Open Access

Triple‑negative breast cancer: A run‑through of features, classification and current therapies (Review)

  • Authors:
    • Meghana Manjunath
    • Bibha Choudhary
  • View Affiliations

  • Published online on: May 5, 2021
  • Article Number: 512
  • Copyright : © Manjunath et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY 4.0].

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Breast cancer is the most prevalent cancer in women worldwide. Triple‑negative breast cancer (TNBC) is characterized by the lack of expression of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. It is the most aggressive subtype of breast cancer and accounts for 12‑20% of all breast cancer cases. TNBC is associated with younger age of onset, greater metastatic potential, higher incidence of relapse, and lower overall survival rates. Based on molecular phenotype, TNBC has been classified into six subtypes (BL1, BL2, M, MES, LAR, and IM). TNBC treatment is challenging due to its heterogeneity, highly invasive nature, and relatively poor therapeutics response. Chemotherapy and radiotherapy are conventional strategies for the treatment of TNBC. Recent research in TNBC and mechanistic understanding of disease pathogenesis using cutting‑edge technologies has led to the unfolding of new lines of therapies that have been incorporated into clinical practice. Poly (ADP‑ribose) polymerase and immune checkpoint inhibitors have made their way to the current TNBC treatment paradigm. This review focuses on the classification, features, and treatment progress in TNBC. Histological subtypes connected to recurrence, molecular classification of TNBC, targeted therapy for early and advanced TNBC, and advances in non‑coding RNA in therapy are the key highlights in this review.


Breast cancer is a heterogeneous disease with varying biological and clinical characteristics. It is the most common cancer among women worldwide, accounting for 25% of all cancer cases (1). According to GLOBOCAN 2020, the incidence and mortality of breast cancer reported worldwide were 34,65,951 new cases and 11,21,413 deaths, respectively; in India, 1,204,532 new cases and 436,417 deaths were recorded in 2020 (2).

Immunohistochemical analysis of breast tumors is the gold-standard method used in clinics to classify them based on the hormone receptor expression for improved therapeutic decisions. Based on this, breast cancer can be broadly grouped into five types, namely: i) Progesterone receptor (PR)-positive, estrogen receptor (ER)-positive and human epidermal growth factor 2 (Her2)-negative (luminal A); ii) ER-positive, PR-positive/negative and Her2-positive (luminal B); iii) Her2-overexpressing, ER- and PR-negative; iv) ER-, PR- and Her2-negative (basal-like or triple-negative), and v) normal-like (expression status similar to luminal A and resemble normal breast profile) (35). Additionally, molecular breast cancer analysis identified a distinctive phenotype with low claudin expression, immune receptor, and EMT markers expression (6). Cancer types with the claudinlow phenotype are highly metastatic and associated with poor prognosis (7). Her2-overexpressing cancer also displays high metastasis and poor prognosis (8). Among ER-positive subtypes, luminal B is associated with a significantly worse prognosis than luminal A (9,10). Patients with basal subtypes of cancer with BRCA1 mutations have a poor prognosis (9).

Based on specific gene expression patterns, breast cancers are categorized into five intrinsic or molecular subtypes. Among the intrinsic subtypes, basal-like triple-negative breast cancer (TNBC) accounts for 12–20% of breast cancers (11). TNBC has drawn specific attention due to the lack of expression of all three receptors (ER, PR, and Her2). Thus, it cannot be treated using anti-estrogen hormonal therapies or trastuzumab (12). Morphologically, TNBC is characterized by hyperdense masses without calcification, usually occurring in women <50 years of age. Histological features include significant lymphocyte infiltration, central necrosis, pushing tumor borders, and fibrosis (13). Cytokeratins, fascin, epidermal growth factor receptor (EGFR), caveolin, and vimentin are usually expressed in basal-like TNBC (14,15). TNBC is challenging to treat, as it is quite complex due to poor cell differentiation, molecular heterogeneity, and rapid metastasis, often leading to chemoresistance and recurrence of the disease (16). Fast relapse and invasions are common features of TNBC tumors and show poor prognosis (17). Recent advances in omics technologies have provided insight into the molecular mechanisms underlying TNBC (18). The present review focuses on the different subtypes of TNBC and therapeutic approaches currently employed in the treatment of TNBC.

Histology-guided classification of TNBC

Histologically, most TNBC is categorized as no special type (IDC-NST) (17). Most IDC is characterized by pleomorphic cells with prominent nucleoli. The cells are organized into diffuse sheets, cords, nests with ductal differentiation. The rest of the tumors are categorized into 47 specific subtypes, such as invasive lobular carcinoma (relatively common), metaplastic carcinoma, medullary carcinoma, mucinous carcinoma, adenoid cystic carcinoma, secretory carcinoma, acinic cell carcinoma, neuroendocrine tumors, as well as the rarest glycogen-rich clear cell carcinoma (19,20).

Among these specific subtypes (Fig. 1), medullary breast carcinoma occurs in <1% of patients and shows distinctive features, such as high lymphoplasmacytic infiltration, overexpression of BCLG (a pro-apoptotic gene); it bears more losses of heterozygosity than other subtypes and is immunomodulatory (21,22). It is associated with better outcomes compared with other TNBC subtypes (22). Metaplastic carcinoma presents unique pathologic features, where the glandular component may be partially or completely replaced by a non-glandular component(s), and based on their differentiation status further divided into i) Squamous type, tumor with keratinization and squamous differentiation; ii) matrix-producing type, tumor with more cells in the periphery; iii) mixed type, tumor showing both squamous differentiation and large high-grade cells with pleomorphic nuclei; and iv) spindle-cell type, tumor with storiform-like spindle cells. These metaplastic tumors harbor mutations in the PIK3CA, Wnt (Wingless-Type MMTV Integration Site Family) signaling pathway genes and display a unique copy number alteration pattern (2325). Adenoid cystic carcinoma (ACC) is characterized by the presence of dividing epithelial cells and myoepithelial cells producing mucinous membrane. ACC occurs in 0.1% of patients with basal-like features (26,27) and expresses markers, such as cytokeratin 5, −5/6, −14 and −17 (28). Secretory carcinoma is characterized by microcystic, solid and tubular architecture and presence of vacuolated tumor cells producing intracellular and extracellular secretions. It occurs in <1% of the patients and is referred to as juvenile carcinoma, as it is common in adolescents and often reported to have favorable outcomes. It is also characterized by ETV6-NTRK3 fusion (2931). The rarest among all the subtypes is glycogen-rich clear cell carcinoma, in which the tumors appear in sheets and cells are polygonal in shape, with a clear cytoplasm and the presence of glycogen (32). In these sheets, there are areas of lymphocytic infiltration and plasma cells.

Among the histological subtypes, adenoid cystic carcinoma has a median recurrence of only 2 months, and metaplastic carcinoma has ~9.9 months (33), compared to IDC-NST and matrix-producing metaplastic carcinoma, which are less aggressive, with 34 and 31.4 months of median time to recurrence, respectively (20).

Although the histological assessments were pointing to the presence of WBCs in and around the TNBC subtypes, focus on the presence of WBCs has led to the identification of TILS and TAMs, which are the parameters defining prognosis and therapy of TNBC. The TNBCs might be immunogenic due to mutations that lead to aberrant protein expression on the cell membrane (34). Tumor-infiltrating lymphocytes (TILs) are white blood cells that migrate towards the tumor from the bloodstream via the newly formed blood vessels (angiogenesis), which cancer cells use for their nutritional and oxygen requirements (35). They consist of a mixture of B cells, macrophages, natural killer cells and are dominated by T cells (35). TILs are present in ~20% of TNBC tumors and carry a pivotal prognostic and predictive value (36). The presence of TILs indicates a good prognosis (37). High number of TILs indicate that there is an equilibrium between the immune status and cancer (38). The ratio of cancer cells: TILs is tilted towards TILs after surgical removal of a tumor, resulting in an improved prognosis in TNBC (38). A high mutation load and clonal heterogeneity are associated with a low number of TILs, which may provide an escape route to tumor cells from immune surveillance (39). However, in addition to TILs, the tumor microenvironment components also influence the outcome of patients with TNBC (39). Relapsing patients with TNBC have been shown to have low levels of TILs and a high number of CD163+ tumor-associated macrophages (TAMs) compared with that of patients without relapse (39). High levels of CD8+ T cells may reflect improved sensitivity to chemotherapy, whereas high levels of TAMs correlate with poor patient outcomes (36). Nevertheless, a previous study in TNBC has reported paradoxical findings, with high levels of CD8+ T cells in the tumor stroma leading to the low infiltration of the tumor epithelium, thereby indicating a poor outcome (40). Therefore, immunohistological assessment for TILS or TAMS will help develop immunotherapies detailed in section 7.

Multiomics-guided molecular classification of TNBC

Profiling based on gene expression has led to improved insight into tumor heterogeneity at the molecular level and has generated an impartial classification (Fig. 1). The PAM50 microarray set of 50 genes is used to identify breast cancer intrinsic subtypes (41). A set of 374 TNBC samples taken from 14 microarray datasets was analyzed to characterize TNBC subtypes using PAM50. The results from this analysis categorized most of the TNBC as basal-like (80.6%). The rest of the tumours were classified as Her2-positive(0.2%), normal-like (14.6%), luminal B (3.5%) and luminal A (1.1%) (Table I) (41).

Table I.

Molecular classification of triple-negative breast cancer.

Table I.

Molecular classification of triple-negative breast cancer.

First author, yearCountry or regionMethodClassificationFeatures/Pathways enriched(Refs.)
Perue et al, 2000Norway and StanfordMicroarray ScanArray 3000; PAM50Luminal AEstrogen receptor and transcription factors (GATA, X-box binding proteins, EST downregulation)(3)
Luminal BEstrogen receptor and transcription factors (GATA, X-box binding proteins)
Her2+ERBB2 and GRB7 overexpression
Normal-likeOverexpression of adipose tissue and other non-epithelial cell types expressed genes
Basal-likeKeratin 5 and −17, laminin and fatty acid binding protein 7 overexpression
Lehmann et al, 2014Sweden, UK, Netherlands, USA, Singapore/BelgiumAffymetrixBasal-like 1Cell cycle, DNA replication reactome, RNA polymerase, and(42)
Luminal Basal-like 2EGF pathway, NGF pathway, MET pathway, Wnt/β-catenin, and IGF1R pathway
MesenchymalCell motility, ECM receptor interaction and cell differentiation pathways
Mesenchymal stem cell-likeCell motility, cellular differentiation, growth pathway, inositol phosphate metabolism, EGFR, PDGF, calcium signalling,
Immunomodulatory subtypeImmune cell signalling cytokine signalling, antigen processing and presentation, and signalling through core immune signal transduction pathways
Androgen receptor subtypeSteroid synthesis, porphyrin metabolism, and androgen/oestrogen metabolism
Curtis et al, 2012UK and CanadaAffymetrix; IlluminaIntegrative cluster 117q23/20q cis-acting(47)
(METABRIC)HT-12 v3 platformIntegrative cluster 211q13/14 cis-acting
Integrative cluster 3Low genomic instability
Integrative cluster 4CNA-devoid
Integrative cluster 5 ERBB2-amplified
Integrative cluster 68p12 cis-acting
Integrative cluster 716p gain/16q loss, 8q amplification
Integrative cluster 81q gain/16q loss
Integrative cluster 98q cis-acting/20q-amplified
Integrative cluster 10cis-acting alterations 5 loss/8q gain/10p gain/12p gain
Burstein et al, 2015USA and EuropeanAffymetrixLuminal-ARandrogen receptor, oestrogen receptor, prolactin, and ERBB4 signalling(43)
Mesenchymalcell cycle, mismatch repair and DNA damage networks, and hereditary breast cancer signalling pathways
Basal-like immune-suppresseddownregulation of B cell, T cell and natural killer cell immune-regulating pathways and cytokine pathways
Basal-like immune-activatedupregulation of genes controlling B cell, T cell, and natural killer cell function
Liu et al, 2016ChinaAffymetrixImmunomodulatory subtypeCytokine-cytokine receptor interaction, T cell receptor signalling pathway, B cell receptor signalling pathway, chemokine signalling pathway(45)
Luminal-ARSteroid hormone biosynthesis, Porphyrin and chlorophyll metabolism, PPAR signalling pathway, Androgen and oestrogen metabolism
MesenchymalECM-receptor interaction, Focal adhesion, TGF-β signalling pathway, ABC transporter, Adipocytokine signalling pathway
Basal-like immune-suppressedMitotic cell cycle, Mitotic prometaphase, M phase of mitotic cell cycle, DNA replication, DNA repair

[i] ABC, ATP-binding cassette; GRB2, growth factor receptor bound protein 2; SNP, single nucleotide polymorphism; ECM, extracellular matrix; CAN, copy number alteration; PPAR, peroxisome proliferator-activated receptor; EST, expressed sequence tag.

Lehmann et al (42) performed gene expression profiling of 2,188 genes from 587 patients with TNBC and classified TNBC into six new groups, namely, basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), luminal androgen receptor (LAR), mesenchymal stem cell-like (MSL) and mesenchymal (M). The rest was classified as an unstable type (UNS/UNC). Each subtype had its characteristic feature. Basal-like was the most common type of TNBC (BL1, 22%; BL2, 12%) and was characterized by high Ki67 and DNA damage response levels. The IM subtype (18%) had basal-like characteristics with activation of IFNα and IFNγ signaling and high cytotoxic T-lymphocyte associated protein 4 gene expression. Mesenchymal subtypes (M, 21%; MSL, 10%), along with cell differentiation pathways, showed deregulation of EGFR, calcium signaling, MAPK, and PI3K signaling. In the LAR subtype (9%), an ~10-fold increase in androgen receptor (AR) expression was seen, compared with other subtypes. Activation of various pathways, such as steroid synthesis and FOXA1 and ERBB signaling, were observed in this subtype (Table I) (42,43).

Burstein et al (43) used a non-negative matrix factorization method to derive a panel consisting of 80 core genes that divided TNBC into four subtypes, luminal-AR (LAR), mesenchymal (MES), basal-like immune-suppressed (BLIS), and basal-like immune-activated (BLIA). BLIA has the best disease-free survival outcome compared to other subtypes (44). Based on DNA copy number, these subtypes can be placed into two groups, LAR or others (Table I) (31).

Liu et al (45) performed mRNA and long non-coding RNA (lncRNA) expression analysis in 165 TNBC tumor samples at Fudan University Shanghai Cancer Centre. The tumor samples were categorized into four subtypes (IM, LAR, MES, and BLIS subtypes), consistent with the classification by Burstein et al (43). The IM subtype comprised of genes related to immune functions such as CCR2, CXCL13, CXCL11, CD1C, CXCL10, and CCL5, along with ENST00000443397 long ncRNA. In contrast, the LAR subtype had enrichment of hormone regulation signaling and ENST00000447908 lncRNA (45). The MES subtype expressed lncRNA NR_003221 together with genes and pathways that promoted epithelial-to-mesenchymal (EMT) transition. Pathways and molecules such as DNA repair, replication, and mitosis, lncRNA TCONS_00000027 were enriched in the BLIS subtype (45,46).

Genomic/transcriptomic data from a set of 997 primary tumors were extracted, and an integrated analysis was performed by Curtis et al (47). A set of 995 tumors from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort was used as a validation set that divided TNBC into ten groups, named Integrated Clusters (IntClust) 1–10 (47). Basal-like breast cancer mostly fell in IntClust 4 and 10 (~80%). IntClust 4 is known to have greater TIL counts, while IntClust 10 subtype can display genomic instability and chromosomal aberrations (Table I) (4749).

Molecular aberrations in TNBC

Through whole-exome and whole-genome data, it is evident that most of the genetic alterations in TNBC are copy number alterations and somatic mutations (40). The BRCA1 and BRCA2 tumor suppressor genes are required for the maintenance of genomic stability. These genes play a role in DNA repair and replication error control (50,51). A total of 10% of patients with TNBC are known to harbor germline mutations in BRCA1 or BRCA2 (12,26,27). The lifetime risk of breast cancer becomes 60–70% in the presence of such mutations (52). Gene alterations leading to homologous recombination (HR) defects other than germline BRCA mutations are termed ‘BRCAness’ (53). Moreover, ~35% of TNBC tumors show abnormalities in the HR pathway, making them sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents (54).

Other common mutations observed in TNBC patients include those in TP53 (50–60%) and PIK3CA (~10%) (18,42). An analysis from the Catalogue of Somatic Mutations in Cancer (COSMIC) database revealed that the top genes mutated in TNBC, apart from BRCA1/2, TP53, and PIK3CA, were RB1, PTEN, NOTCH1 and BRAF (Fig. 2A). Among the point mutations observed, 34% of them were nonsense substitutions (where a base change leads to a stop codon in the DNA sequence), 21% were synonymous mutations (where a change in a base in the exon of a coding gene does not change the structure of the protein) (Fig. 2B). The rest of the mutations were missense mutations, frameshift insertion/deletions, and in-frame insertions/deletions. In the metastatic disease setting, genes from HR repair showed a larger frequency of biallelic loss-of-function mutations than in early TNBC (55).

Integrated analysis of The Cancer Genome Atlas (56) has demonstrated deletions in PTEN, DUSP4, and INPP48 involved in the PI3K-AKT pathway. Gene amplifications were seen in MYC, PIK3CA, KRAS, BRAF, FGFR, MET, and EGFR. Mutations in genes, such as ERBB2, AKT1, ATR, MAP3K1, CDKN2A, ATM, and NOTCH2 (18,42,51), were also observed. Based on the mutation signatures obtained from whole-genome sequencing of 560 tumors, TNBC could be classified into four mutation subtypes, namely, APOBEC-based signatures, HR deficiency-based signature (signature 3), Clock-like signatures (signatures 1 and 5), and mixed (no prominent signature) (56,57). These mutations suggest that DNA repair, the PI3K/AKT pathway, cell cycle checkpoints, and Notch signaling are possible druggable pathways in TNBC (58).

Circulating tumor cells (CTCs) in TNBC

Recently, much focus has been put on bringing liquid biopsies, such as circulating tumor cells (CTC) and circulating tumor DNA (ctDNA), into the clinical setting for diagnostic and prognostic use (59). CTCs are nucleated cancer cells present in the bloodstream that can be detected using techniques, such as reverse transcription-quantitative PCR, flow cytometry, and immunohistochemistry (60). Tumor cells that undergo necrosis or apoptosis release DNA fragments into the plasma are referred to as ctDNA (61). In breast cancer, ctDNA and CTCs have been studied as potential biomarkers for prognosis (60). Stover et al (62) performed studies in metastatic breast cancer patients receiving chemotherapy and identified an association between CTCs and ctDNA and tumor burden, indicating that these could be used to measure early-treatment response in patients. A retrospective study in 164 patients with metastatic TNBC revealed that >10% of patients with ctDNA had worse disease-free survival (62). A study by Bidard et al (63), with metastatic breast cancer, revealed that patients with CTC levels >5 per 7.5 ml were associated with lower progression-free survival (PFS) and OS compared with patients who had CTC levels <5 per 7.5 ml. Cristofanilli et al (64) reported that CTC counts could be utilized to classify metastatic patients into two groups. Patients with CTCs levels >5 per 7.5 ml were categorized as aggressive stage IV and those <5 per 7.5 ml as indolent stage IV (64). ctDNA has been associated with chemotherapy in studies by Riva et al (65), in which ctDNA-positive patients before and after chemotherapy experienced poor OS and disease-free survival (DFS). Additionally, Radovich et al (66) reported that patients with early-stage TNBC and positive ctDNA after chemotherapy had a higher risk of disease relapse. Therefore, liquid biopsies are being developed as a non-invasive method to study recurrence, treatment response, and survival in the clinical setting.

Conventional mode of treatment in TNBC

TNBC treatment involves a combination of surgery, radiotherapy, and chemotherapy. New methods, such as targeted therapy and immunotherapy, have been developed to improve patient survival and prognosis. Lumpectomy and mastectomy are the surgical procedures performed for TNBC patients and are usually followed by radiotherapy and chemotherapy (67). Neoadjuvant therapy is given before the surgery, which may help shrink the tumor size and avoid mastectomy (Fig. 3) (61). Taxanes and anthracyclines form the current standard of care for TNBC in both the neoadjuvant and the adjuvant settings. Epirubicin and doxorubicin are the most common anthracyclines (anticancer antibiotics known to disrupt DNA replication and mitochondrial functions to activate apoptosis) (68,69). Taxanes block angiogenesis by inhibiting epidermal growth factor receptor signaling (70).

Paclitaxel and docetaxel are familiar examples of taxanes used in the first line of therapy (71). TNBC shows a 40% pathological complete response (pCR) for taxane and anthracycline-based therapy in the neoadjuvant setting (7274). Adjuvant therapy guidelines are usually identical for all the subtypes of breast cancer and TNBC. Chemotherapy in the adjuvant setting is recommended for tumors >0.5 cm in size, as they exhibit increased aggressiveness, with a faster growth rate and metastasis (75). Anthracycline chemotherapy (cyclophosphamide and 5-fluorouracil) in patients with metastatic TNBC exhibited a response to survival within 22 months (69). However, acute toxicity is a major concern with anthracycline-based chemotherapy (76). Metastatic patients who develop resistance to anthracycline have shown sensitivity to capecitabine, gemcitabine and vinorelbine (7779). The combination of docetaxel with capecitabine has improved the OS of patients with metastatic TNBC (78).

Carboplatin and cisplatin are platinum salts that are used in the treatment of TNBC. These generate DNA lesions, and apoptosis occurs in cells unable to repair these breaks (80). For TNBC, carboplatin as a neoadjuvant addition increases the response rate from 37 to 52.1% (81). A phase-II study of 86 patients evaluating the efficacy of platinum monotherapy demonstrated a 32% overall response rate (ORR) for cisplatin and 19% for carboplatin in early TNBC. Patients with BRCA1/2 mutations showed an improved response compared with patients without BRCA1/2 mutations (82). Moreover, phase-II trials showed an improved ORR of 72% in metastatic patients with BRCA mutation with neoadjuvant cisplatin monotherapy (83,84). Recently, the PEARLY trial (NCT02441933) has explored combination therapy of taxanes and carboplatin in the neoadjuvant setting (85). Carboplatin with docetaxel or paclitaxel combination has demonstrated promising efficacy in patients with TNBC and brain metastasis (86). Although TNBC is sensitive to chemotherapy, early relapse is a major concern (75). Therefore, optimizing a tailored standard regime to address chemotherapy issues, such as toxicity, and relapse has led to customizing personalized therapy based on tumor type.

Emerging role of targeted therapy as a strategy to treat TNBC

Therapies targeted to TNBC are being developed based on the expression of specific pathways and genes. Targeted therapy focuses on customizing cancer therapy to an individual patient's tumor (87,88). TNBC being heterogenous, targeting alterations specific to the tumor would be the most effective treatment option. A study using genomics and transcriptomics has led to identifying molecular markers that could be effectively targeted in TNBC (89). PARP inhibitors, PI3K/AKT inhibitors, and anti-androgen therapy are under clinical investigation (Fig. 3) (58).

PARP inhibitors for patients with a BRCA1/2 mutation

PARP is expressed in ample amounts as a nuclear enzyme that plays a critical role in DNA repair, cell proliferation, and signaling. It transfers ADP-ribose to target proteins from NAD+ and ribosylates them (90). In response to DNA damage, PARP is known to activate the DNA repair process through poly (ADP)-ribosylation of multiple nuclear proteins that play a role in chromatin architecture and DNA metabolism (91). Therefore, PARP inhibition leads to the accumulation of double-strand breaks (DSBs) in cells undergoing replication. The presence of wild-type BRCA1/2 in cells results in a homologous recombination mode of repair of DSBs. However, in the cells deficient of BRCA1/2, homologous recombination is disrupted, and PARP repairs the breaks (9294). Therefore, in these BRCA1/2-deficient cases, inhibiting PARP will result in severe, selective toxicity called ‘synthetic lethality’ (95). Using PARP inhibitors in treatment sensitizes the tumor cells to chemotherapy and radiotherapy, causing synthetic lethality in patients with hereditary BRCA1/2 mutations identified in several TNBC subtypes (Fig. 4A) (96).

Olaparib and talazoparib are two of the PARP inhibitors approved by the United States Food and Drug Administration (FDA) for use in patients with deficient BRCA1/2 in metastatic Her2-negative breast cancer as a single agent, based on the phase-III OlympiAD and EMBRACA clinical trials (8688). Patients with a germline BRCA1/2 mutation (gBRCA1/2+) with metastatic breast cancer were grouped into 2:1 to olaparib vs. chemotherapy (capecitabine, eribulin, or vinorelbine) of physician's choice in OlympiAD trial (NCT02000622) (97,98). The ORR was 59.9% in the TNBC patient subgroup for olaparib (n=102) and 29.9% in the case of patients who underwent chemotherapy (n=48). Olaparib showed less toxicity in tumorgrade3 and 4 patients than the chemotherapy arm (98,99). In the EMBARCA trial (NCT01945775), gBRCA1/2+ metastatic patients were given 2:1 Talazoparib 1 mg daily vs. chemotherapy of physician's choice. The ORR was 62.6% in patients given with Talazoparib (n=219) and 27.2% in patients treated with chemotherapy (n=144) (99). Several other PARP inhibitors are currently under phase-II/III clinical trials, including veliparib (NCT02163694) and niraparib (NCT01905592) (100103).

PARP inhibitors are being investigated in combination with chemotherapy and immunotherapy. BrighTNess trial (NCT02032277) is a phase-III trial for stage-II and -III TNBC evaluating the combination of carboplatin with the PARP inhibitor veliparib followed by doxorubicin (104). The ongoing phase-I/II trial (MEDIOLA trial) involves a combination of olaparib and anti-PDL1 checkpoint inhibitor durvalumab (105). The phase-III OlympiA trial (NCT02032823) for early TNBC is currently assessing patients with BRCA1/2 mutation treated with olaparib as monotherapy following neoadjuvant chemotherapy (106). PARTNER (NCT03150576) (107) is a phase-II/III trial that is currently ongoing checking the efficacy of olaparib and carboplatin combination in a neoadjuvant setting (107). Table II summarizes the clinical trials taken from

Table II.

Summary of clinical trials of different group of inhibitors used as targeted therapy in TNBC.

Table II.

Summary of clinical trials of different group of inhibitors used as targeted therapy in TNBC.

A, PARP inhibitors

DrugTrialPhaseStageDisease settingResults
carboplatin + paclitaxel + veliparib → AC vs. carboplatin + paclitaxel + placebo → AC vs. placebo + placebo + placebo → ACBrighTNess, NCT02032277IIIEarlyStage II/III TNBCORR 58% vs. 53% vs. 31%
standard NACT + olaparib vs. standardGeparOla, NCT02789332 NACT + carboplatin AUC2IIEarlyStage I–III HER2 BC with gBRCA1/2m and/or HRDpCR 55.1% vs. 48.6%
talazoparibNCT02282345IIEarlyStage I–III gBRCA1/2m BCOngoing
veliparib + carboplatin → standard NACT vs. standard NACTI-SPY, NCT01042379IIEarlyStage II–III TNBCOngoing
olaparib + carboplatin + paclitaxel → AC/EC vs. Paclitaxel + carboplatin → AC/ECPARTNER, NCT03150576II/IIIEarlyStage II/III TNBC and/or gBRCAm BCOngoing
olaparib vs. placeboOlympiA, NCT02032823IIIEarlyHER2 BC gBRCA1/2mOngoing
olaparib + durvalumab + AZD6738PHOENIX, NCT03740893IIEarlyStage II/III TNBCOngoing
olaparib vs. PCTOlympiAD NCT02000622IIIAdvancedMetastatic TNBC (gBRCA1/2+), prior linesORR 59.9% vs. 29.9%
talazoparib vs. PCTEMBRACA, NCT01945775IIIAdvancedMetastatic TNBC (gBRCA1/2+), prior linesORR 62.6% vs. 27.2%
niraparib vs. PCTBRAVO, NCT01905592IIIAdvancedMetastatic TNBC (gBRCA1/2+), prior linesOngoing
veliparib + paclitaxel + carboplatin vs. placebo + Paclitaxel + carboplatinBROCADE3, NCT02163694IIIAdvancedMetastatic TNBC (gBRCA1/2+), prior linesOngoing
niraparib + pembrolizumabTOPACIO NCT02657889I/IIAdvancedMetastatic TNBCOngoing
olaparib vs. olaparib + ceralasertib vs. olaparib + adavosertibNCT03330847IIAdvancedMetastatic TNBCOngoing
olaparib + durvalumab + bevacizumabMEDIOLA, NCT02734004I/IIAdvancedgBRCAm metastatic HER-2 BCOngoing
olaparib + durvalumabNCT03801369IIAdvancedMetastatic TNBCOngoing
talazoparib + avelumabNCT03330405IIAdvancedMetastatic TNBCOngoing
olaparib + durvalumabNCT03167619IIAdvancedMetastatic TNBCOngoing
olaparibDORA, NCT00679783IIAdvancedMetastatic TNBCOngoing
talazoparib + ZEN003694NCT03901469IIAdvancedMetastatic TNBCOngoing
talazoparibNCT02401347IIAdvancedBRCA1/2 wild-type HER2 BCOngoing
veliparib + cisplatinNCT02595905IIAdvancedMetastatic TNBCOngoing
pembrolizumab + olaparib + gemcitabine + carboplatinNCT04191135II/IIIAdvancedMetastatic TNBCOngoing

B, PI3K inhibitors

DrugTrialPhaseStageDisease settingResults

iptasertib + paclitaxel vs. placebo + paclitaxelLOTUS, NCT02162719IIAdvancedAdvanced TNBCORR 40% vs. 32%
buparlisib +paclitaxel vs. placebo + paclitaxelBELLE-4, NCT01572727IIMetastaticMetastatic Her-2ORR 22.6% vs. 27%
capivasertib + paclitaxel vs. placebo + paclitaxelPAKT, NCT02423603IIMetastaticMetastatic TNBCOngoing
Tak-228 + Tak-117 + cisplatin + Nab-paclitaxelNCT03193853IIMetastaticMetastatic TNBCOngoing
LY3023414 + prexasertibExIST, NCT04032080IIMetastaticMetastatic TNBCOngoing
everolimus + carboplatinNCT02531932IIMetastaticMetastatic TNBCOngoing
ipatasertib + paclitaxelIPATunity130; NCT03337724II/IIIMetastaticMetastatic TNBCOngoing
alpelisib + Nab-paclitaxelNCT04216472IIMetastaticMetastatic TNBCOngoing
capivasertib + paclitaxelCapItello290, NCT03997123IIIMetastaticMetastatic TNBCOngoing
IPI-549 + atezolizumab + bevacizumab + Nab-paclitaxelMARIO-3, NCT03961698IIMetastaticMetastatic TNBCOngoing
gedatolisib + talazoparibNCT03911973IIMetastaticMetastatic TNBCOngoing
vistusertib + selumetinibTORCMEK NCT02583542IIMetastaticMetastatic TNBCOngoing
capivasertib +ceralasertib + adavosertib + olaparibOLAPCO NCT02576444IIMetastaticMetastatic TNBCOngoing

C, AR Antagonists

DrugTrialPhaseStageDisease settingResults

enzalutamide + paclitaxelNCT02689427IIEarlyStage I–IIIOngoing
bicalutamideNCT03055312IIAdvancedMetastatic TNBCCBR 19%
enzalutamideTBCRC011, NCT01889238IIAdvancedMetastatic Her-2CBR 25%
bicalutamideNCT00468715IIAdvancedMetastatic BCOngoing
abiraterone acetate + prednisoneNCT01842321IIAdvancedMetastatic Her-2Ongoing
palbociclib + bicalutamideNCT02605486I/IIAdvancedMetastatic BCOngoing
orteronelNCT01990209IIAdvancedMetastatic TNBCOngoing
enobosarm + pembrolizumabNCT02971761IIAdvancedAR+ Metastatic TNBCOngoing
bicalutamide + palbociclibNCT02605486IIAdvancedAR+ Metastatic BCOngoing
enzalutamide + taselisibNCT02457910I/IIAdvancedAR+ Metastatic TNBCOngoing
enzalutamide + alpelisibNCT03207529IIAdvancedAR+ PTEN+ Metastatic BCOngoing
bicalutamideSYSUCC-007, NCT03055312IIIAdvancedAR+ Metastatic TNBCOngoing
enzalutamideNCT02750358IIAdvancedAR+ Metastatic TNBCOngoing
bicalutamide + ribociclibNCT03090165I/IIAdvancedAR+ Metastatic TNBCOngoing
darolutamide + capecitabineSTART, NCT03383679IIAdvancedMetastatic BCOngoing
orteronelNCT01990209IIAdvancedMetastatic BCOngoing


DrugTrialPhaseStageDisease settingResults

sacituzumab govitecan-hziy (topoisimerase-1 inhibitor SN-38), Trop2 ADCNCT01631552I/IIAdvancedAdvanced TNBCORR 33%
ladiratuzumab vedotin, MMAE microtubule inhibitor, LIV-1NCT01969643IAdvancedAdvanced TNBCORR 25%
sacituzumab govitecan chemotherapyASCENT NCT02574455IIAdvancedAdvanced TNBCOngoing
CAB-ROR2-ADC+BA3021NCT03504488I/IIMetastaticMetastatic TNBCOngoing
SKB264A264, NCT04152499I/IIMetastaticMetastatic TNBCOngoing
enfortumab vedotinEV-202, NCT04225117IIMetastaticMetastatic TNBCOngoing

E, Immune Checkpoint Inhibitors

DrugTrialPhaseStageDisease settingResults

durvalumab + Nab-paclitaxel → EC vs. placebo + Nab-paclitaxel → ECGeparNuevo, NCT02685059IIEarlyStage IIpCR 53.4% vs. 44.2%
Nab-paclitaxel + carboplatin + pembrolizumab → AC+ pembrolizumab vs. placebo + Nab-paclitaxel + carboplatin → ACKEYNOTE-173, NCT02622074IEarlyT2/T3 88.3%, ≥N1 66.7%pCR 60%
pembrolizumab + chemotherapy vs. placebo + chemotherapyKEYNOTE-522, NCT0303648IIIEarlyT1cN1-2 or T2-4N0-N2pCR 64.8% vs. 51.2%
carboplatin + nab-paclitaxel + atezolizumab → surgery → AC/EC/FECNeoTRIPaPDL1, NCT02620280IIIEarlyT1cN1, T2N1, T3N0pCR 43.5% vs. 40.8%
pembrolizumab + paclitaxel → AC vs. placebo + Paclitaxel → ACISPY-2, NCT01042379IIEarlyStage II/IIIOngoing
pembrolizumabSWOG1418/BR006, NCT02954874IIIEarlyypT ≥1 cm or ypN1-3, TNBCOngoing
avelumabA-BRAVE, NCT02926196IIIEarlyypT>1 mm or ypN1-3 or IIB-IIIOngoing
atezolizumab + paclitaxel + carboplatin → atezolizumab + AC/EC vs. paclitaxel + carboplatin → AC/ECNSABP B 59, NCT03281954IIIEarly≥ T2N0 or ≥ T1cN1Ongoing
aezolizumab + paclitaxel → atezolizumab + AC/EC vs. paclitaxel → AC/ECIMpassion030, NCT03498716IIIEarlyII–IIIOngoing
atezolizumab + Nab paclitaxel → atezolizumab + AC vs. placebo+ Nab paclitaxel → placebo + ACIMpassion031, NCT03197935IIIEarlycT2-cT4, cN0-cN3, cM0Ongoing
pembrolizumab vs. PTCKEYNOTE-119, NCT02555657IIIAdvancedMetastatic TNBCNegative
atezolizumab + Nab paclitaxel vs. placebo + Nab paclitaxelIMpassion130, NCT02425891IIIAdvancedMetastatic TNBCOS 7.2 vs. 5.5 months
pembrolizumabKEYNOTE-012, NCT01848834IAdvancedMetastatic TNBCORR 18.5%
pembrolizumabKEYNOTE-086, NCT02447003IIAdvancedMetastatic TNBCORR ~5%
avelumabJAVELIN, NCT01772004IAdvancedMetastatic TNBCORR 21.6%
atezolizumabNCT01375842IAdvancedMetastatic TNBCORR 10%
atezolizumab + paclitaxel vs. placebo + paclitaxelIMpassion131, NCT03125902IIIMetastaticMetastatic TNBCOngoing
atezolizumab + gemcitabine + capecitabine + carboplatin vs. placebo + gemcitabine + capecitabine + carboplatinIMpassion132, NCT03371017IIIMetastaticMetastatic TNBCOngoing
pembrolizumab + Nab-paclitaxel + paclitaxel + gemcitabine + carboplatin vs. placebo + Nab-paclitaxel +paclitaxel + gemcitabine + carboplatinKEYNOTE-355, NCT02819518IIIMetastaticMetastatic TNBCOngoing
pembrolizumab + eribulinENHANCE-1, NCT02513472I/IIMetastaticMetastatic TNBCOngoing
NKTR-214 1 nivolumabPIVOT-02 NCT02983045IIMetastaticMetastatic TNBCOngoing
Intratumoral c-MET mRNA CAR T cellsNCT01837602IMetastaticMetastatic TNBCOngoing

F, Conventional platinum agents

DrugTrialPhaseStageDisease settingResults

carboplatin + bevacizumab + standard NAC vs. bevacizumab + standard NACGeparSixto, NCT01426880IIEarlyStage II/III/IVpCR 53.2% vs. 36.9%
cisplatin + paclitaxel + everolimus vs. cisplatin + paclitaxel + placeboNCT00930930IIEarlyStage II/III, TNBCpCR 36% vs. 48%
paclitaxel + carboplatin vs. paclitaxel + epirubicinNCT01276769IIEarlyStage II/III, TNBCpCR 38.6% vs. 14.0%
cisplatin + paclitaxelSHPD001, NCT02199418IIEarlyTNBCpCR 64.7%
gemcitabine + carboplatin + iniparibPreECOG 0105NCT00813956IIEarlyStage I–IIIApCR 62.4% vs. 22.3%
paclitaxel + carboplatin + bevacizumab → dose-dense AC vs. standard NACCALGB40603, NCT00861705IIAdvancedLocally advanced TNBCpCR 62.4% vs. 22.3%

[i] ORR, overall response rate; CBR, clinical benefit rate; OS, overall survival; PCT, physician's choice therapy; PFS, progression-free survival; AC, doxorubicin/cyclophosphamide; ADC, antibody-drug conjugate; EC, epirubicin/cyclophosphamide; pCR, pathological complete response; FEC, fluorouracil/epirubicin/cyclophosphamide; AR, androgen receptor; Her2, human epidermal growth factor receptor 2; gBRCA1/2, germline BRCA1/2; gBRCA1/m, gBRCA1/2-mutated; TNBC, triple-negative breast cancer; NAC, doxorubicin and cyclophosphamide; NACT, neoadjuvant chemotherapy; AUC2, area under the free carboplatin plasma concentration vs. time curve, value 2; HRD, homologous recombination deficiency; cT, clinical classified tumour; cN, clinical node staging; yPT, pathologic post-therapy tumour stage; yPN, pathologic post-therapy node stage; CM, clinical modification.

PI3K/AKT inhibitors for PTEN low TNBC

PI3K/AKT pathway is involved in cell growth and glucose metabolism. Under normal conditions, growth factors, such as insulin-activated receptor tyrosine kinases (RTKs) result in PI3K activation (108). This is followed by phosphorylation of phosphatidylinositol-4,5-trisphosphate (PIP2) by PI3K and conversion to phosphatidylinositol-3,4,5-trisphosphate (PIP3) (109). AKT binds to membrane-bound PIP3, bringing AKT close to phosphoinositide-dependent kinase 1 (PDK1) (110). PDK1 phosphorylates AKT resulting in the activation of multiple downstream pathways like cell growth, cell cycle, and metabolic pathways. This pathway is negatively regulated by the PTEN phosphatase (108,109,111). In TNBC, this pathway is active in 9.6% of patients due to the loss of PTEN activity (110) (Fig. 4B). Therefore, studies using PI3K inhibitors have been conducted in patients with TNBC (Table II), such as the LOTUS trial (NCT02162719), which is a phase-II trial evaluating ipatasertib in 124 patients (ORR in the PTENlow group was 48% compared with patients with PTEN expression) (112). The oral pan-PI3K inhibitor buparlisib has also been used in combination with paclitaxel in a phase-II trial (NCT01572727) involving metastatic Her2-negative patients; the ORR was 22.6% compared with placebo and paclitaxel (113).

Capivasertib and AZD5363 are AKT inhibitors that are currently being investigated for PFS in patients with metastatic TNBC in the CAPItello-290 (NCT03997123) and PAKT (NCT02423603) trials, respectively (114,115). In the Phase-II trial under neoadjuvant setting, mTOR inhibitor and chemotherapy combined did not show any effect in early TNBC treatment (116). The mTOR inhibitors temsirolimus or everolimus in combination with doxorubicin and bevacizumab displayed an objective response rate of 21% in mesenchymal subtype of TNBC (117).

AR inhibitors for AR-overexpressing TNBC

AR belongs to the nuclear steroid hormone family of receptors, is highly expressed in the LAR subtype of TNBC (118). AR antagonists have shown an effect in vitro and in vivo in the LAR type (Fig. 4C). Gucalp et al (119) used the AR inhibitor bicalutamide in a phase-II trial involving 424 AR-positive patients, which showed a clinical benefit rate of 19% and a median progression-free survival of 12 weeks (119). Among the ongoing clinical trials, Bicalutamide treatment response is being compared to standard chemotherapy in patients with metastatic TNBC in an ongoing phase-III as the first line of therapy (NCT03055312). Enzalutamide is another AR antagonist with which a phase-II trial (NCT01889238) was conducted in AR-positive patients with advanced TNBC, in which a clinical benefit of 25% was observed (120). Androgen-driven gene expression signature (Dx-signature) stratified patients into a Dx-positive and a Dx-negative group. Dx-positive patients had an improved response to enzalutamide compared with Dx-negative patients (120,121). In AR-positive patients with early-stage TNBC, enzalutamide is currently under investigation both as a monotherapy (NCT02750358) and in combination with paclitaxel (NCT02689427). Around 40% of AR-positive TNBC patients show activation of the PI3K-AKT pathway (122). Therefore, the combined effect of enzalutamide and the PI3K inhibitor taselisib was evaluated in the TBRC032 trial(NCT02457910) where CBR was 35.7% (123). Further details are provided in Table II.

Antibody-drug conjugates targeting surface antigens

Antibody-drug conjugates (ADC) are made up of a linker, an inhibitor, and an antibody. The antibody is selected to be specific to cell surface molecules of cancer cells and not normal cells. The payload of cytotoxic agents must be potent to kill the cancer cell. Usually, a stable molecule is used as a linker that will bind strongly to the inhibitor (124,125) (Fig. 4D). Elevated expression of tumor-associated calcium-linked signal-transducer two cell surface glycoprotein (Trop-2) has been reported in TNBC and often correlated with poor prognosis (126). Sacituzumab Govitecan (IMMU-132) is an ADC used to target Trop-2 that delivers a topoisomerase-I inhibiting payload resulting in DSBs. Bardia et al (127) conducted a phase-I/II study involving patients with advanced-stage TNBC who had previously received two lines of treatment, and the ORR was 33.33%. A phase-III study (NCT02574455) of sacituzumab govitecan in relapsed patients with TNBC is ongoing. SKB264 is another anti-Trop2 currently under investigation in the NCT04152499 phase-I trial with metastatic TNBC patients (128). Another ADC, ladiratuzumab vedotin, an immunoglobulin G1 antibody with a microtubule inhibitor (MMAE), has shown an ORR of 25% of patients with TNBC (129).

Inhibitors targeting other signaling pathways

In addition to PARP and PI3K inhibitors, inhibitors of other molecular targets are being investigated in TNBC. HDAC inhibitors are currently being investigated as monotherapy (NCT02623751) and in combination with cisplatin (NCT02393794). Various Ataxia Telangiectasia and Rad3-Related Protein (ATR) and Wee inhibitors are also in clinical trials for TNBC (1). MEK inhibitors and inhibitors of cell cycle-regulating agents, such as Aurora kinase, showed antitumor effects in animal xenografts (130,131). Palbociclib, a cyclin-dependent kinase 4/6 inhibitor, was used in a phase-I study along with paclitaxel in patients with metastatic TNBC (n=9). Clinical benefit was experienced in one-third of the patients (132). BCL2 inhibitors in TNBC cell lines have shown to decrease cell proliferation (133). In TNBC cells, BCL2 expression is high (134). Therefore, BCL2 inhibitors should be further investigated for their impact as monotherapy and in combination.

Immunotherapy as monotherapy and combination therapy for TNBC

In the last decade, substantial evidence has been generated describing the immune system's role in guiding the disease progression of TNBC (135). It is one of the rapidly progressing areas of breast cancer research. The T cell receptor (TCR) recognizes antigen presented on major histocompatibility complex molecules by cancer cells (136). It is followed by signaling from co-stimulatory factors such as CD28, modulated by immune-checkpoint (co-inhibitory) molecules (137). In TNBC, programmed death-ligand 1 (PD-L1) functions as a critical mediator of the balance and escape stages of cancer immunoediting (138140). Around 20% of TNBC tumors express PD-L1, which is associated with poor prognostic features, such as higher grade, HER2-positive status, ER-negative status and large tumor size (141). Quantification of PD-L1 can be carried out on immune cells or tumor cells using immunohistochemistry (141143). Studies have suggested that PD-L1 expression varies depending on the stage of TNBC and cell type (141143). Expression of PD-L1 in TNBC has been associated with improved pCR (50% vs. 21%) (39,144). Along with PD-L1, TILs are also high in number in TNBC (144,145). TILs are considered to be a good prognostic marker in TNBC (146). Inhibitors of PD-1/PD-L1 block the interaction between PD-1 and PD-L1, thereby initiating a positive immune response that results in tumor killing (123). Over the last few years, immune checkpoint inhibitors (CPIs) have been in the limelight due to improved efficacy shown during clinical trials (Fig. 4E). Pembrolizumab (NCT04191135 and NCT01042379), nivolumab (NCT03818685 and NCT03414684), atezolizumab (NCT03281954 and NCT03498716) and durvalumab (NCT03167619 and NCT03616886) are some of the CPIs currently used in ongoing clinical trials for TNBC (147). The IMpassion130 trial (NCT02425891) evaluated the use of atezolizumab with paclitaxel as the first line of therapy for patients with metastatic TNBC (n=901), showing PD-L1 positivity. Atezolizumab is a PD-LA inhibitor that blocks the interaction between PD-L1 and PD-1, thereby promoting T cell activity. It is now an FDA-approved drug for PD-L1-positive patients with TNBC (148). The KEYNOTE-119 phase-III clinical trial (149) evaluated pembrolizumab's effect as monotherapy in patients with metastatic TNBC vs. physician's choice chemotherapy (capecitabine, vinorelbine, gemcitabine, or eribulin). The OS of this study was not encouraging (149). In the recent trial KEYNOTE-355 (NCT02819518), PD-L1-positive patients with metastatic TNBC showed improved PFS when pembrolizumab was given in combination with chemotherapy, in comparison with patients given chemotherapy alone (150). Currently, two trials, IMpassion131 (NCT03125902) and IMpassion132 (NCT03371017), are being carried out: The former is investigating the outcomes for paclitaxel and atezolizumab in untreated metastatic patients who are PD-L1 positive, while the latter is for atezolizumab along with chemotherapy (gemcitabine, capecitabine and carboplatin) in early relapsing recurrent patients with TNBC (PD-L1 positive). For early-stage breast cancer, the KEYNOTE-173 phase-Ib trial evaluated pembrolizumab along with taxane and anthracycline neoadjuvant therapy, which resulted in an ORR of 100% (151). The ISPY-2 trial was a phase-III trial evaluating pembrolizumab in combination with chemotherapy (vs. placebo) in patients with stage-II/III TNBC, which demonstrated an ORR of 60 and 20%, respectively (152). The SWOG S1418 (NCT02954874) trial is investigating anti-PD-1/-PD-L1 in the adjuvant setting for a year in order to determine whether there is an improvement in DFS. The NSABP B-59 (NCT03281954) and IMpassion030 (NCT03498716) trials are addressing whether the combination of neoadjuvant/adjuvant chemotherapy and atezolizumab might improve DFS compared with chemotherapy alone (153).

Non-coding RNA as therapy

Sequencing of all the RNA species in a given cell using RNA-seq identified several RNA species, including mRNA. The two major classes of non-coding RNA studied in TNBC development and treatment are miRNA and Long non-coding RNA.

MicroRNA (miRNA/miR) is a small non-coding RNA, usually 20–22 nucleotides in length, regulating gene expression. miRNA is known to bind to the 3′untranslated region of mRNA. This binding either degrades mRNA or represses translation (154). miRNA is a key player in tumorigenesis, stemness, and drug resistance in TNBC (155157). For instance, tumour suppressor miRNAs, involved in tumour development, miR-190a, miR-136-5p, miR-126-5p, miR-135b-5p and miR-182-5p are downregulated in TNBC (158). miR-22 is downregulation in TNBC, is associated with migration and metastasis. miR-22 exerts its effect through eukaryotic elongation factor 2 kinase (eEF2K) expression, which activates PI3K signaling pathway (159). Also, oncosuppressor, miR-200b, activate target genes like SRY-box transcription factor 2 (SOX2), CD133, and zinc finger E-box binding homeobox 1 (ZEB1), aiding in migration and invasion and stemness (157,160). High expression of miR-95 in TNBC indicates radiotherapy resistance that occurs by targeting sphingosine-1-phosphate signaling (161). Downregulated miR-449 upregulates CDK2, CCNE2 causing doxorubicin resistancein TNBC (162,163) (Table III). Multiple studies also show that miRNAs are expressed in different stages of TNBC Multiple studies also show that miRNAs are expressed in different stages of TNBC (164166). These studies give hope for miRNA-based therapies, as the use of miRNA mimics or inhibitor oligonucleotides could serve as a therapeutic approach for TNBC (167). A study conducted by Shu et al (168) used miR-21 combined with aptamer targeting EGFR, blocking tumor growth in murine models. Yin et al (169) designed an RNA aptamer bound to CD133 with a sequence complementary to miR-21 carried by a three-way junction motif scaffold that reduced cell migration in TNBC cells (169). Non-coding RNA is being pursued as one of the TNBC therapy.

Table III.

Role of miRNA and lncRNA expressed in triple negative breast cancer.

Table III.

Role of miRNA and lncRNA expressed in triple negative breast cancer.

A, miRNA

First author, yearNamesRole in TNBC(Refs.)
Gorur et al, 2021; Pang et al, 2018;miR-22 and miR-200 family Epithelial-to-mesenchymal transition(159,160)
Lyng et al, 2012miR-190a, miR-136-5p, miR-126-5p, miR-135b-5p, miR-182-5pTumorigenesis(158)
Huang et al, 2013; Tormo et al, 2019miR-95, miR-449, and miR15a/16Drug resistance(161,162)

B, lncRNA

First author, yearNamesRole in TNBC(Refs.)

Lin et al, 2016LINKAGlycolysis and tumorigenesis(170)
Jiang et al, 2018; Ke et al, 2016NEAT1Migration, invasion and apoptosis(172,173)
Yang et al, 2019POU3F3Inhibits apoptosis(171)
Sha et al, 2017DANCRInhibits apoptosis(177)

[i] miR/miRNA, microRNA; TNBC, triple-negative breast cancer; LINKA, long intergenic non-coding RNA for kinase activation; NEAT1, nuclear paraspeckle assembly transcript 1; POU3F3, POU domain class 3 transcription factor 3; differentiation antagonizing non-protein coding RNA; DANCR, differentiation antagonizing nonprotein coding RNA.

lncRNA (long non-coding RNA), ~200 nucleotides in length, regulates gene expression at the epigenetic, transcription, post-transcription levels, and post-translation modification (16). The long intergenic non-coding RNA for kinase activation activates HIF-1α by phosphorylating it via leucine-rich repeat kinase 2to promote glycolysis and tumorigenesis in TNBC (170). Yang et al (171) demonstrated the involvement of POU domain class 3 transcription factor 3 (POU3F3) in inhibiting apoptosis and promoting proliferation in TNBC (171). Nuclear paraspeckle assembly transcript 1 (NEAT1) plays a role in TNBC metastasis (172174). Some lncRNAs (HOTAIR, LncRNA-ATB, LincRNA-ROR) are known to be co-expressed with transcription factors involved in EMT and proliferation (175). Vaidya et al (176) demonstrated that nanoparticle-mediated transfer of RNA interference molecules targeting differentiation antagonizing non-protein coding RNA, a lncRNA that is enriched in TNBC, showed some efficacy in a murine xenograft model of TNBC (Table III). These studies have shed light on the use of antisense oligonucleotides against oncogenic lncRNA as a potential approach to TNBC therapy.


TNBC is associated with poor prognosis compared to other breast cancer subtypes, and its treatment remains challenging. New technology and tools have provided insight into the molecular mechanism of the disease. This knowledge has led to the identification of druggable targets and the development of biomarker-driven therapy. The FDA-approved drugs for TNBC to date include PARP inhibitors for patients with BRCA1/2 mutations and atezolizumab for PD-L1+ tumors. Emerging targeted therapies have given hope for the treatment of TNBC. The inclusion of immunotherapy has shown promising results. Additionally, attempts to identify combinations that work effectively against TNBC are ongoing. A combination of the molecular profiles, including non-coding RNA and histology, has improved the prognosis and guided the treatment for TNBC.


The authors would like to thank Dr Raksha Rao K. (Institute of Bioinformatics and Applied Biotechnology, Bengaluru, Karnataka, India) for the critical reading of the manuscript and suggestions.


Financial support was provided by The Department of Science and Technology Fund for Improvement of S&T Infrastructure in Higher Educational Institutions (grant no. SR/FST/LSI-5361/2012), The Department of Biotechnology, India, Glue grant (BTIPR23078/MED/29/1253/2017), and The Departments Information Technology, Biotechnology and Science and Technology, Government of Karnataka, India. MM is supported by The Senior Research Fellowship from Department of Science and Technology-Innovation in Science Pursuit for Inspired Research, India (DST/INSPIRE Fellowship/2016/IF160535).

Availability of data and materials

Not applicable.

Authors' contributions

MM and BC conceived the article, performed the literature search and data analysis, drafted and critically revised the work, and confirm the authenticity of the raw data. All authors read and approved the final manuscript.

Ethics approval and consent to participate

Not applicable.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.





triple-negative breast cancer


fibroblast growth factor receptor


overall response rate


overall survival


progression free survival


physician's choice therapy



Hwang SY, Park S and Kwon Y: Recent therapeutic trends and promising targets in triple negative breast cancer. Pharmacol Ther. 199:30–57. 2019. View Article : Google Scholar : PubMed/NCBI


Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. Feb 4–2021.(Epub ahead of print). doi: 10.3322/caac.21660. View Article : Google Scholar : PubMed/NCBI


Perue CM, Sorlie T, Elsen MB, van de Rijn M, Jeffrey S and Rees C: Molecular portraits of human breast tumors. Nature. 406:747–52. 2000. View Article : Google Scholar : PubMed/NCBI


Penault-Llorca F and Viale G: Pathological and molecular diagnosis of triple-negative breast cancer: A clinical perspective. Ann Oncol. 23:vi19–vi22. 2012. View Article : Google Scholar : PubMed/NCBI


Yeh IT and Mies C: Application of immunohistochemistry to breast lesions. Arch Pathol Lab Med. 132:349–358. 2008. View Article : Google Scholar : PubMed/NCBI


Fedele M, Cerchia L and Chiappetta G: The epithelial-to-mesenchymal transition in breast cancer: Focus on basal-like carcinomas. Cancers. 9:1342017. View Article : Google Scholar : PubMed/NCBI


Dias K, Dvorkin-Gheva A, Hallett RM, Wu Y, Hassell J, Pond GR, Levine M, Whelan T and Bane AL: Claudin-low breast cancer; clinical & pathological characteristics. PLoS One. 12:e01686692017. View Article : Google Scholar : PubMed/NCBI


Spigel DR and Burstein HJ: HER2 overexpressing metastatic breast cancer. Curr Treat Options Oncol. 3:163–174. 2002. View Article : Google Scholar : PubMed/NCBI


Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, et al: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA. 100:8418–8423. 2003. View Article : Google Scholar : PubMed/NCBI


Hu Z, Fan C, Oh DS, Marron JS, He X, Qaqish BF, Livasy C, Carey LA, Reynolds E, Dressler L, et al: The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics. 7:962006. View Article : Google Scholar : PubMed/NCBI


Wang Q, Xu M, Sun Y, Chen J, Chen C, Qian C, Chen Y, Cao L, Xu Q, Du X and Yang W: Gene expression profiling for diagnosis of triple-negative breast cancer: A multicenter, retrospective cohort study. Front Oncol. 9:3542019. View Article : Google Scholar : PubMed/NCBI


Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, et al: Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 365:1273–1283. 2011. View Article : Google Scholar : PubMed/NCBI


Marotti JD, de Abreu FB, Wells WA and Tsongalis GJ: Triple-negative breast cancer: Next-generation sequencing for target identification. Am J Pathol. 187:2133–2138. 2017. View Article : Google Scholar : PubMed/NCBI


Reis-Filho JS and Tutt ANJ: Triple negative tumours: A critical review. Histopathology. 52:108–118. 2008. View Article : Google Scholar : PubMed/NCBI


Kaplan HG, Malmgren JA and Atwood M: T1N0 triple negative breast cancer: Risk of recurrence and adjuvant chemotherapy. Breast J. 15:454–460. 2009. View Article : Google Scholar : PubMed/NCBI


Chang-Qing Y, Jie L, Shi-Qi Z, Kun Z, Zi-Qian G, Ran X, Hui-Meng L, Ren-Bin Z, Gang Z, Da-Chuan Y and Chen-Yan Z: Recent treatment progress of triple negative breast cancer. Prog Biophys Mol Biol. 151:40–53. 2020. View Article : Google Scholar : PubMed/NCBI


Weigelt B and Reis-Filho JS: Histological and molecular types of breast cancer: Is there a unifying taxonomy? Nat Rev Clin Oncol. 6:7182009. View Article : Google Scholar : PubMed/NCBI


Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, Turashvili G, Ding J, Tse K, Haffari G, et al: The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 486:395–399. 2012. View Article : Google Scholar : PubMed/NCBI


Malhotra GK, Zhao X, Band H and Band V: Histological, molecular and functional subtypes of breast cancers. Cancer Biol Ther. 10:955–960. 2010. View Article : Google Scholar : PubMed/NCBI


Balkenhol MC, Vreuls W, Wauters CA, Mol SJ, van der Laak JA and Bult P: Histological subtypes in triple negative breast cancer are associated with specific information on survival. Ann Diagn Pathol. 46:1514902020. View Article : Google Scholar : PubMed/NCBI


Romero P, Benhamo V, Deniziaut G, Fuhrmann L, Berger F, Manié E, Bhalshankar J, Vacher S, Laurent C, Marangoni E, et al: Medullary breast carcinoma, a triple-negative breast cancer associated with BCLG overexpression. Am J Pathol. 188:2378–2391. 2018. View Article : Google Scholar : PubMed/NCBI


Huober J, Gelber S, Thurlimann B, Goldhirsch A, Coates AS, Viale G, Öhlschlegel C, Price KN, Gelber RD, Regan MM and Thürlimann B: Prognosis of medullary breast cancer: Analyses of 13 International Breast Cancer Study Group (IBCSG) trials. Ann Oncol. 23:2843–2851. 2012. View Article : Google Scholar : PubMed/NCBI


Geyer FC, Weigelt B, Natrajan R, Lambros MB, de Biase D, Vatcheva R, Savage K, Mackay A, Ashworth A and Reis-Filho JS: Molecular analysis reveals a genetic basis for the phenotypic diversity of metaplastic breast carcinomas. J Pathol. 220:562–573. 2010. View Article : Google Scholar : PubMed/NCBI


Hennessy BT, Gonzalez-Angulo AM, Stemke-Hale K, Gilcrease MZ, Krishnamurthy S, Lee JS, Fridlyand J, Sahin A, Agarwal R, Joy C, et al: Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 69:4116–4124. 2009. View Article : Google Scholar : PubMed/NCBI


Hayes MJ, Thomas D, Emmons A, Giordano TJ and Kleer CG: Genetic changes of Wnt pathway genes are common events in metaplastic carcinomas of the breast. Clin Cancer Res. 14:4038–4044. 2008. View Article : Google Scholar : PubMed/NCBI


Thomas DN, Asarian A and Xiao P: Adenoid cystic carcinoma of the breast. J Surg Case Rep. 2019:rjy3552019. View Article : Google Scholar : PubMed/NCBI


Ichikawa K, Mizukami Y, Takayama T, Takemura A, Miyati T and Taniya T: A case of adenoid cystic carcinoma of the breast. J Med Ultrasonics. 34:193–196. 2007. View Article : Google Scholar : PubMed/NCBI


Sun JY, Wu SG, Chen SY, Li FY, Lin HX, Chen YX and He ZY: Adjuvant radiation therapy and survival for adenoid cystic carcinoma of the breast. Breast. 31:214–218. 2017. View Article : Google Scholar : PubMed/NCBI


Aktepe F, Sarsenov D and Özmen V: Secretory carcinoma of the breast. J Breast Health. 12:1742016. View Article : Google Scholar : PubMed/NCBI


Li L, Wu N, Li F, Li L, Wei L and Liu J: Clinicopathologic and molecular characteristics of 44 patients with pure secretory breast carcinoma. Cancer Biol Med. 16:1392019. View Article : Google Scholar : PubMed/NCBI


Pareja F, Geyer FC, Marchiò C, Burke KA, Weigelt B and Reis-Filho JS: Triple-negative breast cancer: The importance of molecular and histologic subtyping, and recognition of low-grade variants. NPJ Breast Cancer. 2:160362016. View Article : Google Scholar : PubMed/NCBI


Kuroda H, Sakamoto G, Ohnisi K and Itoyama S: Clinical and pathological features of glycogen-rich clear cell carcinoma of the breast. Breast Cancer. 12:189–195. 2005. View Article : Google Scholar : PubMed/NCBI


Geyer FC, Pareja F, Weigelt B, Rakha E, Ellis IO, Schnitt SJ and Reis-Filho JS: The spectrum of triple-negative breast disease: High-and low-grade lesions. Am J Pathol. 187:2139–2151. 2017. View Article : Google Scholar : PubMed/NCBI


Degnim AC, Brahmbhatt RD, Radisky DC, Hoskin TL, Stallings-Mann M, Laudenschlager M, Mansfield A, Frost MH, Murphy L, Knutson K and Visscher DW: Immune cell quantitation in normal breast tissue lobules with and without lobulitis. Breast Cancer Res Treat. 144:539–549. 2014. View Article : Google Scholar : PubMed/NCBI


Aaltomaa S, Lipponen P, Eskelinen M, Kosma VM, Marin S, Alhava E and Syrjänen K: Lymphocyte infiltrates as a prognostic variable in female breast cancer. Eur J Cancer. 28:859–864. 1992. View Article : Google Scholar : PubMed/NCBI


Matsumoto H, Koo S, Dent R, Tan PH and Iqbal J: Role of inflammatory infiltrates in triple negative breast cancer. J Clin Pathol. 68:506–510. 2015. View Article : Google Scholar : PubMed/NCBI


Fridman WH, Galon J, Pagès F, Tartour E, Sautès-Fridman C and Kroemer G: Prognostic and predictive impact of intra-and peritumoral immune infiltrates. Cancer Res. 71:5601–5605. 2011. View Article : Google Scholar : PubMed/NCBI


Karn T, Jiang T, Hatzis C, Sänger N, El-Balat A, Holtrich U, Becker S, Bianchini G and Pusztai L: Abstract S1-07: Immune sculpting of the triple negative breast cancer genome. Cancer Res. 772017.doi: 10.1158/1538-7445.SABCS16-S1-07.


Bottai G, Raschioni C, Losurdo A, Di Tommaso L, Tinterri C, Torrisi R, Reis-Filho JS, Roncalli M, Sotiriou C, Santoro A, et al: An immune stratification reveals a subset of PD-1/LAG-3 double-positive triple-negative breast cancers. Breast Cancer Res. 18:1212016. View Article : Google Scholar : PubMed/NCBI


Gruosso T, Gigoux M, Bertos N, Manem VSK, Guiot MC, Buisseret L, Salgado R, Van den Eyden G, Haibe-Kains B and Park M: Distinct immune microenvironments stratify triple-negative breast cancer and predict outcome. Ann Oncol. 28:i162017. View Article : Google Scholar


Abramson VG, Lehmann BD, Ballinger TJ and Pietenpol JA: Subtyping of triple-negative breast cancer: Implications for therapy. Cancer. 121:8–16. 2015. View Article : Google Scholar : PubMed/NCBI


Lehmann BD and Pietenpol JA: Identification and use of biomarkers in treatment strategies for triple-negative breast cancer subtypes. J Pathol. 232:142–150. 2014. View Article : Google Scholar : PubMed/NCBI


Burstein MD, Tsimelzon A, Poage GM, Covington KR, Contreras A, Fuqua SA, Savage MI, Osborne CK, Hilsenbeck SG, Chang JC, et al: Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clin Cancer Res. 21:1688–1698. 2015. View Article : Google Scholar : PubMed/NCBI


Ahn SG, Kim SJ, Kim C and Jeong J: Molecular classification of triple-negative breast cancer. J Breast Cancer. 19:223–230. 2016. View Article : Google Scholar : PubMed/NCBI


Liu YR, Jiang YZ, Xu XE, Yu KD, Jin X, Hu X, Zuo WJ, Hao S, Wu J, Liu GY, et al: Comprehensive transcriptome analysis identifies novel molecular subtypes and subtype-specific RNAs of triple-negative breast cancer. Breast Cancer Res. 18:332016. View Article : Google Scholar : PubMed/NCBI


Yin L, Duan JJ, Bian XW and Yu S: Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Res. 22:612020. View Article : Google Scholar : PubMed/NCBI


Curtis C, Shah SP, Chin SF, Turashvili G, Rueda OM, Dunning MJ, Speed D, Lynch AG, Samarajiwa S, Yuan Y, et al: The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature. 486:346–352. 2012. View Article : Google Scholar : PubMed/NCBI


Venkitaraman AR: Linking the cellular functions of BRCA genes to cancer pathogenesis and treatment. Ann Rev Pathol. 4:461–487. 2009. View Article : Google Scholar : PubMed/NCBI


Atchley DP, Albarracin CT, Lopez A, Valero V, Amos CI, Gonzalez-Angulo AM, Hortobagyi GN and Arun BK: Clinical and pathologic characteristics of patients with BRCA-positive and BRCA-negative breast cancer. J Clin Oncol. 26:4282–4288. 2008. View Article : Google Scholar : PubMed/NCBI


Foulkes WD, Stefansson IM, Chappuis PO, Bégin LR, Goffin JR, Wong N, Trudel M and Akslen LA: Germline BRCA1 mutations and a basal epithelial phenotype in breast cancer. J Natl Cancer Inst. 95:1482–1485. 2003. View Article : Google Scholar : PubMed/NCBI


Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature. 490:61–70. 2012. View Article : Google Scholar : PubMed/NCBI


Antoniou A, Pharoah PD, Narod S, Risch HA, Eyfjord JE, Hopper JL, Loman N, Olsson H, Johannsson O, Borg A, et al: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies. Am J Hum Genet. 72:1117–1130. 2003. View Article : Google Scholar : PubMed/NCBI


Turner N, Tutt A and Ashworth A: Hallmarks of ‘BRCAness’ in sporadic cancers. Nat Rev Cancer. 4:814–819. 2004. View Article : Google Scholar : PubMed/NCBI


Lord CJ and Ashworth A: BRCAness revisited. Nat Rev Cancer. 16:110–120. 2016. View Article : Google Scholar : PubMed/NCBI


Bertucci F, Ng CK, Patsouris A, Droin N, Piscuoglio S, Carbuccia N, Soria JC, Dien AT, Adnani Y, Kamal M, et al: Genomic characterization of metastatic breast cancers. Nature. 569:560–564. 2019. View Article : Google Scholar : PubMed/NCBI


Jiang YZ, Ma D, Suo C, Shi J, Xue M, Hu X, Xiao Y, Yu KD, Liu YR, Yu Y, et al: Genomic and transcriptomic landscape of triple-negative breast cancers: Subtypes and treatment strategies. Cancer Cell. 35:428–440.e5. 2019. View Article : Google Scholar : PubMed/NCBI


Nik-Zainal S, Davies H, Staaf J, Ramakrishna M, Glodzik D, Zou X, Martincorena I, Alexandrov LB, Martin S, Wedge DC, et al: Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature. 534:47–54. 2016. View Article : Google Scholar : PubMed/NCBI


Bianchini G, Balko JM, Mayer IA, Sanders ME and Gianni L: Triple-negative breast cancer: Challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol. 13:674–690. 2016. View Article : Google Scholar : PubMed/NCBI


Zhao Y, Sheng M, Zheng L, Xiong D, Yang K and Luo Y: Application of circulating tumor DNA in breast cancer. Breast J. 26:1797–1800. 2020. View Article : Google Scholar : PubMed/NCBI


Lustberg MB, Stover DG and Chalmers JJ: Implementing liquid biopsies in clinical trials: State of affairs, opportunities and challenges. Cancer J. 24:61–64. 2018. View Article : Google Scholar : PubMed/NCBI


Thompson AM and Moulder-Thompson SL: Neoadjuvant treatment of breast cancer. Ann Oncol. 23 (Suppl 10):x231–x236. 2012. View Article : Google Scholar : PubMed/NCBI


Stover DG, Parsons HA, Ha G, Freeman SS, Barry WT, Guo H, Choudhury AD, Gydush G, Reed SC, Rhoades J, et al: Association of cell-free DNA tumor fraction and somatic copy number alterations with survival in metastatic triple-negative breast cancer. J Clin Oncol. 36:543–553. 2018. View Article : Google Scholar : PubMed/NCBI


Bidard FC, Peeters DJ, Fehm T, Nolé F, Gisbert-Criado R, Mavroudis D, Grisanti S, Generali D, Garcia-Saenz JA, Stebbing J, et al: Clinical validity of circulating tumour cells in patients with metastatic breast cancer: A pooled analysis of individual patient data. Lancet Oncol. 15:406–414. 2014. View Article : Google Scholar : PubMed/NCBI


Cristofanilli M, Pierga JY, Reuben J, Rademaker A, Davis AA, Peeters DJ, Fehm T, Nolé F, Gisbert-Criado R, Mavroudis D, et al: The clinical use of circulating tumor cells (CTCs) enumeration for staging of metastatic breast cancer (MBC): International expert consensus paper. Crit Rev Oncol Hematol. 134:39–45. 2019. View Article : Google Scholar : PubMed/NCBI


Riva F, Bidard FC, Houy A, Saliou A, Madic J, Rampanou A, Hego C, Milder M, Cottu P, Sablin MP, et al: Patient-specific circulating tumor DNA detection during neoadjuvant chemotherapy in triple-negative breast cancer. Clin Chem. 63:691–699. 2017. View Article : Google Scholar : PubMed/NCBI


Radovich M, Jiang G, Chitambar C, Nanda R, Falkson C, Lynce FC, Gallagher C, Isaacs C, Blaya M, Paplomata E, et al: Abstract GS5-02: Detection of circulating tumor DNA (ctDNA) after neoadjuvant chemotherapy is significantly associated with disease recurrence in early-stage triple-negative breast cancer (TNBC): Preplanned correlative results from clinical trial BRE12-158. Cancer Res. 802020.doi: 10.1158/1538-7445.SABCS19-GS5-02.


Becker S: A historic and scientific review of breast cancer: The next global healthcare challenge. Int J Gynecol Obstet. 131 (Suppl 1):S36–S39. 2015. View Article : Google Scholar : PubMed/NCBI


Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, et al: Anthracyclines in early breast cancer: The ABC Trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 35:2647–2655. 2017. View Article : Google Scholar : PubMed/NCBI


Mansel RE, Fodstad O and Jiang WG: Metastasis of breast cancer. Springer; 2007, View Article : Google Scholar


Mosca L, Ilari A, Fazi F, Assaraf YG and Colotti G: Taxanes in cancer treatment: Activity, chemoresistance and its overcoming. Drug Resist Updat. 54:1007422021. View Article : Google Scholar : PubMed/NCBI


Bachegowda LS, Makower DF and Sparano JA: Taxanes: Impact on breast cancer therapy. Anticancer Drugs. 25:512–521. 2014. View Article : Google Scholar : PubMed/NCBI


Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P, et al: Pathological complete response and long-term clinical benefit in breast cancer: The CTNeoBC pooled analysis. Lancet. 384:164–172. 2014. View Article : Google Scholar : PubMed/NCBI


Von Minckwitz G, Untch M, Blohmer JU, Costa SD, Eidtmann H, Fasching PA, Gerber B, Eiermann W, Hilfrich J, Huober J, et al: Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol. 30:1796–1804. 2012. View Article : Google Scholar : PubMed/NCBI


Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, Symmans WF, Gonzalez-Angulo AM, Hennessy B, Green M, et al: Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 26:1275–1281. 2008. View Article : Google Scholar : PubMed/NCBI


Park JH, Ahn JH and Kim SB: How shall we treat early triple-negative breast cancer (TNBC): From the current standard to upcoming immuno-molecular strategies. ESMO Open. 3:e0003572018. View Article : Google Scholar : PubMed/NCBI


Greene J and Hennessy B: The role of anthracyclines in the treatment of early breast cancer. J Oncol Pharm Pract. 21:201–212. 2015. View Article : Google Scholar : PubMed/NCBI


Park JS, Jeung HC, Rha SY, Ahn JB, Kang B, Chon HJ, Hong MH, Lim S, Yang WI, Nam CM and Chung HC: Phase II gemcitabine and capecitabine combination therapy in recurrent or metastatic breast cancer patients pretreated with anthracycline and taxane. Cancer Chemother Pharmacol. 74:799–808. 2014. View Article : Google Scholar : PubMed/NCBI


Karachaliou N, Ziras N, Syrigos K, Tryfonidis K, Papadimitraki E, Kontopodis E, Bozionelou V, Kalykaki A, Georgoulias V and Mavroudis D: A multicenter phase II trial of docetaxel and capecitabine as salvage treatment in anthracycline-and taxane-pretreated patients with metastatic breast cancer. Cancer Chemother Pharmacol. 70:169–176. 2012. View Article : Google Scholar : PubMed/NCBI


Anton A, Lluch A, Casado A, Provencio M, Muñoz M, Lao J, Bermejo B, Paules AB, Gayo J and Martin M: Phase I study of oral vinorelbine and capecitabine in patients with metastatic breast cancer. Anticancer Res. 30:2255–2261. 2010.PubMed/NCBI


Kennedy RD, Quinn JE, Mullan PB, Johnston PG and Harkin DP: The role of BRCA1 in the cellular response to chemotherapy. J Natl Cancer Inst. 96:1659–1668. 2004. View Article : Google Scholar : PubMed/NCBI


Huang L, Liu Q, Chen S and Shao Z: Cisplatin versus carboplatin in combination with paclitaxel as neoadjuvant regimen for triple negative breast cancer. Onco Targets Ther. 10:5739–5744. 2017. View Article : Google Scholar : PubMed/NCBI


Isakoff SJ, Mayer EL, He L, Traina TA, Carey LA, Krag KJ, Rugo HS, Liu MC, Stearns V, Come SE, et al: TBCRC009: A multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer. J Clin Oncol. 33:1902–1909. 2015. View Article : Google Scholar : PubMed/NCBI


Byrski T, Dent R, Blecharz P, Foszczynska-Kloda M, Gronwald J, Huzarski T, Cybulski C, Marczyk E, Chrzan R, Eisen A, et al: Results of a phase II open-label, non-randomized trial of cisplatin chemotherapy in patients with BRCA1-positive metastatic breast cancer. Breast Cancer Res. 14:R1102012. View Article : Google Scholar : PubMed/NCBI


Isakoff SJ: Triple negative breast cancer: Role of specific chemotherapy agents. Cancer J. 16:53–61. 2010. View Article : Google Scholar : PubMed/NCBI


Kim GM, Jeung HC, Jung KH, Kim HJ, Lee KH, Park KH, Lee JE, Anh MS, Kohn S, Lee SS, et al: PEARLY: A randomized, multicenter, open-label, phase III trial comparing anthracyclines followed by taxane versus anthracyclines followed by taxane plus carboplatin as (neo) adjuvant therapy in patients with early triple-negative breast cancer. J Clin Oncol. 35 (15_suppl):TPS587. 2017. View Article : Google Scholar


Chen XS, Nie XQ, Chen CM, Wu JY, Wu J, Lu JS, Shao ZM, Shen ZZ and Shen KW: Weekly paclitaxel plus carboplatin is an effective nonanthracycline-containing regimen as neoadjuvant chemotherapy for breast cancer. Ann Oncol. 21:961–967. 2010. View Article : Google Scholar : PubMed/NCBI


Sawyers C: Targeted cancer therapy. Nature. 432:294–297. 2004. View Article : Google Scholar : PubMed/NCBI


Dancey JE and Chen HX: Strategies for optimizing combinations of molecularly targeted anticancer agents. Nat Rev Drug Dis. 5:649–659. 2006. View Article : Google Scholar : PubMed/NCBI


Jhan JR and Andrechek ER: Triple-negative breast cancer and the potential for targeted therapy. Pharmacogenomics. 18:1595–1609. 2017. View Article : Google Scholar : PubMed/NCBI


Audebert M, Salles B and Calsou P: Involvement of poly (ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining. J Biol Chem. 279:55117–55126. 2004. View Article : Google Scholar : PubMed/NCBI


Shall S and de Murcia G: Poly(ADP-ribose) polymerase-1: What have we learned from the deficient mouse model? Mutat Res. 460:1–15. 2000. View Article : Google Scholar : PubMed/NCBI


Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, et al: Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 434:917–921. 2005. View Article : Google Scholar : PubMed/NCBI


Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, Kyle S, Meuth M, Curtin NJ and Helleday T: Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 434:913–917. 2005. View Article : Google Scholar : PubMed/NCBI


Turner N, Tutt A and Ashworth A: Targeting the DNA repair defect of BRCA tumours. Curr Opin Pharmacol. 5:388–393. 2005. View Article : Google Scholar : PubMed/NCBI


Turner NC, Lord CJ, Iorns E, Brough R, Swift S, Elliott R, Rayter S, Tutt AN and Ashworth A: A synthetic lethal siRNA screen identifying genes mediating sensitivity to a PARP inhibitor. EMBO J. 27:1368–1377. 2008. View Article : Google Scholar : PubMed/NCBI


Calabrese CR, Almassy R, Barton S, Batey MA, Calvert AH, Canan-Koch S, Durkacz BW, Hostomsky Z, Kumpf RA, Kyle S, et al: Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst. 96:56–67. 2004. View Article : Google Scholar : PubMed/NCBI


Robson ME, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, Delaloge S, Li W, Tung NM, Armstrong A, et al: OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm). J Clin Oncol. 352017.PubMed/NCBI


Robson ME, Tung N, Conte P, Im SA, Senkus E, Xu B, Masuda N, Delaloge S, Li W, Armstrong A, et al: OlympiAD final overall survival and tolerability results: Olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer. Ann Oncol. 30:558–566. 2019. View Article : Google Scholar : PubMed/NCBI


Litton JK, Rugo HS, Ettl J, Hurvitz SA, Gonçalves A, Lee KH, Fehrenbacher L, Yerushalmi R, Mina LA, Martin M, et al: Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 379:753–763. 2018. View Article : Google Scholar : PubMed/NCBI


Poggio F, Bruzzone M, Ceppi M, Conte B, Martel S, Maurer C, Tagliamento M, Viglietti G, Del Mastro L, de Azambuja E and Lambertini M: Single-agent PARP inhibitors for the treatment of patients with BRCA-mutated HER2-negative metastatic breast cancer: A systematic review and meta-analysis. ESMO Open. 3:e0003612018. View Article : Google Scholar : PubMed/NCBI


Miller K, Tong Y, Jones DR, Walsh T, Danso MA and Ma CX; MCSSSM, : Cisplatin with or without rucaparib after preoperative chemotherapy in patients with triple negative breast cancer: Final efficacy results of Hoosier Oncology Group BRE09-146. J Clin Oncol. 33:10822015. View Article : Google Scholar


Isakoff SJ, Puhalla S, Domchek SM, Friedlander M, Kaufman B, Robson M, Telli ML, Diéras V, Han HS, Garber JE, et al: A randomized phase II study of veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in BRCA1/2 metastatic breast cancer: Design and rationale. Future Oncol. 13:307–320. 2017. View Article : Google Scholar : PubMed/NCBI


Zimmer AS, Gillard M, Lipkowitz S and Lee JM: Update on PARP inhibitors in breast cancer. Curr Treat Options Oncol. 19:212018. View Article : Google Scholar : PubMed/NCBI


Rugo HS, Olopade OI, DeMichele A, Yau C, van't Veer LJ, Buxton MB, Hogarth M, Hylton NM, Paoloni M, Perlmutter J, et al: Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med. 375:23–34. 2016. View Article : Google Scholar : PubMed/NCBI


Domchek SM, Postel-Vinay S, Im SA, Hee Park Y, Delord JP, Italiano A, Alexandre J, You B, Bastian S, Krebs MG, et al: Abstract PD5-04: An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): Updated results in patients with germline BRCA-mutated (gBRCAm) metastatic breast cancer (MBC). Cancer Res. 792019.doi: 10.1158/1538-7445.SABCS18-PD5-04.


Tutt A, Kaufman B, Gelber RD, McFadden E, Goessl C, Viale G, Geyer G, Zardavas D, Arahmani A, Fumagalli D, et al: OlympiA: A randomized phase III trial of olaparib as adjuvant therapy in patients with high-risk HER2-negative breast cancer (BC) and a germline BRCA1/2 mutation (gBRCAm). Ann Oncol. 28:V672017. View Article : Google Scholar


Earl HM, Vallier AL, Qian W, Grybowicz L, Thomas S, Mahmud S, Harvey C, McAdam K, Hughes-Davies L, Roylance R, et al: PARTNER: Randomised, phase II/III trial to evaluate the safety and efficacy of the addition of olaparib to platinum-based neoadjuvant chemotherapy in triple negative and/or germline BRCA mutated breast cancer patients. J Clin Oncol. 35:TPS5912017. View Article : Google Scholar


Cantley LC: The phosphoinositide 3-kinase pathway. Science. 296:1655–1657. 2002. View Article : Google Scholar : PubMed/NCBI


Engelman JA: Targeting PI3K signalling in cancer: Opportunities, challenges and limitations. Nat Rev Cancer. 9:550–562. 2009. View Article : Google Scholar : PubMed/NCBI


Delaloge S and DeForceville L: Targeting PI3K/AKT pathway in triple-negative breast cancer. Lancet Oncol. 18:1293–1294. 2017. View Article : Google Scholar : PubMed/NCBI


Katso R, Okkenhaug K, Ahmadi K, White S, Timms J and Waterfield MD: Cellular function of phosphoinositide 3-kinases: Implications for development, immunity, homeostasis, and cancer. Annu Rev Cell Dev Biol. 17:615–675. 2001. View Article : Google Scholar : PubMed/NCBI


Kim SB, Dent R, Im SA, Espié M, Blau S, Tan AR, Isakoff SJ, Oliveira M, Saura C, Wongchenko MJ, et al: Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): A multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 18:1360–1372. 2017. View Article : Google Scholar : PubMed/NCBI


Martín M, Chan A, Dirix L, O'Shaughnessy J, Hegg R, Manikhas A, Shtivelband M, Krivorotko P, Batista López N, Campone M, et al: A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2-advanced breast cancer (BELLE-4). Ann Oncol. 28:313–320. 2017. View Article : Google Scholar


Schmid P, Cortes J, Robson ME, Iwata H, Hegg R, Nechaeva M, Xu B, Verma S, Haddad V, Imedio R, et al: A phase III trial of capivasertib and paclitaxel in first-line treatment of patients with metastatic triple-negative breast cancer (CAPItello290). J Clin Oncol. 38:TPS11092020. View Article : Google Scholar


Schmid P, Abraham J, Chan S, Wheatley D, Brunt M, Nemsadze G, Baird R, Park YH, Hall P, Perren T, et al: AZD5363 plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (PAKT): A randomised, double-blind, placebo-controlled, phase II trial. J Clin Oncol. 36:10072018. View Article : Google Scholar : PubMed/NCBI


Gonzalez-Angulo AM, Green MC, Murray JL, Palla SL, Koenig KH, Valero Brewster NK; SLJKDJ, ; et al: Open label, randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC (T-FEC) versus the combination of paclitaxel and RAD001 followed by FEC (TR-FEC) in women with triple receptor-negative breast cancer (TNBC). J Clin Oncol. 29:10162011. View Article : Google Scholar


Basho RK, Gilcrease M, Murthy RK, Helgason T, Karp DD, Meric-Bernstam F, Hess KR, Herbrich SM, Valero V, Albarracin C, et al: Targeting the PI3K/AKT/mTOR pathway for the treatment of mesenchymal triple-negative breast cancer: Evidence from a phase 1 trial of mTOR inhibition in combination with liposomal doxorubicin and bevacizumab. JAMA Oncol. 3:509–515. 2017. View Article : Google Scholar : PubMed/NCBI


Kim Y, Jae E and Yoon M: Influence of androgen receptor expression on the survival outcomes in breast cancer: A meta-analysis. J Breast Cancer. 18:134–142. 2015. View Article : Google Scholar : PubMed/NCBI


Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey LA, Blackwell K, Rugo H, Nabell L, Forero A, et al: Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer. Clin Cancer Res. 19:5505–5512. 2013. View Article : Google Scholar : PubMed/NCBI


Traina TA, Miller K, Yardley DA, Eakle J, Schwartzberg LS, O'Shaughnessy J, Gradishar W, Schmid P, Winer E, Kelly C, et al: Enzalutamide for the treatment of androgen receptor-expressing triple-negative breast cancer. J Clin Oncol. 36:884–890. 2018. View Article : Google Scholar : PubMed/NCBI


Traina TA, Miller K, Yardley DA, O'Shaughnessy J, Cortes J, Kelly AACM, Trudeau ME, Schmid P, Gianni L, García-Estevez A, et al: Results from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC). J Clin Oncol. 33:10032015. View Article : Google Scholar : PubMed/NCBI


Lehmann BD, Bauer JA, Schafer JM, Pendleton CS, Tang L, Johnson KC, Chen X, Balko JM, Gómez H, Arteaga CL, et al: PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors. Breast Cancer Res. 16:4062014. View Article : Google Scholar : PubMed/NCBI


Lehmann BD, Abramson VG, Sanders ME, Mayer EL, Haddad TC, Nanda R, Van Poznak C, Storniolo AM, Nangia JR, Gonzalez-Ericsson PI, et al: TBCRC 032 IB/II multicenter study: Molecular insights to AR antagonist and PI3K inhibitor efficacy in patients with AR+ metastatic triple-negative breast cancer. Clin Cancer Res. 26:2111–2123. 2020. View Article : Google Scholar : PubMed/NCBI


Panowski S, Bhakta S, Raab H, Polakis P and Junutula JR: Site-specific antibody drug conjugates for cancer therapy. MAbs. 6:34–45. 2014. View Article : Google Scholar : PubMed/NCBI


Nejadmoghaddam MR, Minai-Tehrani A, Ghahremanzadeh R, Mahmoudi M, Dinarvand R and Zarnani AH: Antibody-drug conjugates: Possibilities and challenges. Avicenna J Med Biotechnol. 11:3–23. 2019.PubMed/NCBI


Goldenberg DM, Stein R and Sharkey RM: The emergence of trophoblast cell-surface antigen 2 (TROP-2) as a novel cancer target. Oncotarget. 9:28989–29006. 2018. View Article : Google Scholar : PubMed/NCBI


Bardia A, Mayer IA, Vahdat LT, Tolaney SM, Isakoff SJ, Diamond JR, O'Shaughnessy J, Moroose RL, Santin AD, Abramson VG, et al: Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med. 380:741–751. 2019. View Article : Google Scholar : PubMed/NCBI


Liu Y, Lian W, Zhao X, Diao Y, Xu J, Xiao L, Qing Y, Xue T and Wang J: SKB264 ADC: A first-in-human study of SKB264 in patients with locally advanced unresectable/metastatic solid tumors who are refractory to available standard therapies. J Clin Oncol. 38((15_suppl)): TPS36592020. View Article : Google Scholar : PubMed/NCBI


Lyons TG: Targeted therapies for triple-negative breast cancer. Curr Treat Options Oncol. 20:822019. View Article : Google Scholar : PubMed/NCBI


Giltnane JM and Balko JM: Rationale for targeting the Ras/MAPK pathway in triple-negative breast cancer. Dis Med. 17:275–283. 2014.PubMed/NCBI


Romanelli A, Clark A, Assayag F, Chateau-Joubert S, Poupon MF, Servely JL, Fontaine JJ, Liu X, Spooner E, Goodstal S, et al: Inhibiting aurora kinases reduces tumor growth and suppresses tumor recurrence after chemotherapy in patient-derived triple-negative breast cancer xenografts. Mol Cancer Ther. 11:2693–2703. 2012. View Article : Google Scholar : PubMed/NCBI


Finn RS: Östrogenrezeptor-positiver Brustkrebs: Erfolgreiche Palbociblib-Letrozol-Kombination. Breast Cancer. 375:1925–1936. 2016.PubMed/NCBI


Lucantoni F, Lindner AU, O'Donovan N, Düssmann H and Prehn JH: Systems modeling accurately predicts responses to genotoxic agents and their synergism with BCL-2 inhibitors in triple negative breast cancer cells. Cell Death Dis. 9:422018. View Article : Google Scholar : PubMed/NCBI


Inao T, Iida Y, Moritani T, Okimoto T, Tanino R, Kotani H and Harada M: Bcl-2 inhibition sensitizes triple-negative human breast cancer cells to doxorubicin. Oncotarget. 9:25545–25556. 2018. View Article : Google Scholar : PubMed/NCBI


Marra A, Viale G and Curigliano G: Recent advances in triple negative breast cancer: The immunotherapy era. BMC Med. 17:902019. View Article : Google Scholar : PubMed/NCBI


Weber S, Traunecker A, Oliveri F, Gerhard W and Karjalainen K: Specific low-affinity recognition of major histocompatibility complex plus peptide by soluble T-cell receptor. Nature. 356:793–796. 1992. View Article : Google Scholar : PubMed/NCBI


Peggs KS, Quezada SA and Allison JP: Cancer immunotherapy: Co-stimulatory agonists and co-inhibitory antagonists. Clin Exp Immunol. 157:9–19. 2009. View Article : Google Scholar : PubMed/NCBI


Planes-Laine G, Rochigneux P, Bertucci F, Chrétien A-S, Viens P, Sabatier R and Gonçalves A: PD-1/PD-L1 targeting in breast cancer: The first clinical evidences are emerging. A literature review. Cancers (Basel). 11:10332019. View Article : Google Scholar : PubMed/NCBI


Mahoney KM, Rennert PD and Freeman GJ: Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Dis. 14:561–584. 2015. View Article : Google Scholar : PubMed/NCBI


Alsaab HO, Sau S, Alzhrani R, Tatiparti K, Bhise K, Kashaw SK and Iyer AK: PD-1 and PD-L1 checkpoint signaling inhibition for cancer immunotherapy: Mechanism, combinations, and clinical outcome. Front Pharmacol. 8:5612017. View Article : Google Scholar : PubMed/NCBI


Sabatier R, Finetti P, Mamessier E, Adelaide J, Chaffanet M, Ali HR, Viens P, Caldas C, Birnbaum D and Bertucci F: Prognostic and predictive value of PDL1 expression in breast cancer. Oncotarget. 6:5449–5464. 2015. View Article : Google Scholar : PubMed/NCBI


Mittendorf EA, Philips AV, Meric-Bernstam F, Qiao N, Wu Y, Harrington S, Su X, Wang Y, Gonzalez-Angulo AM, Akcakanat A, et al: PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res. 2:361–370. 2014. View Article : Google Scholar : PubMed/NCBI


Patel SP and Kurzrock R: PD-L1 expression as a predictive biomarker in cancer immunotherapy. Mol Cancer Ther. 14:847–856. 2015. View Article : Google Scholar : PubMed/NCBI


Schmidt M, Böhm D, Von Törne C, Steiner E, Puhl A, Pilch H, Lehr HA, Hengstler JG, Kölbl H and Gehrmann M: The humoral immune system has a key prognostic impact in node-negative breast cancer. Cancer Res. 68:5405–5413. 2008. View Article : Google Scholar : PubMed/NCBI


Aguiar PN Jr, Santoro IL, Tadokoro H, de Lima Lopes G, Filardi BA, Oliveira P, Mountzios G and de Mello RA: The role of PD-L1 expression as a predictive biomarker in advanced non-small-cell lung cancer: A network meta-analysis. Immunotherapy. 8:479–488. 2016. View Article : Google Scholar : PubMed/NCBI


Beckers RK, Selinger CI, Vilain R, Madore J, Wilmott JS, Harvey K, Holliday A, Cooper CL, Robbins E, Gillett D, et al: Programmed death ligand 1 expression in triple-negative breast cancer is associated with tumour-infiltrating lymphocytes and improved outcome. Histopathology. 69:25–34. 2016. View Article : Google Scholar : PubMed/NCBI


Vagia E, Mahalingam D and Cristofanilli M: The landscape of targeted therapies in TNBC. Cancers (Basel. 12:9162020. View Article : Google Scholar : PubMed/NCBI


Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, Dieras V, Henschel V, Molinero L, Chui SY, et al: IMpassion130: Updated overall survival (OS) from a global, randomized, double-blind, placebo-controlled, Phase III study of atezolizumab (atezo)+ nab-paclitaxel (nP) in previously untreated locally advanced or metastatic triple-negative breast cancer (mTNBC). J Clin Oncol. 37 (Suppl 15):S10032019. View Article : Google Scholar


Cortés J, Lipatov O, Im SA, Gonçalves A, Lee KS, Schmid P, Tamura K, Testa L, Witzel I, Ohtani S, et al: LBA21 KEYNOTE-119: Phase III study of pembrolizumab (pembro) versus single-agent chemotherapy (chemo) for metastatic triple negative breast cancer (mTNBC). Ann Oncol. 30:v859–v860. 2019. View Article : Google Scholar


Cortes J, Guo Z, Karantza V and Aktan G: Abstract CT069: KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab plus chemotherapy vs placebo plus chemotherapy for previously untreated, locally recurrent, inoperable or metastatic triple-negative breast cancer (mTNBC). Cancer Res. 772017.doi: 10.1158/1538-7445.AM2017-CT069.


Schmid P, Salgado R, Park YH, Muñoz-Couselo E, Kim SB, Sohn J, Im SA, Foukakis T, Kuemmel S, Dent R, et al: Pembrolizumab plus chemotherapy as neoadjuvant treatment of high-risk, early-stage triple-negative breast cancer: Results from the phase 1b open-label, multicohort KEYNOTE-173 study. Ann Oncol. 31:569–581. 2020. View Article : Google Scholar : PubMed/NCBI


Barker AD, Sigman CC, Kelloff GJ, Hylton NM, Berry DA and Esserman LJ: I-SPY 2: An adaptive breast cancer trial design in the setting of neoadjuvant chemotherapy. Clin Pharmacol Ther. 86:97–100. 2009. View Article : Google Scholar : PubMed/NCBI


Keenan TE and Tolaney SM: Role of immunotherapy in Triple-negative breast cancer. J Natl Compr Canc Netw. 18:479–489. 2020. View Article : Google Scholar : PubMed/NCBI


Lin S and Gregory RI: MicroRNA biogenesis pathways in cancer. Nat Rev Cancer. 15:321–333. 2015. View Article : Google Scholar : PubMed/NCBI


Qattan A: Novel miRNA targets and therapies in the triple-negative breast cancer microenvironment: An emerging Hope for a challenging disease. Int J Mol Sci. 21:89052020. View Article : Google Scholar : PubMed/NCBI


Si W, Shen J, Zheng H and Fan W: The role and mechanisms of action of microRNAs in cancer drug resistance. Clin Epigenetics. 11:252019. View Article : Google Scholar : PubMed/NCBI


Ding L, Gu H, Xiong X, Ao H, Cao J, Lin W, Yu M, Lin J and Cui Q: MicroRNAs involved in carcinogenesis, prognosis, therapeutic resistance, and applications in human triple-negative breast cancer. Cells. 8:14922019. View Article : Google Scholar : PubMed/NCBI


Lyng MB, Lænkholm AV, Søkilde R, Gravgaard KH, Litman T and Ditzel HJ: Global microRNA expression profiling of high-risk ER+ breast cancers from patients receiving adjuvant tamoxifen mono-therapy: A DBCG study. PLoS One. 7:e361702012. View Article : Google Scholar : PubMed/NCBI


Gorur A, Bayraktar R, Ivan C, Mokhlis HA, Bayraktar E, Kahraman N, Karakas D, Karamil S, Kabil NN, Kanlikilicer P, et al: ncRNA therapy with miRNA-22-3p suppresses the growth of triple-negative breast cancer. Mol Ther Nucleic Acids. 23:930–943. 2021. View Article : Google Scholar : PubMed/NCBI


Pang Y, Liu J, Li X, Xiao G, Wang H, Yang G, Li Y, Tang SC, Qin S, Du N, et al: MYC and DNMT 3A-mediated DNA methylation represses micro RNA-200b in triple negative breast cancer. J Cell Mol Med. 22:6262–6274. 2018. View Article : Google Scholar : PubMed/NCBI


Huang X, Taeb S, Jahangiri S, Emmenegger U, Tran E, Bruce J, Mesci A, Korpela E, Vesprini D, Wong CS, et al: miRNA-95 mediates radioresistance in tumors by targeting the sphingolipid phosphatase SGPP1. Cancer Res. 73:6972–6986. 2013. View Article : Google Scholar : PubMed/NCBI


Tormo E, Ballester S, Adam-Artigues A, Burgués O, Alonso E, Bermejo B, Menéndez S, Zazo S, Madoz-Gúrpide J, Rovira A, et al: The miRNA-449 family mediates doxorubicin resistance in triple-negative breast cancer by regulating cell cycle factors. Sci Rep. 9:53162019. View Article : Google Scholar : PubMed/NCBI


Naorem LD, Muthaiyan M and Venkatesan A: Identification of dysregulated miRNAs in triple negative breast cancer: A meta-analysis approach. J Cell Physiol. 234:11768–11779. 2019. View Article : Google Scholar : PubMed/NCBI


Malla RR, Kumari S, Gavara MM, Badana AK, Gugalavath S, Kumar DKG and Rokkam P: A perspective on the diagnostics, prognostics, and therapeutics of microRNAs of triple-negative breast cancer. Biophys Rev. 11:227–234. 2019. View Article : Google Scholar : PubMed/NCBI


Liu Y, Cai Q, Bao PP, Su Y, Cai H, Wu J, Ye F, Guo X, Zheng W, Zheng Y and Shu XO: Tumor tissue microRNA expression in association with triple-negative breast cancer outcomes. Breast Cancer Res Treat. 152:183–191. 2015. View Article : Google Scholar : PubMed/NCBI


Kahraman M, Röske A, Laufer T, Fehlmann T, Backes C, Kern F, Kohlhaas J, Schrörs H, Saiz A, Zabler C, et al: MicroRNA in diagnosis and therapy monitoring of early-stage triple-negative breast cancer. Sci Rep. 8:115842018. View Article : Google Scholar : PubMed/NCBI


Mei J, Hao L, Wang H, Xu R, Liu Y, Zhu Y and Liu C: Systematic characterization of non-coding RNAs in triple-negative breast cancer. Cell Prolif. 53:e128012020. View Article : Google Scholar : PubMed/NCBI


Shu D, Li H, Shu Y, Xiong G, Carson WE III, Haque F, Xu R and Guo P: Systemic delivery of anti-miRNA for suppression of triple negative breast cancer utilizing RNA nanotechnology. ACS Nano. 9:9731–9740. 2015. View Article : Google Scholar : PubMed/NCBI


Yin H, Xiong G, Guo S, Xu C, Xu R, Guo P and Shu D: Delivery of anti-miRNA for triple-negative breast cancer therapy using RNA nanoparticles targeting stem cell marker CD133. Mol Ther. 27:1252–1261. 2019. View Article : Google Scholar : PubMed/NCBI


Lin A, Li C, Xing Z, Hu Q, Liang K, Han L, Wang C, Hawke DH, Wang S, Zhang Y, et al: The LINK-A lncRNA activates normoxic HIF1α signalling in triple-negative breast cancer. Nat Cell Biol. 18:213–224. 2016. View Article : Google Scholar : PubMed/NCBI


Yang J, Meng X, Yu Y, Pan L, Zheng Q and Lin W: LncRNA POU3F3 promotes proliferation and inhibits apoptosis of cancer cells in triple-negative breast cancer by inactivating caspase 9. Biosci Biotechnol Biochem. 83:1117–1123. 2019. View Article : Google Scholar : PubMed/NCBI


Jiang X, Zhou Y, Sun AJ and Xue JL: NEAT1 contributes to breast cancer progression through modulating miR-448 and ZEB1. J Cell Physiol. 233:8558–8566. 2018. View Article : Google Scholar : PubMed/NCBI


Ke H, Zhao L, Feng X, Xu H, Zou L, Yang Q, Su X, Peng L and Jiao B: NEAT1 is required for survival of breast cancer cells through FUS and miR-548. Gene Regul Syst Biol. 10 (Suppl 1):S11–S17. 2016.PubMed/NCBI


Wang LI, Liu D, Wu X, Zeng Y, Li L, Hou Y, Li W and Liu Z: Long non-coding RNA (LncRNA) RMST in triple-negative breast cancer (TNBC): Expression analysis and biological roles research. J Cell Physiol. 233:6603–6612. 2018. View Article : Google Scholar : PubMed/NCBI


Xu Q, Deng F, Qin Y, Zhao Z, Wu Z, Xing Z, Ji A and Wang QJ: Long non-coding RNA regulation of epithelial-mesenchymal transition in cancer metastasis. Cell Death Dis. 7:e22542016. View Article : Google Scholar : PubMed/NCBI


Vaidya AM, Sun Z, Ayat N, Schilb A, Liu X, Jiang H, Sun D, Scheidt J, Qian V, He S, et al: Systemic delivery of tumor-targeting siRNA nanoparticles against an oncogenic LncRNA facilitates effective triple-negative breast cancer therapy. Bioconjug Chem. 30:907–919. 2019. View Article : Google Scholar : PubMed/NCBI


Sha S, Yuan D, Liu Y, Han B and Zhong N: Targeting long non-coding RNA DANCR inhibits triple negative breast cancer progression. Biol Open. 6:1310–1316. 2017. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

Volume 22 Issue 1

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
Spandidos Publications style
Manjunath M and Manjunath M: Triple‑negative breast cancer: A run‑through of features, classification and current therapies (Review). Oncol Lett 22: 512, 2021
Manjunath, M., & Manjunath, M. (2021). Triple‑negative breast cancer: A run‑through of features, classification and current therapies (Review). Oncology Letters, 22, 512.
Manjunath, M., Choudhary, B."Triple‑negative breast cancer: A run‑through of features, classification and current therapies (Review)". Oncology Letters 22.1 (2021): 512.
Manjunath, M., Choudhary, B."Triple‑negative breast cancer: A run‑through of features, classification and current therapies (Review)". Oncology Letters 22, no. 1 (2021): 512.