PARP (Poly (ADP-ribose) polymerase) mediates DNA repair involving single-strand breaks and base-excision repair42. BRCA-1/BRCA-2 mutations are sensitive towards PARP inhibitor, which are Olaparib, Veliparib, Rucaparib, Talazoparib. Both Olaparib and Talazoparib are the only PARP inhibitor approved by the FDA for advanced breast cancer40,43.

 

Figure 7. PARP Inhibitor, (a) Olaparib; (b) Veliparib

 

Olaparib, in the brand name as LynparzaTM (AZD2281, KU0059436), is a first-class PARPi (Poly (ADP-ribose) polymerase inhibitor) that intensively used as single and combination therapy in malignancies44. Olaparib is the first novel class of treatment that is showing a beneficial effect in TNBC. Olaparib is metabolized by the CYP3A4 enzyme through oxidation, glucuronide, and sulfate conjugation. The metabolites are excreted via urine and feces, approximately 44% and 42%, respectively45. Veliparib (ABT-88) is a potent inhibitor of both PARP1 and PARP2. It is used in BRCA-1/BRCA-2 mutation-related cancer, including breast cancer and ovarian cancer46,47.

 

b.    CDK (Cyclin-dependent Kinase) Inhibitor:

CDK (Cyclin-dependent kinase) is an enzyme that contributes to cell cycle, including CDK4 and CDK6 (CDK 4/6). CDK 4/6 responsible for hyperphosphorylation in inactivating retinoblastoma protein (Rb), thus progress the transition of G1 to S phase48. The inhibitor of CDK 4/6 can be targeted for TNBC therapy. Few CDK 4/6 inhibitors are Palbociclib, Ribociclib, and Abemaciclib49.

 

Figure 8. CDK Inhibitor, (a) Palbociclib; (b) Ribociclib (c) Abemaciclib

 

Palbociclib, with the brand name IbranceTM, is the first CDK 4/6 inhibitor that exhibits activity against breast cancer cells49. Palbociclib acts by inhibiting the Rb, cyclin D1, and CDK6 protein expression. It has improving efficacy with chemotherapy agents such as paclitaxel or 5-FU. Palbociclib is metabolized through oxidation and sulfonation, with acylation and glucuronidation. It is excreted in feces majorly and the rest of it in urine50,51. Ribociclib, with brand name KisqaliTM, is a reversible CDK 4/6 inhibitor50. Ribociclib is metabolized by CYP3A4 enzymes and excreted through feces and urine. Abemaciclib (VerzenioTM) is the most potent CDK 4/6 inhibitor and CDK 9 and PIM1 inhibitor. It can cross the blood-brain barrier, metabolize in hepatic through CYP3A4 enzymes, and be excreted mainly in feces and the rest of it in urine52.

 

c.     p53 inhibitor:

p53 is playing a vital role in suppressing tumor formation, protects DNA damage through cell cycle arrest, DNA repair, and apoptosis. However, p53 sometimes mutates, called mutant p53 (mut-p53), thus it does not work in suppressing tumor formation. Mutations occur due to amino acid compilation errors. Therefore, mutant p53 becomes a new target for TNBC treatment. PRIMA-1, MIRA-1, and derivates of thiosemicarbazone family are agents targeted in mut-p5353.

 

Figure 9. p53 Inhibitor, (a) PRIMA-1; (b) MIRA-1; (c) Quetiapine

 

PRIMA-1 is quinuclidine derivates that decrease TNBC cell ability to form colonies, inhibit TNBC cell proliferation, and induce apoptosis in mut-p53, thereby the reactivation of p5354. In reactivating mut-p53, PRIMA-1 is converted into the active metabolite: 2-methylene-3-quinuclidinone (MQ) and covalently binding thiol groups mut-p5355. MIRA-1 belongs to the maleimide group with 3-4 double bonds with similar activity with PRIMA-1 in reactivating mut-p53 by binding the thiol groups through nucleophilic addition as alkylation. Thus, it induces mut-p53-dependent apoptosis56. MIRA-1 demonstrates higher potency than PRIMA-156. Another agent that targeted p53 is the Thiosemicarbazone family. One of Thiosemicarbazone derivates is Quetiapine. These agents are serving Zinc (Zn) to allow mut-p53 to refold into its wild-type conformation, thereby inducing apoptosis. These agents chelate zinc in extracellular and donate zinc to mut-p5355,57.58.

 

d.    CHK1 Inhibitor:

Checkpoint kinase 1 (CHK1) is a biomarker in DNA damage related-breast cancer. It becomes a biomarker in cancer cell proliferation. In TNBC, the mutation cell is more sensitive against DNA damage, resulting in checkpoint activation and cell cycle arrest at G1/S, intra S, or G2/M phases by CHK1 phosphorylation. CHK1 inhibitors are currently explored for its potential activity as antitumor, especially TNBC59. A novel CHK1 inhibitor, namely V158411, is a potent, selective CHK1 inhibitor. It inhibits TNBC cell proliferation by inhibiting CHK1. It also induces apoptosis by inducing cascade-3/7 dependent apoptosis and fragmentation of DNA. Apoptosis of cancer cells is usually followed by increased DNA double-strand breaks59.

 

Figure 10. Novel CHK1 Inhibitor, V158411

 

e.     Androgen Antagonist:

Androgen receptor (AR) is a steroidal hormonal receptor for estrogen, glucocorticoid, progesterone, and mineralocorticoid60. AR in TNBC is expressed with a range of 6.6% to 75%. The absence of AR expression increases TNBC recurrence risk and the occurrence of distant metastasis61. Androgen, such as testosterone and dihydrotestosterone, are steroidal hormonal that bind to AR. AR competitively binds to ER (estrogen response elements) and coactivators; thereby, the TNBC cell line proliferation is suppressed61. One TNBC subtype is LAR (Laminal androgen receptor), expressing a high level of AR62.

 

Figure 11. Androgen Therapy, (a) Bicalutamide; (b) enzalutamide

 

Bicalutamide and enzalutamide are androgen antagonists used to treat TNBC62. Bicalutamide is an oral non-steroidal AR antagonist that provided minimal toxicity in advanced AR-positive TNBC63. On the other hand, enzalutamide is an AR inhibitor that binds to the ligand-binding domain of AR competitively, thus inhibiting AR translocation to the cell nucleus and binding it to DNA. Enzalutamide improves disease-free survival (DFS) and overall survival (OS) of patients63.

 

f.      DNMT1 (DNA Methyltransferase 1) Inhibitor

DNMT1 (DNA Methyltransferase 1) is an enzyme that catalyzes DNA methylation that responsible for the methylation pattern of DNA replication. DNMT1 is overexpressed in TNBC and become a biomarker for TNBC, caused by the methylation pattern of the TNBC cell64,65.

 

Figure 12. DNMT1 inhibitor, (a) Azacytidine; (b) Decitabine

 

Azacytidine and decitabine are DNMT1 inhibitors approved by the FDA. These agents are downregulating hypermethylation, thus suppress cancer progression and improve overall survival (OS)66.  Azacytidine is effective in brain metastasis TNBC patients66. On the other hand, decitabine combined with doxorubicin increasing the sensitivity of breast cancer against doxorubicin67.

 

g.     Anti-EGFR:

EGFR is a receptor tyrosine kinase (RTK) that playing a role in promoting cell proliferation, motility, and survival through the activation of signaling pathways such as Ras-Raf-MEK-ERK, PI3K-AKT-mTOR, and Src-STAT3. In TNBC, EGFR is overexpressed 13%-76% and is closely associated with BRCA-mutant, which upregulates the EFGR in TNBC. Anti-EGFR, including gefitinib, afatinib, erlotinib, cetuximab, and panitumumab, are becoming conventional therapies that can be used to treat patients with TNBC. Anti-EGFR acts by binding to ligand binding sites on the surface of EFGR in competing for with EGR ligands, thereby they inhibit activation and dimerization of EGFR68.

 

Figure 13. EGFR Inhibitor, (a) Gefitinib; (b) Erlotinib; (c) Afatinib

 

Gefitinib and erlotinib are an oral Moab that selectively inhibits EGFR-tyrosine kinase, thereby blocking the signal transduction pathway involved in proliferation, survival, and metastasis of cancer cells. Although gefitinib alone is not effective in TNBC, it showed synergistic inhibition of growth cells in TNBC combined with PI3K/AKT/mTOR inhibitor, which is everolimus69. On the other hand, erlotinib, combined with selected antioxidants, showed increased sensitivity of drugs against the TNBC cell line70. Afatinib is an oral Moab that irreversibly inhibits EGFR and shows antiproliferative of TNBC cell lines. It also has antitumor activity71. Cetuximab is a recombinant Moab that binds to EFGR, preventing the dimerization of receptors and downstream phosphorylation and kinase-related receptor activation, thus inhibiting cell growth and induces apoptosis, and inhibits VEGF production72.  A combination of cetuximab and paclitaxel enhances apoptosis, mitotic catastrophe, and inhibiting tumors in patients with EGFR-positive TNBC72. Panitumumab is a fully human recombinant IgG2 Moab that targeting EGFR73. It is usually used in cancer that expresses EGFR74. Panitumumab combines with neoadjuvant chemotherapy is increasing the pathological complete response (PCR) rate in TNBC patients74,75.

 

Figure 14. EFGR Inhibitor, (a) Cetuzimbab; (b) Panitumumab

 

h.    PI3K/AKT/mTOR Inhibitor:

PI3K is a lipid kinase family that involves in carcinogenesis. PI3K is activated upstream through growth factor with receptor tyrosine kinase (RTK) bind-growth factor or ligand76. It is thus leading to phosphorylation of AKT and mTOR complex 1 (mTORC1). The carcinogenesis of TNBC results in overexpression of upstream RGK. It leads to activating mutation of PIK3CA (PI3K catalytic subunit α), function loss of down regulator of PI3K by decreased expression of PTEN (phosphatase and tensin homolog) and proline-rich inositol polyphosphates77.

 

 

Figure 15. PI3K/AKT/mTOR, (a) Buparlisib; (b) Ipatasertib; (c) temsirolimus; (d) everolimus

 

PI3K inhibitor is an agent used to inhibit PI3K, such as buparlisib, pictilisib, alpelisib, and serabelisib. These agents are usually used as a combination with other agents or chemotherapy agents. Buparlisib (BKM120) increased PFS (prognosis-free survival) from 4 to 6.8 months77. AKT inhibitor is an agent to inhibit the downstream to PI3K, which is ipatasertib. Ipatasertib, combined with paclitaxel in untreated metastatic TNBC patients, improved PFS significantly77. mTOR (mechanistic target of rapamycin, formerly known as mammalian target of rapamycin) inhibitor, such as temsirolimus and everolimus, targets mTOR, thus blocking the activation of AKT. These agents increase the overall response rate (ORR) of TNBC patients. Antitumor activity, including in TNBC, is also reported in these agents77.

 

i.      Anti-VEGF (Vascular Endothelial Growth Factor):

VEGF is the most critical factor in breast cancer, including in TNBC. VEGF promotes angiogenesis and lymphomagenesis, invasion, and increasing vascular permeability by binding to tyrosine kinase receptor VEGFR-1 and VEGFR-2 on the endothelial cell. VEGF is expressed in large tumors and metastatic lesions. In TNBC, VEGF induces TNBC cell line proliferation, invasiveness of cancer cells, and metastases high rate to distant organs78,79,80.

 

Figure 16. Bevacizumab as VEGF inhibitor

 

Bevacizumab is an anti-angiogenic recombinant humanized monoclonal antibody (Moab) binds to VEGF-A, thus preventing its interaction with VEGFR in circulation leads to the activation of the angiogenesis process. Bevacizumab is a first-line treatment in metastatic breast cancer with poor prognosis, including TNBC. Bevacizumab is increasing progression-free survival (PFS) rate81. On the other hand, bevacizumab, combined with other chemotherapy agents, showed excellent efficacy in TNBC with chest wall metastasis82.

 

j.      Src

Src is a proto-oncogene involved in the control of multiple biological functions, including cell proliferation, cell differentiation, migration, angiogenesis, and survival. Src is expressed in 73% of TNBC patients. Therefore, the Src inhibitor, such as dasatinib, is potentially used in treating TNBC83,84. Dasatinib is the latest generation of tyrosine kinase enzyme inhibitor activity of the BCR-ABL fusion gene, which inhibits Src kinase that mediates differentiation, proliferation, and cell survival85,86.

 

Figure 17. Src Inhibitor, Dasatinib

 

CONCLUSION:

The treatment of TNBC are surgery, including Breast-conserving surgery (BCS)/lumpectomy, followed with radiation therapy (RT) or mastectomy in loco-regional TNBC; chemotherapy with platinum based-chemotherapy, alkylator, anthracycline, and taxanes, followed with neoadjuvant including capecitabine or carboplatin in the early stage of TNBC; and chemotherapy and immunotherapy in metastatic stage of TNBC. The therapy as monotherapy or combination (chemotherapy agent with targeted therapy) improve disease-free survival (DFS) and overall survival (OS) and sensitizes the resistant TNBC cell lines.

 

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Received on 02.09.2020            Modified on 18.02.2021

Accepted on 29.04.2021           © RJPT All right reserved

Research J. Pharm. and Tech 2022; 15(1):409-418.

DOI: 10.52711/0974-360X.2022.00068