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Introduction
Triple negative breast cancer is an aggressive subtype of breast cancer which do not have any receptors that are commonly found in other subtypes of breast cancer. It shows negative for the progesterone receptors (PR), estrogen receptors (ER) and human epidermal growth factor (HER2) protein. About 12 to 20 percent of all breast cancers are triple negative breast cancer and it is associated with poor survival rate [1]. Its recurrence and metastasis rates are higher compared to other breast cancer (BC) subtypes with the median overall survival only about 9 to 12 months [2]. TNBC has the least number of therapeutic options among the subsets of breast cancer because of lack of well-defined targets. This paper aims to discuss and compare different treatment techniques for triple negative breast cancer (TNBC).
Pembrolizumab and immunotherapy
Programmed cell death protein 1 (PD-1) is a protein on the surface of cells that protects the human body’s cells from the body’s immune system. PD-1 inhibitors are a class of drugs that block PD-1 to activate the immune system to attack cancer cells. The drug pembrolizumab is a monoclonal antibody which belongs to the class. In a study [3], pembrolizumab was given intravenously at 10 mg/kg every two weeks to heavily pre-treated patients with advanced TNBC. It gave preliminary evidence of the safety and efficacy of the drug. A decrease from the baseline in tumor burden was seen in 37.5% of the patients and the disease control rate was 25.9%.
An advantage of this method is that pembrolizumab is an established successful treatment for advanced melanoma. This guarantees the safety of the drug. But this study is limited because only 26 evaluable patients were tested. We cannot rely completely on the evidence. Another limitation is that 56.3% of patients experienced at least one treatment-related toxicity. The study also shows that patients with increased lactate dehydrogenase levels cannot profit from treatment.
Platinum-based chemotherapy
When mutations arise in BRCA1/2 gene, there is an increased risk of breast cancer. About 80% of breast cancers which occur due to a BRCA1 mutation are TNBC. Cisplatin and carboplatin are drugs with platinum. When they bind with DNA, they interfere with its repair mechanism leading to cell death. In a study [4], patients with metastatic or locally recurrent unresectable TNBC are given either cisplatin (75 mg/m2) or carboplatin (at area under the time concentration curve 6) every three weeks. Cisplatin therapy had a response rate of 32.6% while the carboplatin had response rate of 18.6%. Progress was seen in 33% of the patients.
Cisplatin therapy shows a high response rate when compared to other trials treating TNBC patients. Both cisplatin and carboplatin are only mildly toxic. One limitation is that the response rate varies when compared with other similar trials [5] but the study does shed some light on this treatment not working on people with low homologous recombination deficiency (HRD) scores. The testing population of 86 patients was small in this study.
Precision combination therapy
In a study [6], amphiphilic co-polymer P (MEO2MA-co-OEGMA-co-DMAEMA)-b-PLGA is used as a building block for a core structured nanoparticle. Doxorubicin and paclitaxel are loaded into the hydrophilic core and hydrophobic layer of the nanoparticles while the small interfering RNA is absorbed onto the surface of the nanoparticle. This structure is the modified with PDA at the outer layer and named NP-DTS-PDA. This drug is injected intravenously into mouse affected with tumor. When NP-DTS-PDA treatment was followed by laser irradiation, significant levels of karyolysis and apoptosis were observed. Eighty percent of the tumor cells died when this method which combines chemotherapy, gene therapy and photothermal therapy was used. NP-DTS-PDA had sensitized the cancer cells to chemotherapy.
This method shows significant results in reducing tumor size and almost no major side effects. The drugs are not toxic. All the results have proper evidence and data backing it up. One limitation is that this has only been tested in mouse. We do not yet know its affects and efficacy on humans.
Sacituzumab govitecan-hziy
Trop-2 is a human gene which plays a role in the proliferation of cells. This gene is overexpressed in tumor cells and helps in its proliferation. Sacituzumab govitecan-hziy is a drug that delivers high concentrations of the antibody SN-38 to tumor cells. Sn-38 is an antibody that targets Trop-2 and kills the cancer cells. In this study [7], 108 pretreated patients were given Sacituzumab govitecan-hziy (10 mg/kg). The response rate was 33.3% and the clinical benefit rate was 45.4%.
This method is the first FDA approved antibody-drug conjugate for TNBC treatment. It shows a good response rate over a diverse population and it was deemed safe and effective. There are some side effects including nausea, anemia, fatigue, and diarrhea. The median overall survival was 13 months which is a good number for this disease.
Combined CDK4/6 and PI3Kα Inhibition
CDKs are cyclin dependent kinase which helps regulating cell cycles. PI3Kα or Phosphoinositide 3-kinases are enzymes which helps in proliferation and growth of cells. Inhibiting both will increase apoptosis in cancer cells. In a study [8], the drugs BYL719, LEE011 and PD991 were given to mouse in different dosages to find out the immune response, safety and efficacy. The combination of BYL719 and LEE011 showed an increase in DNA damage and apoptosis of cancer cells.
The tumor volume decreased significantly with the drug combination. No side affects were mentioned in the study. As these tests were run in a mouse model, we do not know how humans will be affected from it. There is not enough evidence to back up the results.
Discussion
Immunotherapy showed a lot of adverse side effects while the results varied in the studies involving platinum-based chemotherapy. Even though these two techniques showed good disease control and response rate, these methods would not be advised due to its limitation. The combined drug inhibitors did not have much evidence backing it up too. The better treatments that we have for treating TNBC would be precision combination therapy and Sacituzumab govitecan-hziy. As the later is approved by the FDA and has good response rates, that will the preferred method now. Precision combination therapy has shown good results and proof. It has a lot of potential to be the best therapeutic option in few years. Overall, there is not much research on TNBC which is a very important field. Development in this area should be encouraged.
Conclusion
The advantages and limitations of five therapeutic techniques of triple negative breast cancer were reviewed. Sacituzumab govitecan-hziy is the best current technique among the five while precision combination therapy has promise to be the best in near future.
References
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