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Chemotherapy Resistant TNBC: Comparison
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Please note this is a comparison between Version 2 by Beatrix Zheng and Version 1 by Andrea Nicolini.

Triple-negative breast cancer (TNBC) is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival (OS). Taxane and anthracycline-containing chemotherapy (CT) is currently the main systemic treatment option for TNBC, while platinum-based chemotherapy showed promising results in the neoadjuvant and metastatic settings. An early arising of intrinsic or acquired CT resistance is common and represents the main hurdle for successful TNBC treatment. Numerous mechanisms were uncovered that can lead to the development of chemoresistance. These include cancer stem cells (CSCs) induction after neoadjuvant chemotherapy (NACT), ATP-binding cassette (ABC) transporters, hypoxia and avoidance of apoptosis, single factors such as tyrosine kinase receptors (EGFR, IGFR1), a disintegrin and metalloproteinase 10 (ADAM10), and a few pathological molecular pathways. Some biomarkers capable of predicting resistance to specific chemotherapeutic agents were identified and are expected to be validated in future studies for a more accurate selection of drugs to be employed and for a more tailored approach, both in neoadjuvant and advanced settings.

  • breast cancer
  • triple-negative
  • chemoresistance
  • biomarkers
  • emerging therapies

1. Introduction

Triple-negative breast cancer (TNBC) is defined as a tumor lacking estrogen (ER) and progesterone (PR) receptor expression and human epidermal growth factor receptor 2 (HER-2) overexpression/amplification. TNBC represents 10–20% of breast cancers and is more frequent in young women [1]. As compared to that of the other breast cancer (BC) subtypes, TNBC is associated with higher incidence of recurrence and distant metastases, and shorter overall survival (OS) [2]. Despite better pathological complete response (pCR) rates after neoadjuvant chemotherapy, prognosis of TNBC patients is worse as compared to non-TNBC tumors; this phenomenon is known as “triple negative paradox” [3]. In TNBC patients, disease progression and recurrence typically occur within the first 3–5 years after diagnosis; brain and lung metastases are more common [2,4][2][4]. This behavior is attributed to higher biological aggressiveness, including the emergence of resistance to chemotherapy (CT), which is the mainstay treatment in TNBC. In fact, although chemoresistance is shared with most other malignancies, an intrinsic origin or an earlier occurrence is much more common in this molecular subtype. TNBC is usually diagnosed by immune-histochemistry (IHC).
Basing upon gene expression patterns, five molecular subtypes of breast cancer with distinctive clinical behavior were identified, i.e., Luminal A, Luminal B, Her-2 enriched, Normal-like, and Basal-like [5,6][5][6]. Among them, basal-like breast cancers are most commonly triple-negative. However, these two terms are not synonymous, as 70–80% of TNBCs are basal-like and about 70% of basal-like cancers are triple-negative [6]. More recently, a TNBC subgroup termed claudin-low molecular subtype was identified. This subtype lacks basal markers and is enriched in stem cell and epithelial–mesenchymal transition (EMT) markers [7]. Overall, these findings underline the heterogeneous nature of TNBC.
In early-stage TNBC, various rates of pCR after neoadjuvant chemotherapy (NACT) as well as different response to treatment and different survival in the metastatic setting were found [8]. Tumor heterogeneity and multiple mechanisms of chemoresistance may be largely responsible for this phenomenon [9,10][9][10]. The molecular heterogeneity of TNBC was better clarified by genomic sequencing studies. In particular, basal-like 1 (BL1), basal-like 2 (BL2), immunomodulatory (IM), mesenchymal (M), mesenchymal stem-like (MSL), and luminal androgen receptor (LAR) molecular subtypes were identified [9]. A further classification into four subtypes was made by Burstein et al.: androgen receptor (AR) positive, mesenchymal, basal-like immune sup-pressed, and basal-like immune activated [10]. These subtypes might predict response to targeted therapy; however, they are not used in clinical practice, and cytotoxic chemotherapy remains the mainstay in TNBC treatment.

2. Drugs Currently Recommended or Helpful in Chemoresistant TNBC

Recently, based on specific biomarkers, some therapies were tailored to TNBC subsets and became available in clinical practice: olaparib and talazoparib for BRCA1/2 germline mutations carriers; larotrectinib and entrectinib for NTRK gene fusion carriers; anti-trophoblast cell surface antigen 2 (Trop2) antibody drug conjugate therapy. Other targeted therapies are under investigation [163][11].

2.1. Polymerase ADP-Ribose Inhibitors (PARPi) Are Recommended in TNBC BRCA1/2 Germline Mutation Carriers

About 10–20% of TNBC has BRCA1/2 germline (gBRCA) mutation. In the POSH study, no significant difference in OS was found in positive versus negative gBRCA carriers. Despite this, when the primary analysis in patients with TNBC excluding 37 (7%) patients who developed a new primary breast or ovarian cancer was repeated, OS at 10 years was 78% (95% CI 69–85) in BRCA-positive versus 69% (64–74; HR 1.24 [95% CI 0.39–3.96], p = 0.73 in BRCA-negative patients [164][12]. Better response to conventional CT depending on HRD deficiency or better immune response might explain the prolonged OS in gBRCA TNBC. Particularly, in the former instance the activity of DNA-damaging agents such as platinum salts and PARPi should be increased by gBRCA 1/2 mutations. In two Phase III trials carried out in metastatic setting, significantly increased PFS by PARPi as monotherapy compared with standard CT occurred in patients with gBRCA1/2 mutated breast cancer [165,166][13][14]. Currently, olaparib is recommended in adjuvant and metastatic settings, while talazoparib is recommended in metastatic setting alone of gBRCA carriers [12,13][15][16]. In the Phase II PETREMAC trial, patients with primary TNBC more than 20 mm received neoadjuvant olaparib for up to 10 weeks before CT. Eighteen out of thirty-two patients showed an objective response (OR) to olaparib (56.3%). Sixteen out of eighteen responders compared to 4/14 nonresponders, had homologous recombination (HR) mutations and/or BRCA1 methylation [167][17]. In a study, 107 patients with untreated primary HER2-negative and TNBC with HRD were randomized either to paclitaxel plus olaparib for 12 weeks or paclitaxel plus carboplatinum for 12 weeks, both followed by epirubicin/cyclophosphamide (EC). The pCR rate with paclitaxel-olaparib was 55.1% versus paclitaxel-carboplatin 48.6% [168][18]. In another neoadjuvant study, 20 patients with HER2 negative, gBRCA-positive disease received six months of once per day oral talazoparib, followed by definitive surgery; fifteen patients had TNBC; pCR rate was 53% [169][19]. PARPi are under evaluation in combination with CT in neoadjuvant setting (NCT03740893, NCT03150576, NCT02789332), or in combination with chemo and/or immunotherapy in advanced TNBC (NCT03801369, NCT02484404, NCT04690855).

2.2. Larotrectinib and Entrectinib for NTRK Gene Fusion Carriers

About 1% of all solid tumors show somatic chromosomal rearrangements involving the neurotrophic tropomyosin receptor kinase (NTRK1, NTRK2, and NTRK3) genes [170][20]. Tumor growth promotion derives from TRK gene fusion through overexpression of the proteins and their constitutive downstream activation. The efficacy of larotrectinib, a tropomysin receptor kinase inhibitor, was assessed in the LOXO-101 trial, which showed 71% OR rate and led to FDA approval [170,171][20][21]. Entrectinib, another tropomysin receptor kinase inhibitor that proved to be efficacious for patients with NTRK-fusion-positive solid tumors [172][22], was successively approved by the FDA. NTRK fusions occur, more similarly than in other types, in less than 1% breast cancers. Ross et al., using comprehensive genomic profiling, identified only 16 tumors (0.13%) with NTRK gene fusions among 12,214 locally aggressive, relapsed, or metastatic breast cancers. Among them, nine cases were ductal carcinomas, and three were secretory carcinomas. All tumors were HER2-negative, more often TNBC, and the majority had NTRK1 fusions [173][23]. Interestingly, human secretory breast carcinoma is less than 0.02% of all breast cancers [174][24], and very often (above 90%) harbor ETS variant transcription factor 6 (ETV6)-NTRK3 gene fusion previously cloned in pediatric mesenchymal cancers [175][25]. Most secretory breast carcinoma are classified by genomic profiling as basal-like tumors with triple-negative receptor status [176,177][26][27]. However, ETV6-NTRK3 gene fusion is often associated with indolent, slow-growing tumors. This highlights the molecular heterogeneity of TNBCs [178][28]. To date, in 15 patients with metastatic breast cancer treated with these tropomysin receptor kinase inhibitors, response rates of approximately 80% were reported [171,172,179][21][22][29]. Metastatic breast cancer harboring NTRK fusions and progressing despite previous treatment is approved for receiving TRK inhibitors [12,13][15][16].

2.3. Anti-Trop2 Antibody Drug Conjugate Therapy

Trop-2 is a glycoprotein overexpressed in multiple epithelial cancers that accounts for pro-growth signaling [180][30]. Sacituzumab govitecan-hziy is an anti-Trop-2 antibody conjugated to an active metabolite of irinotecan (SN-38) [181,182][31][32]. This drug inhibits topoisomerase activity and its DNA binding, impedes ligation of cleaved DNA strands and gives rise to double-strand DNA breaks, induces cell death, and blocks DNA replication in tumor cells [180,181][30][31]. In heavily pretreated mTNBC patients [182,183[32][33][34],184], sacituzumab govitecan-hziy improved response rate and median PFS compared to that of standard CT (33.3% and 5.5 months vs. 10–15% and 2–3 months respectively) [184][34]. The phase 3 ASCENT trial (NCT02574455), a randomized study carried out in the same type of patients to validate the safety and efficacy data [185][35] was stopped due to the evidence of drug efficacy. The mTNBC patients receiving sacituzumab govitecan-hziy had a PFS of 5.6 months (95% CI, 4.3–6.3), compared to 1.7 months for patients who received CTs of physician’s choice (p < 0.0001) [184][34]. In 2020, Sacituzumab govitecan-hziy received accelerated FDA approval for heavily pretreated and advanced mTNBC.

2.4. Other Emerging Targeted Therapies

2.4.1. Targeting Pathological TGF-Beta, Notch, Wnt/Beta-Catenin, Hedgehog, NF-kB, the PI3K-AKT-mTOR, and STAT3/JAK Molecular Pathways

CT-induced TGF-β signaling enhances tumor recurrence through IL-8-dependent expansion of CSCs and TGF-β pathway inhibitors prevent the development of drug-resistant CSCs. Thus, a combination of TGF-β inhibitors and anticancer CT could be useful in patients with TNBC [24][36]. An ongoing Phase I clinical trial is investigating galunisertib, a potent inhibitor of TGF beta type I receptor, in combination with CT in metastatic TNBC (NCT02672475).
In breast cancer cell lines, doxorubicin induced Notch-1 signaling which led to increased ABCC1 expression. Gamma-secretase inhibitor (GSI) inhibited the Notch-1 upregulation of ABCC1, thus rendering the cells more susceptible to doxorubicin [71][37]. This effect was confirmed in TNBC cells, where GSI enhanced the efficacy of doxorubicin [63][38]; GSIs-CT combination to treat advanced breast cancer, including TNBC, was investigated in two phase I clinical trials. PF-03084014 GSI, combined with docetaxel, was well tolerated and showed clinical benefit in patients with advanced TNBC [186][39]. In a recent preclinical study conducted in TNBC patient-derived xenografts with abnormal Notch signaling, a novel GSI, AL101, showed important antitumor effects [185][35].
Wnt/beta-catenin inhibitors, such as SRI33576, SRI35889, and salinomycin, can inhibit breast CSC proliferation, invasion, and self-renewal in addition to induce apoptosis [187,188][40][41]. CWP232228, which inhibits Wnt pathway signaling by blocking nuclear beta-catenin interaction with T-cell factor, decreased tumor growth in TNBC xenograft models and was strongly efficacious against chemoresistant breast CSC both in vitro and in vivo [54][42]. A repurposed drug, clofazimine, decreased the proliferation of TNBC cells and tumor growth in xenograft models. Moreover, clofazimine showed a relevant synergistic effect with doxorubicin with a good tolerability [189][43]. A recombinant human Frizzled-7 protein antagonist (rhFzd7) decreased proliferation, invasion, and angiogenesis by inhibiting Wnt/beta-catenin pathway, while sensitizing TNBC cells to docetaxel both in vivo and in vitro [190][44]. LGK974, a small molecule blocking Wnt ligand secretion, is under evaluation in patients with Wnt-ligand dependent malignancies, including TNBC (NCT01351103). Similarly, PTK7-ADC, an antibody–drug conjugate targeting a component of the Wnt/beta pathway, is currently assessed as a therapeutic combination in metastatic TNBC (NCT03243331).
The majority of Hh signaling pathway inhibitors are directed against SMO. However, their efficacy in breast cancer, including TNBC, was disappointing. SMO independent activation of the Hh pathway was demonstrated in TNBC and could partially account for the lack of efficacy of SMO inhibitors [191][45]. Preclinical data indicate that the use of GLI inhibitors might be preferred for TNBC treatment. GANT61, a direct GLI inhibitor, promoted apoptosis, decreased proliferation, and CSC population in TNBC cell lines [192,193][46][47]. However, so far, none of the GLI inhibitors were entered into clinical trials.
Most NF-kB inhibitors are nonspecific as they affect many other targets besides the NF-kB pathway. This and the pleiotropic effects of NF-B likely account for their high toxicity [194][48]. Plumbagin, a nonspecific inhibitor, and genistein, a major soy isoflavone inhibiting NF-kB activity via Notch-1 pathway, exert anti-growth and pro-apoptotic effects in TNBC cells [195,196][49][50]. Dehydroxymethylepoxyquinomicin (DHMEQ), which inhibits nuclear translocation of NF-B, decreased growth and induced apoptosis in TNBC cells, likely by reducing the activation of this pathway [197][51].
Targeting the PI3K-AKT-mTOR pathway together with CT can be a useful strategy in aggressive TNBCs with PTEN loss. Everolimus, an mTOR inhibitor, was effective against TNBC in preclinical investigations. Promising results were also obtained for NVP-BEZ235, a PI3K/mTOR inhibitor, in TNBC cell lines [102][52] and several Phase I and II clinical trials investigating the effects of mTOR and PI3KA inhibitors, alone or in combination with CT, mainly in advanced TNBC are underway (NCT02531932, NCT01931163, NCT01629615, NCT04216472). Recently, AKT proved an important therapeutic target in advanced/metastatic TNBC. A combination of the AKT inhibitor ipatasertib with paclitaxel prolonged PFS and OS of TNBC patients compared to paclitaxel alone. A greater benefit occurred in patients with alterations in the molecular PIK3CA/AKT1/PTEN pathway thus highlighting the relevance of careful patient selection [198][53]. Accordingly, an ongoing trial is investigating ipatasertib in advanced TNBCs preselected for PIK3CA/AKT1/PTEN alterations (NCT03337724). Uprosertib, another AKT inhibitor, is under evaluation in a Phase II clinical trial on metastatic TNBC (NCT01964924). AZD5363, a novel AKT inhibitor evaluated combined with CT in metastatic TNBC, prolonged OS in a Phase II trial [199][54].
Promising preclinical results targeting STAT3 and JAK2 in solid tumors including breast cancer were followed by a few clinical studies [200][55]. For example, JAK1/2 inhibitor ruxolitinib in combination with NACT and AZD9150, a novel antisense nucleotide inhibitor of STAT3, together with durvalumab and paclitaxel are under investigation in triple-negative inflammatory breast cancer (NCT02876302) and in a Phase I/II clinical trial in metastatic TNBC (NCT03742102), respectively.

2.4.2. Targeting Apoptosis, miRNAs, EGFR, and AR

Many studies among anticancer strategies focused on Bcl2 family members, TRAIL receptors, and inhibitors of apoptosis (IAPs) [201][56]. A recent phase II clinical study conducted in metastatic TNBC and investigating tigatuzumab combined with CT was unsuccessful [202][57]. MEDI3039, a novel death receptor (DR) multivalent agonist, showed elevated antitumoral efficacy both in-vitro and in-murine models of TNBC [203][58]. Following pro-apoptotic stimuli, mitochondria release the second mitochondria-derived activator of caspases (SMAC) which acts as an antagonist of IAPs. Thus, SMAC mimetics were constructed as proapoptotic, anticancer agents that could be particularly effective in TNBC [204][59]. For example, Debio 1143 (AT406) with good preclinical results is under investigation in several Phase I trials on advanced solid tumors, including TNBC (NCT01078649, NCT01930292). In preclinical studies, another SMAC mimetic, LCL161 promoted apoptosis and showed synergistic effects with paclitaxel. Particularly, in a phase II clinical trial, LCL161 administered as a neoadjuvant agent in association with paclitaxel was highly effective; in fact, in localized TNBC, LCL161/paclitaxel combination more than doubled the pCR rate compared with that of paclitaxel alone, although with increased toxicity. However, the pCR effect was only present in the TNBC group preselected for the tumor necrosis factor (TNF) gene expression profile [205][60].
Regarding therapeutic involvement of miRNAs, two basic strategies were developed: oncogenic miRNAs inhibition and the use of substitutes for rehabilitation of tumor suppressor miRNAs function [206][61]. Anti-miRNA oligonucleotides, miRNA sponges, small RNA zipper molecules, antagomiRNAs, locked nucleic acid anti-miRNAs, and small molecule inhibitors are the agents commonly used to inhibit oncogenic miRNAs. Antisense-miRNAs and restoration of tumor suppressor miRNAs using miR-mimics inhibited TNBC growth, migration, and invasion in cell lines and xenograft models [207,208][62][63]. MiRNAs-based therapeutic approach seems promising, although further improvements in delivery systems, toxicity, selectivity, and specificity are needed.
EGFR activation/amplification was detected in approximately 25–50% of TNBC [209[64][65],210], and therefore EGFR inhibition should be effective in the treatment of EGFR-driven TNBC. In TNBC, mAbs specific for the receptor and the use of tyrosine kinase inhibitors (TKIs) are two common strategies used for targeting EGFR (and other receptor tyrosine kinases). Cetuximab, an anti-EGFR mAb evaluated in metastatic TNBC in association with cisplatin, moderately increased PFS and OS [211][66]. However, a Phase II study of cetuximab in combination with carboplatin in metastatic TNBC obtained disappointing results [212][67]. Panitumumab, another EGFR mAb, showed different efficacy in clinical trials [213,214][68][69] and clinical trials of panitumumab in combination with CT in inflammatory TNBC are ongoing (NCT02876107, NCT01036087). Among TKIs, promising findings were reported for apatinib in TNBC [86,215,216,217][70][71][72][73]. A clinical trial investigating icotinib in metastatic TNBC is currently recruiting patients (NCT02362230), while the association of anti-EGFR mAbs and TKIs could result in a stronger antitumor action likely due to a synergistic effect [218][74]. However, in TNBC, although it is a tumor characterized by relatively high rate of EGFR overexpression EGFR, targeted therapy has poor performance. The “EGFR paradox” could explain this phenomenon. According to this hypothesis, EGFR signaling changes during tumor progression, and while EGFR is overexpressed in primary tumors, metastatic cells become intrinsically resistant to EGFR targeted therapy. Accordingly, the two clinical studies of panitumumab that reported the greatest benefit were conducted on operable, primary TNBC [213,219][68][75].
Findings from clinical and preclinical studies suggest that LAR is a resistant subtype [104][76]. LAR tumors are relatively quiescent, which at least in part could explain their CT resistance [106][77]. Bicalutamide, a first-generation AR antagonist, induces cell apoptosis and inhibits cell motility and invasiveness in cell line MDA-MB-453 [220][78] and cell lines representing the LAR subtype are sensitive to AR antagonist bicalutamide and 17-DMAG [102][52]. In a first phase II study of metastatic AR-positive TNBC breast cancer patients treated with bicalutamide, a six-month clinical benefit rate of 19% and a median PFS of 12 weeks occurred [221][79]. In another Phase II single-arm trial conducted in 146 AR-positive TNBC patients with inoperable locally advanced or metastatic diseases whose tumors had > 10% AR expression, a different AR inhibitor, abiraterone acetate plus prednisone, showed comparable results to bicalutamide [222][80]. Enzalutamide, a second-generation AR antagonist, showed clinical activity in a Phase II study recruiting patients with locally advanced or metastatic AR-positive TNBC [223][81]. Moreover, AR inhibition with enzalutamide was an inductor of radiation sensitivity in AR-positive TNBC cell lines, proposing AR inhibition as a radio-sensitization strategy [224][82]. The START trial (NCT03383679) is an ongoing randomized Phase II study testing the efficacy of darolutamide, a new AR antagonist, compared to capecitabine for AR-positive, locally recurrent, or metastatic TNBC.
Drugs currently recommended or potentially helpful in chemoresistant TNBC are reported in Table 31A–C.
Table 31.
Drugs currently recommended or potentially helpful in chemoresistant TNBC.
A.
Drug Target/Mechanism of Action CS/ES Outcome Reference/NCT Number
Currently recommended
Olaparib PARP inhibitor Metastatic, in HER2 negative BC pts with a germline BRCA mutation (CS) Higher objective RR and PFS [165][13]
Talazoparib Advanced, in BC pts with germline BRCA mutation (CS) [166][14]
Larotrectinib Inhibitor of tropomyosin receptor kinase (TRK) Advanced, in NTRK gene fusion-positive solid tumours (CS) ORR 71% [170][20]
Entrectinib ORR 57%; Median duration of response 10 months [172][22]
Sacituzumab govitecan Anti-Trop2 antibody drug conjugate Metastatic, in heavily pretreated pts (CS) RR 33.3%; median duration of response 7.7 months; clinical benefit rate 45.4%; median PFS 5.5 months; OS 13.0 months [184][34]
Under investigation
Galunisertib TGF beta type I receptor inhibitor Metastatic, in combination with CT (CS) NA NCT02672475 (phase I)
PF-03084014 Gamma secretase inhibitor Advanced, in combination with docetaxel (CS) Median PFS 4.1 months [186][39]
AL101 Patient-derived xenografts with abnormal Notch signaling (ES) Inhibition of tumor growth [185][35]
SRI33576, SRI35889 wnt/beta-catenin inhibitors Cell lines (ES) Pro-apoptotic effects by downregulating LRP6 [187][40]
Salinomycin Breast CSCs (ES) inhibition of proliferation, invasion, and self-renewal while inducing apoptosis [185,186][35][39]
CWP232228 Xenograft models (ES) Inhibition of tumor growth [54][42]
Clofazimine Cells and xenograft models (ES) inhibition of proliferation; [189][43]
Frizzled-7 protein antagonist (rhFzd7) Cells and xenografts (ES) Inhibition of proliferation, invasion, and angiogenesis while sensitizing cells to docetaxel [190][44]
LGK974 Advanced, in pts with wnt-ligand dependent malignancies, including TNBC (CS) NA NCT01351103 (phase I)
PTK7-ADC Metastatic, in combination with gedatolisib (dual PI3K-mTORC1/2 inhibitor) (CS) NCT03243331 (phase I)
B.
Drug Target/Mechanism of Action CS/ES Outcome Reference/NCT Number
Under investigation
GANT61 Hh/direct GLI inhibitor Cell lines (ES) promoted apoptosis, reduced proliferation, and decreased CSC population [192,193][46][47]
Plumbagin Non-specific NF-kB inhibitor Decreased cell viability and promoted apoptosis [195][49]
Genistein NF-kB inhibitor Anti-growth and pro-apoptotic effects [196][50]
DHMEQ Nuclear translocation of NF-B inhibitor Decreased growth and induction of apoptosis [197][51]
Everolimus mTOR inhibitor Advanced, in combination with carboplatin (CS) NA NCT02531932 (phase II)
Advanced, in combination with cisplatin (CS) NCT01931163 (phase II)
BKM120 PI3K inhibitor Metastatic (CS) NCT01629615 (phase II)
Alpelisib Neoadjuvant, in combination with nab-paclitaxel in anthracycline refractory pts with PIK3CA or PTEN alterations (CS) NCT04216472 (phase I)
Ipatasertib AKT inhibitor Locally advanced/metastatic, first line (phase II), in combination with paclitaxel (CS) Prolonged PFS and OS [198][53]
Ipatasertib Advanced, in PIK3CA/AKT1/PTEN-altered pts, in combination with paclitaxel versus placebo + paclitaxel (CS) NA NCT03337724 (phase III)
Uprosertib Metastatic, in combination with trametinib (CS) NCT01964924 (phase II)
AZD5363 Metastatic, in combination with CT (CS) Prolonged OS [201][56]
Ruxolitinib JAK1/2 inhibitor Neoadjuvant, in combination with CT (CS) NA NCT02876302 (phase II)
C.
Drug Target/Mechanism of Action CS/ES Outcome Reference/NCT Number
Under investigation
AZD9150 Antisense nucleotide inhibitor of STAT3 Metastatic, in combination with durvalumab and paclitaxel (CS) NA NCT03742102 (phase I/II)
MEDI3039 Apoptosis/DR agonist In-vitro and in-murine models (ES) Tumor growth inhibition [205][60]
Debio 1143 IAP antagonist Advanced, solid tumors including TNBC (CS) NA NCT01078649, NCT01930292 (phase I)
LCL161 SMAC analog Neoadjuvant, in combination with paclitaxel (CS) Doubled pCR rate in a group preselected for the tumor necrosis factor (TNF) gene expression profile [205][60]
antisense-miRNA-21 and antisense-miRNA-10b co-delivery Inhibition of oncogenic miRNAs Murine models (ES) reduced tumor growth [207][62]
miR-mimic recombinant vectors Restoration of tumor suppressor miRNAs Cell line (ES) Reduced migration and invasion [209][64]
Panitumumab anti-EGFR mAb Neoadjuvant, in combination with CT NA NCT02876107 (phase II)

NCT01036087 (phase II)
Apatinib Anti-EGFR TKI Advanced, alone or in combination with CT (CS) NCT05019690 (phase I/II)

NCT03932526 (phase II)

NCT03254654 (phase II)
Icotinib Metastatic, pre-treated (CS) Under evaluation NCT02362230 (phase II)
Bicalutamide AR antagonist Metastatic, AR-positive (CS) six-month CBR 19%, median PFS 12 weeks [221][79]
Abiraterone acetate Advanced or metastatic, AR-positive pts, in combination with prednisone (CS) six-month CBR 20.0%, ORR 6.7%, median PFS 2.8 months [222][80]
Enzalutamide Locally advanced or metastatic AR-positive pts (CS) 16 weeks CBR 33%, median PFS 3.3 months, median OS 17.6 months [223][81]
Darolutamide Locally recurrent or metastatic, in AR-positive pts (CS) NA NCT03383679 (phase II)
CT: chemotherapy; CS: clinical setting; ES: experimental setting; NA: not available; PARP: polymerase ADP-ribose; RR: response rate; PFS: progression free survival; NTRK: neurotrophic tropomyosin receptor kinase; ORR: overall response rate; Trop-2: trophoblast cell-surface antigen; TGF: tumor growth factor; LRP6: lipoprotein receptor-related protein-6; CSCs: cancer stem cells; PI3K: phosphatidyl inositol 3-kinase; mTORC1/2: mammalian target of rapamycin complex 1/2; GLI: glioma-associated oncogene transcription factor; NFkB: nuclear factor kappa-light-chain-enhancer of activated B cells; mTOR: mammalian target of rapamycin; Akt: protein kinase B; PTEN: phosphatase and tensin homolog; JAK1/2: Janus kinase 1/2; STAT: signal transducer and activator of transcription; DR: death receptor; IAP: inhibitor of apoptosis; SMAC: second mitochondria-derived activator of caspases; TKi: tyrosine kinase inhibitor; AR: androgen receptor; pCR: pathological complete response; CBR: clinical benefit rate; OS: overall survival.

 

 

 

3. Current Insights

Among breast cancer subtypes, TNBC is associated with the worst prognosis [2[2][4],4], and in spite of efforts performed in the last decades, no significant improvement in PFS and OS was obtained [225,226][83][84]. At present, CT is the mainstay treatment in TNBC; however, resistance to CT frequently occurs. However, TNBC is a heterogeneous disease, and many molecular mechanisms are involved in chemoresistance. Identification of these mechanisms is of particular relevance, as it can help in improving prognosis and therapy. Some biomarkers capable of predict resistance to specific chemotherapeutic agents were identified and are expected to be validated in future studies. These predictive factors could guide the therapeutic approach in both early and advanced disease. Current guidelines recommend NACT in operable TNBC > 2 cm or for breast conservation or in cN+ disease likely to become cN0; recently, NACT was considered not an option, but rather the preferred treatment strategy for TNBC patients in clinical practice [15][85]. However, disease progression during NACT is a potential risk [12,13][15][16]. Therefore, both in neoadjuvant and advanced settings, a more tailored approach and a more accurate selection of the employed drugs are main aims. Many studies based upon molecular biology defined the use of new drugs that could be essential in identifying the mechanisms accounting for chemoresistance to a specific antiblastic in each patient. Therefore, emerging therapies allow to select specific antiblastics that, alone or by integrating the conventional therapeutic approach, may overcome/hinder chemoresistance.
In particular, PARP inhibitors improved prognosis in metastatic BRCA mutated patients [165,166][13][14] and are under evaluation in the neoadjuvant setting; TRK inhibitors showed activity and are approved in rare metastatic breast cancers harboring NTRK fusions and progressing despite previous treatment [171,172][21][22]; sacituzumab govitecan, based on the results of the phase III ASCENT trial, showed a PFS of 5.6 months compared to 1.7 months for patients who received chemotherapies of physician’s choice, and received accelerated FDA approval for pretreated and advanced metastatic TNBC [184][34]. However, some criticism arose around the results and the cost/effectiveness ratio of this trial [227,228][86][87]. PI3K/Akt/mTOR and EGFR inhibitors as well as antiandrogens showed promising results and are under evaluation in Phase II/III clinical trials. Immunotherapy is another interesting option. However, pembrolizumab or atezolizumab combined with CT increased the median PFS 4.1 and 2.5 months, respectively, and the clinical benefit was modest. Only about 40% of TNBCs are PD-L1 + and not all PD-L1 + patients with advanced TNBC respond to PD-L1 inhibitors. It is likely that redundant pathways of immune suppression are active in breast cancer or that important pathways of immune activation are silent. Therefore, new strategies targeting multiple pathways of immunoregulation [229][88] can improve the efficacy of the currently available and other new developed immunotherapies.

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