1Polygence (advised by Khloe Gordon)
*Corresponding author: email@example.com
Triple-Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer that accounts for 10-20% of all breast cancer diagnoses, yet it has a poor prognosis and few effective therapeutic options . Typically diagnosed at grade 3 or above, TNBC grows relatively quickly compared to other breast cancers, and it has a high recurrence rate. A key characteristic of TNBC is that it lacks expression of 3 receptors: the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER-2). The 5-year survival rate of this breast cancer is 91 percent; however if this cancer has metastasized, the survival rate drops to about 11 percent . Here we review current standard therapies available, second-line therapies, and other emerging treatments for this disease with an emphasis on risks associated with specific patient attributes.
TNBC is a devastating cancer with very high metastatic and recurrence rates. It is a very intricate disease with a variety of different subtypes and molecular breakdowns, making it very difficult to treat. TNBC accounts for approximately 15 percent of breast cancers diagnosed worldwide, amounting to almost 200,000 cases each year . Also, TNBC appears to be more commonly diagnosed among black women compared with Caucasian women . Because TNBC is hormone receptor negative and epidermal growth factor negative, TNBC is insensitive to endocrine therapies and other therapies targeting these receptors.
TNBC is an aggressive subtype of breast cancer that is so complex, it can be further broken down into its own 6 subtypes: basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M), mesenchymal stem-like (MSL), immunomodulatory (IM), and luminal androgen receptor (LAR) . These subtypes are characterized by different gene signatures and cellular characteristics (Figure 1).
Figure 1. Description of TNBC subtypes and characteristics. Created with BioRender.com. Adapted from “Intrinsic and Molecular Subtypes of Breast Cancer”, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates
The basal-like subtypes are characterized by the BRCA mutation. The BRCA mutation, a mutation in the BRCA 1 or 2 genes, is a common cause of TNBC, as it is a tumor suppressor gene that regulates DNA growth and repair . Having this mutation drastically increases the chances of developing breast cancer as 55%–72% of women with the BRCA1 mutation and 45%–69% of women with the BRCA2 mutation will develop breast cancer by 70–80 years of age [8, 10, 22]. Some treatments for tumors harboring the BRCA mutation include PARP inhibitors because it damages the DNA of the cancer cells containing mutated BRCA (which are already deficient in DNA repair mechanisms due to the BRCA mutation).
Like many types of cancer, TNBC is also defined by the interaction between the PD-1 and PD-L1 inhibitor pathways, a key modulator of cancer immune surveillance. This interaction is a defining feature in the immunomodulatory subtype of TNBC, but is not limited to this subtype. The PD-1 receptor is expressed on immune cells and acts as an inhibitor of activation and anti-tumor function, while it’s ligand, PD-L1, is expressed by many tissues in the body but is often upregulated in cancer cells, essentially hiding from the tumor cells . Immunotherapies can be used to block this interaction and prevent the inhibition of immune cells (Figure 2). Generally these therapies only work if there is already an immune response present within the tumor.
Figure 2. Mechanism of action for checkpoint inhibitors targeting PD-1 and PD-L1. Created with BioRender.com. Adapted from “Immune Checkpoint Inhibitor Against Tumor Cell”, by BioRender.com (2021). Retrieved from https://app.biorender.com/biorender-templates
Standard Treatment of Care for Triple-Negative Breast Cancer
For early stages of localized TNBC, surgery and adjuvant or neoadjuvant chemotherapy are the standard first line treatment. For early stage disease that has not yet metastasized, surgery is used to remove smaller tumors. However, if the tumor is large or present in the lymph nodes, radiation can also follow surgery. For more advanced tumors, chemotherapy is the most common course of action . Chemotherapy drugs that are often used include docetaxel, doxorubicin, anthracyclines, taxanes, capecitabine, gemcitabine, and cyclophosphamide .
However, for more advanced metastatic TNBC, more aggressive forms of treatment may be required. Platinum-based chemotherapies, specifically cisplatin and carboplatin, are typically used for TNBC that harbor the BRCA mutation. Both are alkylating agents that stop tumor growth by cross-linking guanine bases and adding alkyl groups to cause DNA damage and induce cell death [37, 39, 40].
Carboplatin is often used in combination with paclitaxel, a chemotherapy drug, to get the most effective results [37, 39]. Both cisplatin and carboplatin are most effective as neoadjuvant treatments. Cisplatin displays a slight survival advantage over carboplatin, but they both offer a can serve as a relatively effective treatment for local TNBC [39, 40]. Neoadjuvant treatment with cisplatin and carboplatin resulted in a high pathologic complete response rate for BRCA-1 mutation carriers. They also show a high pathological complete response (pCR) rate, rate of disappearance of all invasive cancer, BRCA mutated, metastatic TNBC . In a very early study in 2015, Carboplatin administration, when given prior to chemotherapy, was shown to increase the 3 year survival rate for non-relapsed patients to 85.5% compared to 76.1% with just chemotherapy .
Like many chemotherapies, these platinum-based drugs carry a risk of inducing hematological toxicity, including neutropenia, anemia, leukopenia, lymphopenia, and thrombocytopenia . Therefore, platinum-based chemotherapy may not be the right form of treatment for an immunocompromised patient, or a patient who already has a low red blood cell or platelet count due to other causes. Carboplatin is not recommended for patients who are pregnant, and cisplatin is not recommended for patients who are breastfeeding [12, 40].
Second-line Treatment Options
As the TNBC becomes more advanced, the treatment options become more intricate as well. Most of these treatments are considered second-line treatments, which can follow standard treatment upon relapse or disease progression. PARP inhibitors are a type of treatment for metastatic TNBC arising from the BRCA-1 mutation. The 2 main PARP inhibitors used for TNBC are Olaparib (Lynparza) and Talazoparib (Talzenna) [21, 31]. Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes — PARP 1, PARP 2, PARP 3 . Since PARP enzymes are involved in normal cell homeostasis, Olaparib is able to obstruct overall tumor growth . It is typically used as a monotherapy, or as follow-up treatment to platinum-based therapies . Talazoparib is also a poly (ADP-ribose) polymerase inhibitor, inhibiting PARP1 and PARP 2 . The efficacy of olaparib was a 56.3% objective response rate in a study done in February 2021 . The FDA approved Talazoparib for treatment of HER negative, advanced breast cancer in October of 2018 . In the FDA study, the primary efficacy outcome was a median progression free survival (PFS) of 8.6 months for treatment with talazoparib compared to 5.6 months for regular treatment, where the control group was receiving a placebo .
Some common adverse effects of these PARP inhibitors include anemia, neutropenia, leukopenia, thrombocytopenia, nasopharyngitis/upper respiratory tract infection/influenza, respiratory tract infection, stomatitis–a condition that causes painful swelling and soreness inside the mouth, and alopecia–an autoimmune disorder associated with hair loss [16, 23, 25, 26 41]. If the patient has a history of chronic respiratory tract infections or other issues regarding the respiratory tract or low white blood cell, red blood cell, or platelet count, this treatment may not be the right treatment for the patient. Both olaparib and talazoparib are not recommended for pregnant patients [16, 23, 25, 26 41].
Immunotherapy is another class of advanced treatment options,and in the treatment of TNBC, has focused on preventing the PD-1 and PD-L1 interaction. The two primary immunotherapies used for TNBC are Atezolizumab (Tecentriq) and Pembrolizumab (Keytruda) [24, 34, 36]. Atezolizumab is often used in combination with paclitaxel. It is a humanized IgG antibody that binds to PD-L1, preventing its interaction with PD-1 and B7-1.2 . Pembrolizumab is a highly selective IgG4-kappa humanized monoclonal antibody against the PD-1 receptor [24, 36]. By inhibiting the interaction of PD-1 and PD-L1, these monoclonal antibodies cause a shift in the activation state of tumor-specific immune cells by alleviating inhibitory signals, thereby increasing anti-tumor immune response. In March of 2019, the FDA approved atezolizumab for PD-L1 positive metastatic TNBC . The efficacy for atezolizumab and paclitaxel treatment was a median PFS of 7.4 months versus a median of 4.8 months without atezolizumab. Also, the overall response rate was 53% with the immunotherapy treatment versus 33% without it (placebo). This study done by the FDA shows that atezolizumab has a promising future in TNBC treatment. In July of 2021, the FDA approved pembrolizumab for high-risk, early-stage TNBC . Pembrolizumab with neoadjuvant chemotherapy showed a 63% pCR rate out of 1174 patients compared to a 56% pCR rate for patients who just received chemotherapy, displaying that the treatment is not as promising as atezolizumab .
The common adverse reactions of immunotherapy treatment of either atezolizumab or pembrolizumab are asthenia, dyspnea—or difficulty breathing, alopecia, peripheral neuropathy—damage to the peripheral nerves that causes muscle weakness and numbness, mucosal inflammation—which causes abdominal pain with a burning or tingling sensation, stomatitis, insomnia, anemia, and neutropenia [14, 15]. For these symptoms, a patient who already suffers from a condition that causes difficulty breathing, has a low white or red blood cell count, or already suffers from conditions regarding the intestines may not consider this treatment as it could worsen health severely. Pembrolizumab should not be used during pregnancy and atezolizumab isn’t recommended during pregnancy [14, 15].
Antibody-Drug Conjugate (ADC) therapies are another advanced treatment option that are designed to deliver potent molecules to cancer cells. These ADC’s consist of an antibody that is specific for a tumor-associated antigen linked to a drug that is meant to inhibit growth of the tumor (Figure 3) . This serves as a more targeted treatment as it harms only the tumor cells and not healthy, normal cells. One of the few FDA-approved ADC is sacituzumab govitecan . Some other ADC’s in earlier stages are ladiratuzumab vedotin, trastuzumab deruxtecan, AVID100, U3-1402, CAB-R0R2-ADC, and Anti-CA6-DM4 . These drugs are used with various different kinds of antibodies. Sacituzumab govitecan works by targeting Trop-2, which is an intracellular calcium signal transducer, and selectively delivering SN-38, an active metabolite of irinotecan  According to the FDA, the median PFS was 4.8 months and the median overall survival was 11.8 months for patients receiving sacituzumab govitecan. This was compared to lower PFS and lower overall survival with patients who just received chemotherapy . This is still in its early stages but is showing promising results for patients of all ages and differing numbers of previous treatments. The FDA granted regular approval to sacituzumab govitecan in April 2021 .
The adverse effects of sacituzumab govitecan are neutropenia, alopecia, anemia, hypophosphatemia—low levels of phosphorus in the blood, and asthenia—or abnormal physical weakness . Thus, patients with very low white blood cell counts or low red blood cell counts prior to treatment should consider not receiving treatment. Also, patients who already have hypophosphatemia due to other causes, or are already suffering from other forms of physical weakness may consider not taking this treatment. Sacituzumab govitecan should not be used if the patient is pregnant .
Figure 3. Composition of antibody-drug conjugates targeting cancer cells. Potent, toxic molecules are delivered in a cancer-specific manner via tumor antigen-specific antibodies to induce apoptosis in the cancer cell while sparing healthy tissue. Created with BioRender.com
The harmful molecules are delivered with the antibody that binds to the antigen (specific to the tumor cell). This makes it a targeted therapy as it only targets the tumor cells and doesn’t harm normal cells. The toxins are delivered into the cancer cell, harming or killing (apoptosis) the tumor cell.
Emerging Treatment Options/ Future of Treatment for TNBC
The mammalian target of rapamycin (mTOR) is a protein from the phosphatidylinositol 3-kinase-related kinase family of protein kinases and is highly active in TNBC as it is involved in tumor regulation, growth, and sensing and integrating multiple signals from growth factors and nutrient signals . It may have a strong involvement in malignant transformation . Inhibiting the PI3K/AKT/mTOR signal pathway is a great mechanism to stop/reduce tumor growth. Currently, such treatments are in early clinical trials and are still developing as a treatment strategy for TNBC.
There is a specific subtype of TNBC that is associated with overexpression of the epidermal growth factor receptor (EGFR). Targeting this pathway appears to be promising, but not much research seems to be present of the growth factor receptor itself .
There is also a new development in the scientific realm of mRNA vaccines, and this may be a future possibility in treating cancer .
Triple Negative Breast Cancer is a very deadly form of breast cancer that does not express hormone receptors (estrogen and progesterone receptors) nor the human epidermal growth factor (HER 2). Since these receptors cannot be targeted, the therapeutic options have historically been limited to standard chemotherapy and radiation following surgery, if possible. However, a number of treatments for TNBC have arisen in the last couple of decades and are producing marginal benefits over standard treatments, but they represent promising new avenues for approaching treatment of TNBC. With so many promising treatments under development, this paper attempted to explore their utility and their implications for specific patient cohorts. These emerging treatments are in the early stages of development and, per FDA regulations, are typically only used as second line treatments following standard therapy, or—in dire cases—may be used in compassionate use cases. As the scientific field continues to expand, new aspects of treatment will continue to emerge, leaving the future of TNBC treatment very bright.
Tanya Ghai, Youth Medical Journal 2022
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