Common Treatment Methods for TNBC
Molecular Subtypes of TNBC
TNBC is characterized by molecular heterogeneity, which comprises distinct subtypes with diverse
biological features and
clinical behaviors (Table 1). Understanding these subtypes and their underlying pathogenesis is
essential for guiding
treatment decisions and improving patient outcomes.
Table 1. Molecular subtypes of TNBC[1].
| Subtype |
Molecular features |
Clinical characteristics |
| Basal-like |
Expression of basal cytokeratins (CK5/6, CK14, CK17), TP53 mutations |
High histological grade, aggressive phenotype, poor prognosis |
| Mesenchymal (M) |
Upregulation of genes associated with epithelial-to-mesenchymal transition (EMT)
|
Increased motility, invasiveness, resistance to therapy |
| Immunomodulatory (IM) |
Upregulation of immune response genes, enrichment of tumor-infiltrating lymphocytes
(TILs) |
Better prognosis, higher response rates to immunotherapy |
| Luminal androgen receptor (LAR) |
Expression of androgen receptor (AR), luminalassociated genes |
Less proliferative, luminal-like features, may have better prognosis |
The accurate diagnosis of TNBC is vital for informing treatment decisions and forecasting
patient outcomes. However,
diagnosing TNBC remains challenging due to difficulties in identifying specific biomarkers,
evaluating tumor heterogeneity,
and distinguishing it from other breast cancer subtypes.
Figure 1. Diagnostic challenges in triple negative breast cancer[1].
Therapeutic Strategies for TNBC
TNBC poses significant therapeutic challenges due to the absence of specific molecular
targets——such as ER,
PR, and HER2——that are
typically targeted in other breast cancer subtypes. Consequently, TNBC management relies on a
multimodal approach, which includes chemotherapy, surgery, and radiation therapy, along with
emerging targeted therapies and immunotherapeutic agents (Figure 2).
Figure 2. Therapeutic strategies for TNBC[1].
• Chemotherapy
As the cornerstone of TNBC treatment across all stages, chemotherapy can shrink tumors using
anthracycline
(e.g.,
doxorubicin and
epirubicin) -
cyclophosphamide regimen, and can improve pathological
complete response (pCR)
rates by adding taxanes (e.g.,
paclitaxel and
docetaxel) in neoadjuvant settings. Platinum
agents work well for
BRCA-mutated patients, while novel agents and combination regimens are under development
[3].
• Surgery
Surgery aims to achieve complete tumor resection and local disease control, with options of
breast-conserving surgery (lumpectomy)
or mastectomy. Sentinel lymph node biopsy evaluates lymph node involvement, and some patients
undergo neoadjuvant chemotherapy first
to downstage tumors for breast conservation[4].
• Radiation Therapy
Radiation therapy is a key component of TNBC multidisciplinary management. Preoperative
radiotherapy reduces recurrence risk and improves
survival with manageable toxicity, while its combination with chemotherapy enhances pCR rates
(23%-71%). Moderate hypofractionation regimens
show promise but require further evaluation for long-term efficacy[5].
• Emerging Targeted Therapies
Table 2. Emerging targeted therapies, mechanisms and clinical trials for TNBC[1].
| Target |
Therapeutic agent |
Cat. No. |
Mechanism of action |
Clinical trials and results |
| PARP |
Olaparib |
HY-10162 |
Inhibits PARP enzyme, leading to DNA damage and cell death |
Phase III trials.
(OlympiAD, EMBRACA) demonstrated improved
progression- free survival in BRCA-mutated TNBC |
| Talazoparib |
HY-16106 |
| Niraparib |
HY-10619 |
| AR |
Enzalutamide |
HY-70002 |
Blocks AR signaling pathway |
Phase II trials showed promising activity in AR-positive TNBC |
| Bicalutamide |
HY-14249 |
| EGFR |
Cetuximab |
HY-P9905 |
Inhibits EGFR signaling pathway |
Limited efficacy in unselected TNBC patients |
| Geftinib |
HY-50895 |
| PI3K/AKT/mTOR pathway |
Everolimus |
HY-10218 |
Inhibits PI3K/AKT/mTOR signaling pathway |
Phase II trials ongoing, with mixed results in TNBC patients |
| Alpelisib |
HY-15244 |
• Immunotherapy in TNBC
PD-1/PD-L1 inhibitors (e.g.,
Pembrolizumab) combined with chemotherapy have been FDA-approved for
neoadjuvant therapy, improving
survival of PD-L1-positive patients. Clinical trials such as TORCHLIGHT have demonstrated that
immunotherapy plus chemotherapy
prolongs
progression-free survival (PFS) in advanced TNBC.
Meanwhile, CAR-T therapies targeting ROR1/MUC1 and tumor vaccines are
under active development
[7].
Table 3. Immunotherapy in TNBC[1].
| Therapeutic agent |
Cat. No. |
Mechanism of action |
Clinical trials and results |
| Pembrolizumab (anti-PD-1) |
HY-P9902 |
Blocks PD-1/PD-L1 interaction, enhances T-cell-mediated anti-tumor immune response
|
KEYNOTE-086, KEYNOTE-119 trials demonstrated improved overall response rates and
survival in PD-L1-positive TNBC |
| Atezolizumab
(anti-PD-L1) |
HY-P9904 |
Blocks PD-L1 interaction with PD-1, enhances T-cell activation and anti-tumor
immunity |
IMpassion130, IMpassion131 trials showed improved progression-free survival in
PD-L1-positive TNBC patients |
• Precision Medicine Approaches
Precision medicine formulates regimens based on tumor molecular characteristics: genomic
profiling (e.g., NGS) identifies genetic
alterations and potential therapeutic targets, thereby enabling targeted therapies that
selectively inhibit pathogenic molecules to
enhance efficacy and reduce toxicity for personalized treatment[8].
Drug Resistance in TNBC Treatments
Chemotherapy Resistance Mechanisms
Chemotherapy remains a first-line treatment for TNBC in current clinical practice, with
taxanes and anthracyclines as standard regimens.
Platinum-based therapies have also shown efficacy in metastatic TNBC. However, most patients
eventually develop chemotherapy resistance
during treatment, reducing efficacy and contributing to TNBC’s higher recurrence rate
compared
with other breast cancer subtypes[9].
Chemotherapy resistance arises from intrinsic, acquired, and overlapping mechanisms.
Intrinsic factors include
ABC transporters
(e.g., ABCG2, ABCC1, ABCB1) that reduce intracellular drug accumulation, tumor
heterogeneity, anti-
apoptotic signaling
(e.g.,
BCL-2 upregulation,
p53 loss), and metabolic reprogramming (e.g., glycolysis, fatty
acid oxidation). Overlapping
factors involve BCSC self-renewal and aberrant signaling (e.g.,
NF-κB, PI3K/AKT/mTOR), while
acquired mechanisms such as
hypoxia (e.g., limiting doxorubicin uptake and stabilizing HIF-1α) and the
tumor
microenvironment (e.g.,
CAFs and inflammatory
cytokines promoting metastasis and immune suppression) further exacerbate resistance (Figure
3)
[10].
Figure 3. Mechanisms of chemotherapy resistance in TNBC[10].
Immunotherapy Resistance Mechanisms
Elucidation of tumors’ intrinsic immune evasion mechanisms has enhanced understanding of
immunotherapy responses in breast cancer.
TNBC exhibits higher immunotherapeutic potential due to its elevated tumor mutational burden
and abundant lymphocyte infiltration,
with
immune checkpoint inhibitors (ICIs) representing the
first clinically successful immunotherapy. However, some patients have poor
responses and develop acquired resistance
[11].
Similar to chemotherapy, TNBC also develops resistance to immunotherapy via multiple
mechanisms. Intrinsic mechanisms include altered
TMB and epigenetic modifications that shape tumor growth and the immune microenvironment.
Intrinsic/acquired factors such as loss
antigen presentation (e.g., MAL2-mediated reduction) and aberrant signaling pathways (e.g.,
Ras-MAPK/IFN-γ, PTEN-PI3K/Akt) impair
immune recognition and T-cell infiltration. Acquired resistance involves dysfunctional
immune cells, including exhausted T cells,
impaired NK cell activity, and immunosuppressive populations like TAMs and MDSCs, all
contributing to immune evasion and reduced
response to checkpoint inhibitors (Figure 4)[10].
Figure 4. Drug resistance in immunotherapy for TNBC[10].
Strategies to Overcome Therapeutic Resistance in TNBC
TNBC refractoriness primarily arises from its complex biological characteristics, including
both primary and acquired
resistance to multiple chemotherapeutic drugs. This resistance not only limits therapeutic
efficacy but also significantly
compromises patients’ quality of life and overall survival. Researchers are actively
developing novel therapeutic
strategies to overcome these resistance mechanisms (Figure 5)[10].
Novel Immunotherapies
Chemotherapy resistance in TNBC often increases with prolonged treatment. ICIs have partially addressed this challenge
but cannot overcome all chemoresistance mechanisms, and some patients eventually develop immunotherapy resistance.
Extensive studies have elucidated the main mechanisms of resistance, providing a foundation for the development of
novel immunotherapies targeting TNBC (Table 4).
• Combination of ICIs with Other Therapies
ICIs remain the core of TNBC immunotherapy. Researchers are exploring their combination with
chemotherapy, radiotherapy, etc.,
to reduce resistance and improve efficacy through multi-biological synergy. For example,
pembrolizumab combined with chemotherapy
prolongs median progression-free survival in advanced TNBC. When combined with radiotherapy,
it achieves a higher overall response
rate. Oncolytic viruses have also been shown to enhance ICI efficacy.
• Tumor Vaccines
Reduced tumor immunogenicity in TNBC contributes to immunotherapy resistance. Tumor vaccines
enhance immunogenicity and activate
the immune system by introducing tumor antigens, thereby improving therapeutic efficacy. For
example, ASPH-targeted nano-vaccines
enhance doxorubicin efficacy, and neoantigen DNA vaccines have achieved an 87.5%
recurrence-free survival rate in early studies.
Most vaccines are currently in early clinical stages.
• Cellular Immunotherapy
ICI-resistant TNBC often involves TIL-mediated resistance. Cellular immunotherapy involves
ex vivo activation of immune cells,
such as NK cells or CAR-T cells, followed by infusion to target tumor cells. This approach
is often combined with chemotherapy
to enhance efficacy. For example, cytokine-induced killer (CIK) cells combined with
cetuximab have been shown to inhibit tumor
growth.
• Bispecific Antibody Therapy (BsAb)
TNBC is highly heterogeneous. Bispecific antibodies simultaneously engage immune cells and
tumor antigens to enhance cytotoxicity.
For example, TROP2/CD3-targeted BsAb have demonstrated activity against TNBC, and multiple
BsAbs are currently under clinical
investigation.
• Antibody-Drug Conjugates (ADCs)
ADCs deliver cytotoxic drugs directly to tumor cells with high precision. The FDA has
approved three ADCs for breast cancer:
T-DM1,
T-DXd (HER2-targeted),
and
sacituzumab govetican (Trop-2-targeted), the latter
achieving a 33.3% response rate in
metastatic TNBC with manageable side effects.
Table 4. Strategies to overcome therapeutic resistance in TNBC[10].
| Therapeutic type |
Therapeutic regimen |
Specific drugs |
Cat. No. |
| Novel immunotherapies |
Combination of ICIs and other treatments |
Pembrolizumab combined with Paclitaxel |
HY-P9902
HY-B0015 |
| Tumor vaccine |
The MUC1 peptide vaccine |
/ |
| Cellular immunotherapy |
Combination therapy with haNK + N-803 |
HY-P991077 |
| BsAb |
KN046 |
HY-P99943 |
| ADCs |
Sacituzumab govetican |
HY-132254 |
| Molecular targeted
therapies |
PARP Inhibitors |
Niraparib |
HY-10619 |
| CDK inhibitors |
Abemaciclib |
HY-16297A |
| PI3K/AKT/mTOR pathway inhibitors |
Buparlisib |
HY-70063 |
| EGFR inhibitors |
Cetuximab + Cisplatin |
HY-P9905
HY-17394 |
| VEGFR inhibitors |
Emodin |
HY-14393 |
| Notch inhibitors |
RO4929097 |
HY-11102 |
| Epigenetic modifications |
Niclosamide |
HY-B0497 |
| Targeting regulated cell death |
ENMD-2076 |
HY-10987A |
| Drug delivery systems |
Nab-Paclitaxel + Bevacizumab |
HY-P9906 |
| Other novel therapies |
Photodynamic therapy |
I2BC-Pt |
/ |
| Ferroptosis |
Chemotherapeutics delivered with Ferrocene and GPX4 inhibitor RSL3 |
HY-100218A |
| Fasting-mimicking diets |
Fasting-mimicking diet + Carboplatin-based chemotherapy |
HY-17393 |
| Oncolytic virotherapy |
Oncolytic T-VEC virotherapy + neoadjuvant chemotherapy |
/ |
Molecular Targeted Therapies
Some patients develop resistance to ICIs. TNBC resistance is often associated with gene
mutations, aberrant signaling
pathways, etc. Multi-omics analyses facilitate the identification of therapeutic targets,
enabling the development of
targeted therapies against specific molecules or pathways with reduced side effects (Table
4).
• Targeted Inhibitors
Inhibitors targeting abnormal molecules or signaling pathways in TNBC enable precise
treatment and reduce resistance. Major classes include:
PARP inhibitors: Leveraging BRCA mutations. For example, talazoparib combined with
radiotherapy enhances tumor senescence.
CDK inhibitors: CDK4/6 inhibitors arrest the cell cycle, while CDK7 inhibitors show
efficacy against TNBC.
Other pathway inhibitors: Targeting PI3K/AKT/mTOR, EGFR, VEGFR,
TGF-β, Notch and STAT3 pathways demonstrates anti-tumor activity.
• Epigenetic Modifications
Epigenetic modifications regulate gene expression and can mitigate therapeutic resistance.
For example, LSD1 inhibitor-loaded hydrogels
have been shown to restore chemosensitivity and stimulate anti-tumor immunity in TNBC.
• Targeting Regulated Cell Death (RCD)
Evasion of apoptosis contributes to TNBC resistance. Small molecules targeting regulated
cell death (RCD), such as ENMD-2076,
can effectively induce cancer cell death.
• Drug Delivery Systems
Nanocarrier-based drug delivery systems, including SLR-LNPs and Pos3Aa-p53 crystals, enhance
tumor-targeted drug delivery and improve therapeutic efficacy.
Other Novel Therapies
Multiple novel therapeutic strategies have demonstrated significant potential in overcoming
TNBC resistance, including the following categories:
• Photodynamic Therapy (PDT)
Photodynamic therapy (PDT) relies on photosensitizers, specific wavelengths of light, and
oxygen to generate reactive oxygen
species through photochemical reactions, directly killing tumor cells. PDT also disrupts
tumor vasculature and activates
immune responses. Studies have shown that combining PDT with OXPHOS inhibitor
Rubioncolin C (RC) effectively alleviates
tumor hypoxia and significantly enhances anti-TNBC efficacy.
• Ferroptosis-Inducing Therapy
Ferroptosis-inducing therapy triggers iron-dependent, non-apoptotic cell death through lipid
peroxidation, thereby bypassing
resistance associated with traditional apoptotic pathways. Nano-prodrug systems loaded with
chemotherapeutics, ferrocene and
GPX4 inhibitors, or simvastatin-encapsulated magnetic nanoparticles efficiently induce
ferroptosis in TNBC cells.
• Fasting-Mimicking Diet (FMD)
Fasting-mimicking diet (FMD) regulates cellular stress responses, enhancing the stress
resistance of healthy cells while increasing
therapeutic sensitivity of cancer cells. This approach improves immunotherapy efficacy and
reduces the population of breast cancer
stem cells (BCSCs). Additionally, FMD can inhibit NRAS/IGF1-mediated mTORC1 signaling,
thereby reversing acquired resistance of
TNBC to CDK4/6 inhibitors.
• Oncolytic Virotherapy
Oncolytic virotherapy exploits viruses’ ability to selectively infect and kill tumor cells.
Mumps virus strains
MuV-UA/UC have shown efficacy against chemo-resistant TNBC cell lines. Recombinant measles
virus rMV-SLAMblind
targeting Nectin-4 can inhibit tumor growth without observable toxicity following
intravenous administration.
Figure 5. Strategies targeting drug resistance in TNBC treatment[10].
Summary
TNBC remains a major therapeutic challenge due to its molecular heterogeneity and complex
resistance mechanisms.
Small-molecule inhibitors, characterized by precise targeting, structural flexibility, and
combinatorial potential,
are emerging as important tools to overcome TNBC resistance. By modulating signaling
pathways such as PI3K/AKT/mTOR,
Notch, and STAT3, as well as epigenetic regulation, these agents can reverse resistance and
enhance
treatment sensitivity. The integration of multi-omics data with AI-driven drug discovery is
expected to
accelerate the development of novel inhibitors, providing more precise and effective options
for TNBC.
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Common Treatment Methods for TNBC
Drug Resistance in TNBC
Strategies to Overcome Therapeutic Resistance in TNBC
