By Dr. Praseetha a/p Prabakharan
Breast cancer is a heterogeneous disease comprising of cells with stem cell properties to more differentiated cells which determines the fate of the disease. GLOBOCAN 2020 has ranked female breast cancer as the most frequently diagnosed cancer with a total of 2.3 million new cases (11.7%) and 5th most death causing cancer globally. In Malaysia, lack of awareness and being in a state of denial among women is presumed to be the leading cause of increased number of cases as well late stage diagnosis. As such, it is pivotal for all women to be aware of breast health, diagnostics options, types of breast cancer and the prognosis. Breast cancer is often treatable with good prognosis if the cancer is detected at an early stage. In order to be detected at early stages, it is crucial for all women to have regular examination of the breast which includes physical examination at home to detect lumps on the breasts, abnormal growth detection via mammogram and ultrasound as well as screening of cancer markers via blood tests.
For someone who is newly diagnosed with breast cancer, knowing the subtype and stage of breast cancer is important as the treatment proposed would be completely dependent on these 2 factors. In the past, Breast cancer has been staged based on the size and the location of the tumor in the breast/body parts. However, in the recent years with extensive research conducted around the globe, the diagnosis of breast cancer is made based on more significant characteristics which are the molecular subtypes and expression of specific genes/markers in the tumor. There are 5 know subtypes which include Luminal A, Luminal B, HER2 over expression, Triple Negative (TN), and Normal-like breast cancers. These subtypes are characterized based on the protein receptors (Oestrogen@ER, Progesterone@PR and HER2) expressed by the tumors. Receptors are proteins on the surface or inside a cell in which a signal binds to it to activate a signalling pathway. In general, growth hormones and growth factors act as the signal molecules which bind to these respective receptors and consequently activate cell growth. It should be noted that these hormone and growth receptors are needed for healthy cell growth, however, overexpression of these receptors often lead to uncontrolled growth (proliferation). For instance, the ER and PR hormone levels are commonly elevated during the menstrual cycle, pregnancy and lactating mothers and not otherwise. Therefore, it is recommended for women experiencing hormonal imbalance to seek advice from a doctor as some breast cancer develop due to hormonal issues including ER and PR. In general, the ER, PR and HER hormone/growth factors play important role in communicating with the breast cells to grow. This event is especially seen in the ER, PR and HER overexpressed breast cancers in which breast cells grow in an uncontrolled manner.
The Triple Negative Breast Cancer (TNBC) is considered a rare and aggressive form of breast cancer that lacks the hormonal (ER and PR) and HER2 receptors, hence the name Triple Negative. TNBC is defined as the negative expression (absence) of ER, PR and HER2 receptors. These receptors are commonly targeted to treat the related breast cancers leading to better prognosis and increased survival rates among patients. In general, TNBC accounts for about 15-20 % of breast cancers and are more prevalent among females below the age of 50 and mutations in the breast cancer susceptibility gene 1 (BRCA1). Many people are unaware of the existence of the TNBC subtype as it was only identified in 2006 and therefore, extensive studies are required and are still on going. It can be scary and overwhelming to hear and not understanding new terms.
As TNBC tumors lack the expression of ER, PR and HER2 receptors, this particular subtype of breast cancer is unable to be treated via a targeted therapy as seen with the other subtypes mentioned in Table 1. In addition to that, TNBC can be further be characterized into more distinct subtypes and features which make this breast cancer type very different and require in depth study on the tumor cell biology in order to design potential targeted therapies. As such, the prognosis of TNBC is considered poor and makes it an invasive form of breast cancer . Currently, chemotherapy is the main standard of care for treating TNBC . Early stages of TNBC are known to respond well to chemotherapy and are commonly treated using drugs such as platinum-based drugs (cisplatin, carboplatin) and taxanes. However, the chemosensitivity of TNBC is often short lived and acquire resistance with later stages and time leading to relapses and distal metastases. This acquired resistance and metastatic ability of TNBC can be correlated with the presence of a subpopulation within the tumor known as the Cancer Stem Cells (CSCs), or Tumor Initiating Cells (TICs). The CSCs/TICs are known to possess the same characteristics as normal tissue stem cells which are able to repair cell damage and similarly the CSCs are resistant to chemotherapeutic agents . In other words, TNBC tumors possess the ability to repair and renew themselves post treatment which would explain the relapses and metastases in patients. Thus, targeting cancer stem cells has become a major interest in the treatment of breast cancer as well as other difficult to treat cancers enriched with the CSCs/TICs. Targeting the CSCs/TICs is believed to be able to interrupt the cell communication and consequently the related signalling pathways involved in breast cancer stem cell (BCSC) maintenance and survival .
In parallel with studies on potential treatment via targeting CSCs/TICs, studies on targeting checkpoint inhibitors correlating with BRCA1 mutations and BCSCs (such as Poly ADP-ribose polymerase (PARP) inhibitor, androgen receptor, Epidermal Growth Factor receptor (EGFR) have shown promising results. Targeting of these checkpoints with an inhibitor drug would lead to the inhibition of tumor growth and development and have shown positive outcome is patients tested under different clinical trial phases. In addition, the immune checkpoint inhibitors, mainly targeting the programmed death receptor 1 (PD-1) and its ligand (PD-L1) have also shown promising results in TNBC patients expressing high levels of the PD-1/PD-L1 . Previous studies have shown a clear relationship between TNBC and its host immunity which aided in enhanced survival among patients with early stage TNBC. Just last year, FDA had approved the very first immunotherapy drug against PD-L1 for breast cancer in which people with TNBC treated with this immunotherapy along with chemotherapy have revealed significant survival benefit . An important key to designing novel therapeutic agents/strategies is to have proper understanding of the mechanism that leads to resistance to help prevent cancer metastasis and eventually increase the survival and quality of life in patients. It is hoped that more such potential targeted therapies will be identified for TNBC and other difficult to treat cancers with all the efforts being put globally to treat and manage cancer. However, despite these potential targeted treatments studied and positive response among TNBC patients to treatment, it is important to take note that the impact and response to a treatment may vary with patients as it depends on the TNBC state (stage, subtype) and the body’s aptitude to respond towards any treatment.
Regardless of the fact that every woman has the risk of getting breast cancer and In addition to treatment received by breast cancer patients, practicing nutritious diet, taking in sufficient amount of fluids and doing regular exercises are key factors to prevent/lower cancer risk, as well as reducing side effects and improving quality of health in cancer patients undergoing treatment. Breastfeeding has also shown to reduce breast cancer risk . Studies have shown that healthy food that includes leafy green vegetables, Fruits (eg: berries, citrus fruits), beans, herbs & spices (eg: ginger, turmeric, black cumin) that are enriched with vitamins, fatty acids, fibre and antioxidants help to reduce the risk of breast cancer. There are various studies on the effect of dietary natural products and their bioactive compounds that possess significant anticancer properties and have proven to sensitize breast tumor cells to chemotherapy and radiotherapy. In addition to the nutritious diet, regular exercises are very important in order to stay active and prevent obesity which aids in lowering the risk of many cancers as well as to regulate hormone levels in our body. Erroneous/ imbalanced hormonal regulation can contribute to breast and other cancers as well.
In conclusion, educating oneself on the breast cancer basics can help one understand how triple-negative breast cancer is different from the other types of breast cancer as well as the steps to be taken for proper management of the cancer, be it preventive or post diagnosis measures.
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