October 3, 2022

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What are the strategies for personalized treatment of breast cancer?

What are the strategies for personalized treatment of breast cancer?



 

What are the strategies for personalized treatment of breast cancer?

 

Breast cancer (BC) is the leading cause of high (11.7%) cancer-related mortality. In 2020, the number of new cases worldwide was 2,261,419, which is expected to increase to 30.2 million by 2040.

According to the WHO Cancer Profile, BC deaths accounted for 6.9% of all cancer deaths in 2020. Women have a 10% chance of developing breast cancer in their lifetime .

 

What are the strategies for personalized treatment of breast cancer?
Figure 1 Global Cancer Observatory
(Source: http://gco.iarc.fr/)

 

 

Given the complex dynamic and hormonal regulation of breast tissue architecture (Figure 2A), BC requires a clear classification to select the most appropriate treatment.


The first classification was based on histopathological analysis to assess the invasiveness of BC cells . Divided into the following categories (Figure 2B):


• Non-invasive carcinoma. Cancer cells remain confined to the lobular ductal system and do not spread to surrounding tissues.


• Invasive carcinoma. Cancer cells invade surrounding tissue.

 


The second classification is based on the immunohistochemically characterized molecules . Divided into the following categories (Figure 2C):


• Luminal-A subtype. It is characterized by high expression of estrogen receptor (ER) and progesterone receptor (PR), while human epidermal growth factor receptor-2 (HER2) is negative.


• Luminal-B subtype. Characterized by positive overexpression of ER, variable PR and HER2.


• HER2 subtype. It is characterized by amplification and increased expression of the HER2 protein.


• Triple Negative (TNBC). Characterized by lack of expression of three receptors: ER, PR and HER2.

 

 

 

What are the strategies for personalized treatment of breast cancer?
Figure 2 Classification of breast cancer
(Source: https://doi.org/10.3389/fbioe.2021.694218)

 

 

The second classification is currently used clinically . Luminal-A subtype and Luminal-A subtype, as ER-positive BC, can be treated with estrogen antagonists , commonly used drugs include estrogen blocker tamoxifen (Tamoxifen) , aromatase inhibitor Letrozole and ovarian hormone production inhibition Agents Anastrozole and Exemestane5 .

The HER2 subtype can be treated with monoclonal antibodies (mAbs) , including Trastuzumab and Pertuzumab .

TNBC is usually more aggressive than other forms of BC and is generally treated with traditional chemotherapy , taxanes and anthracyclines , and can be treated with chemotherapy in combination with bevacizumab (a vascular endothelial growth factor monoclonal antibody) . But over time, breast cancer treatments also face the risk of patient resistance .

 

What are the strategies for personalized treatment of breast cancer?Figure 3 Summary of general treatment strategies for breast cancer
(Source: https://doi.org/10.1016/S0140-6736(16)31891-8)

 

 

Despite major advances in BC treatment, most patients do not respond to conventional chemotherapy or hormone therapy. Therefore, new therapeutic strategies are urgently needed to combat aggressive BC.

 

 

 

New targeted therapy


CDK4/6 inhibitors. CDK4 and CDK6 kinases form complexes with D-type cyclins and promote cell proliferation through hyperphosphorylated retinoblastoma (RB) proteins, resulting in cell cycle checkpoint inactivation and G1-S cell cycle progression.

CDK4/6 inhibitors block RB checkpoint inactivation and restore endocrine against cell cycle progression. There are three CDK4/6 inhibitors currently approved for the treatment of breast cancer: palbociclib , abemaciclib and ribociclib .

 

PI3K/mTOR inhibitor . Aberrant signaling through the PI3K/Akt/mTOR pathway is a common mechanism by which BC cells acquire drug resistance. mTOR inhibitors can improve the efficacy of trastuzumab and other HER2 inhibitors in mBC combination therapy.

 

 

 

Antibody-Drug Conjugates (ADCs)

 

ADCs consist of monoclonal antibodies (Mabs) against cancer cell surface protein antigens, linker regions and cytotoxic drugs.

After binding to cell surface antigens, the ADC is endocytosed, the linker is cleaved, and the active drug is released. In 2014, trastuzumab–emtansine (T-DM1) became the first FDA-approved ADC.

Currently, sacituzumab govitecan and glembatumumab vedotin have entered late-stage clinical trials.

 

What are the strategies for personalized treatment of breast cancer?

Figure 4 The mechanism of action of ADC

(Source: https://link.springer.com/chapter/10.1007/978-3-030-16391-4_2#citeas )



 

Immunotherapy

 

PDL-1/PD-1 inhibitors

 

Programmed death ligand 1 (PDL-1) and its corresponding receptor on T cells (PD-1) allow tumors to evade immune surveillance.

By inhibiting this checkpoint pathway, T cell-mediated immunity is enhanced.

Humanized antibodies Pembrolizumab and Atezolizumab can inhibit PD-L1 and show good activity in triple-negative breast cancer patients. Avelumab is another PD-L1 antibody that has entered clinical studies in mbC.

 

Other molecules

 

Other molecules that stimulate T-cell immunity are currently being studied in breast cancer, such as antibodies targeting T-cell immunoglobulin and immunosensor tyrosine-based inhibitory motif (TIGIT), T-cell co-stimulatory protein (ICOS) Antibody, an antibody targeting tumor necrosis factor superfamily member 4 (OX40). Antibodies against lymphocyte activation gene-3 (LAG3), etc.


What are the strategies for personalized treatment of breast cancer?

Figure 5. List of major steps in the tumor immune response and the immunotherapies (and treatment combinations) that act on each step.

(Source: https://link.springer.com/chapter/10.1007/978-3-030-16391-4_2#citeas)

 


Oncolytic virus therapy

Oncolytic viruses (OVs) are RNA or DNA attenuated viruses capable of killing tumor cells after infecting them, inducing TME remodeling and antitumor immune responses. Most of the available oncolytic viruses are genetically modified to reduce virulence in non-tumor host cells.

 


Figure 6 Mechanism of oncolytic virus immunotherapy

(Source: https://doi.org/10.3332/ecancer.2020.1149)

 

 

 

DNA-damaging drugs

 

PARP inhibitors. Like all dividing cells, cancer cells experience many “gaps,” or single-strand breaks, during DNA replication. PARP (poly(ADP-ribose) polymerase) 1 and 2 are zinc finger binding proteins that are activated in response to DNA damage and bind and repair single-strand breaks through a base excision repair procedure.

If not repaired, these single-strand breaks can become double-strand breaks and potentially induce apoptosis.

Olaparib is a PARP inhibitor approved for the treatment of patients with BRCA gene germline mutations that are highly responsive to platinum and other DNA damaging drugs such as topoisomerase inhibitors and/or have a specific gene expression profile Ovarian and breast cancer.

 

Figure 7 Mechanism of oncolytic virus immunotherapy

(Source: https://doi.org/10.3332/ecancer.2020.1149)

 

 

 

 

ncRNA therapy

 

Long non-coding RNAs (lncRNAs) have functions in chromatin remodeling, EMT, epigenetic regulation, transcription, and post-transcriptional and post-translational modifications, and are involved in processes such as cell cycle, cell proliferation, apoptosis, and differentiation.

Silencing of oncogenic lncRNAs such as H19, MALAT1, NEAT1 or HOTAIR , or upregulation of tumor suppressor lncRNAs such as GAS5 may help reduce or eliminate drug resistance in breast cancer cells.

 


Figure 8 The role of lncRNA in drug resistance

(Source: https://doi.org/10.1016/j.drudis.2022.03.014)

 

miRNAs are single-stranded RNAs containing ∼22 nucleotides that regulate the expression of various genes. Dysregulation and dysfunction of miRNAs have been implicated in many human diseases, including cancer.

Because of their oncogenic and tumor-suppressive roles in tumor development and progression, miRNAs are considered potential therapeutic targets for BC. miRNA antagonists (antagomiRs) , miRNA sponges , and small-molecule inhibitors impair the function of oncogenic miRNAs, while miRNA analogs promote the activity of tumor suppressor miRNAs.

 

Figure 9 miRNA therapy strategy for breast cancer.

(Source: https://doi.org/10.1016/j.drudis.2022.03.014)

 

In recent years, the advent of new technologies, data-sharing tools , and creative clinical trial designs has provided new perspectives on breast cancer drug development and care and the study of molecular complexity.

Here, we review the growing number of breast cancer treatment strategies that predict that more and more breast cancer patients will benefit from personalized treatment regimens.

 

 

 

 

 

 

references

Yardim-Akaydin, Sevgi et al. New therapy strategies in the management of breast cancer. Drug discovery today (2022). https://doi:10.1016/j.drudis.2022.03.014

Cejalvo, Juan Miguel et al. Oncolytic viruses: A new immunotherapeutic approach for breast cancer treatment?. Cancer treatment reviews( 2022). https://doi:10.1016/j.ctrv.2022.102392

What are the strategies for personalized treatment of breast cancer?

(source:internet, reference only)


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