Breast cancer can be a pernicious unforgiving disease and is on the rise, the World Health Organisation has reported that it is the leading cause of death in women and it accounts for 15% of all cancerous deaths (World Health Organisation, 2019). The reason why breast cancer deserves a great deal of awareness is because it is perhaps more common than you think. For instance, recent statistical studies have found that one in seven women in the UK will develop breast cancer in their lifetime (Cancer Research UK, 2019). Although UK deaths due to breast cancer have declined by 40% within the past 20 years (Evans et al, 2012), there is an overwhelming number of patients undergoing treatment still fighting their battles.
Triple negative breast cancer (TNBC) is the most aggressive sub type of breast cancer which also tragically has the worst prognosis rates and essentially no approved targeted therapy (Liu et al, 2017). Though there is some light, due to the nature of such a morbid disease and high prevalence, a lot of research has gone into finding effective treatments. Fu et al (2019) proposes to use bazedoxifene (a medication used for bone diseases) and paclitaxel (a chemotherapy drug used to treat ovarian, breast and lung cancer) as potential treatments for TNBC. The objective of this article is to raise a fundamental awareness of the limited treatments for TNBC and attempt to allow a fundamental understanding of the potential for new treatments.
What can science already tell us?
Oestrogen is the main hormone made in females, it has such a great responsibility for development, growth and maintenance of the female reproductive system. Oestrogen being supplied by the body at correct concentrations at correct times is crucial. Cancer itself occurs when there is an accumulation of damaged genes and uncontrolled growth. When oestrogen fails to do its job, it gives opportunities for breast cancer. About 80% of all breast cancers are oestrogen positive (ER+) meaning cancer cells grow in response to oestrogen. TNBC accounts for ~20% of breast cancer diagnoses, it occurs surprisingly when oestrogen is not involved, nor any other important hormones that are usually causes of breast cancer (Evans et al, 2012). Normal treatment options for breast cancer work with oestrogen on the agenda however this is futile for TNBC as oestrogen is not the problem here. Since hormones are not fuelling this type of cancer then it won’t be defeated by hormonal therapies. Therefore, treatments for TNBC are very limited, currently what is available are immunotherapy and potentially PARP inhibitors to attempt for a disease-free survival for patients (Cadoo et al, 2013). Immunotherapy is like giving your immune system 20 espresso shots for the first time ever all in one go. Think of your immune system as an army, and the cancer is Goliath; what immunotherapy will do is make your army work harder and smarter to win the fight. Though cancer cells can be very intelligent by pulling a trojan horse and disguising themselves to be harmless and part of the body, immunotherapy helps combat this issue as immune cells are now more valiant. However, it is important to note that immunotherapy is pretty much a rude awakening for your immune system (Emans, 2018). It is not natural that it must work so hard. Giving the immune system this abrupt jump start can lead to autoimmune diseases where your own immune system mistakenly attacks healthy tissue like the liver, lungs, pancreas… pretty much anything! Currently in trials for TNBC treatment are PARP inhibitors (Beniey et al, 2019). Since cancer occurs when there is an accumulation of genes being damaged, PARP inhibitors are enzymes that make cancer cells less likely to survive when their genes are damaged (Ibrahim et al, 2012). Essentially PARP inhibitors attempt to nib the cancer in the bud, but it is still being trialled for TNBC. Immunotherapy and PARP inhibitors still remain to have low response rates for TNBC and high side effects, therefore we need something more. Hence why research has continued in search of a more effective treatment.
What is this new treatment and what does it mean?
Bazedoxifene (pronounced BA-ze-DOX- i-feen) is a clinically approved drug used to treat osteoporosis (a bone degrading disease) in post-menopausal women. Fu et al (2019) understood that bazedoxifene works by blocking oestrogen so they strategically used this drug and tested itseffects as a potential treatment for ER+ breast cancer and TNBC. For ER+ breast cancer, it was found that bazedoxifene blocks oestrogen from helping the cancer get bigger and stronger (Fu et al, 2019). For TNBC bazedoxifene reduces cancer cell signalling, as a result the cancer is not able to grow (Fu et al, 2019). Think of cancer cells as millennial teens addicted to their phones, if you cut off their internet signal they struggle to function. Taking away its communication recourses for growth is a common method of combating cancer. STAT3 is an important protein involved in signalling, it is found in human cancer cell lines. STAT3 promotes cancer growth and is activated in most breast cancer subtypes especially TNBC. Bazedoxifene stops STAT3 and its signals resulting in weaker of TNBC cells unable to communicate (Fu et al, 2019).Essentially what Fu et al (2019)’s study showed is evidence that bazedoxifene inhibits important signals for ER+BC and TNBC, and even more so when in combination with the chemotherapy drug paclitaxel. They showed that by asking and answering a series of questions, this is how research is most often done. First, they asked whether bazedoxifene stops breast cancer cells from working properly. They answered this by testing different concentrations of bazedoxifene on different flavours of breast cancer cells for two days and found a correlation; the more bazedoxifene the weaker the cancer cells got. After confirming the effect of bazedoxifene they then pondered if it works best alone or in combination with paclitaxel. They investigated this by doing 5-hour drug treatments of cancer cells immersed in either bazedoxifene, paclitaxel or in combination. The results showed that the combination treatment had made the cancer cells the weakest (figure 1). Fundamentally what this means is that TNBC patients may have another opportunity to fight their battle against cancer. To answer the question in the title of this article: “Do we finally have an effective treatment?” – perhaps. Results are certainly promising for TNBC as Fu et al (2019) has showed us.The exact mechanism of how bazedoxifene works on TNBC remains unknown, I believe this area of research is the next step from what Fu et al (2019) along with extending their work further to clinical human trials. Additionally, the more we understand how something works normally, the better we can solve problems when it goes wrong. Fu et al (2019)’s research is not a magic solution; it has given us a start but there are still many questions to be asked and answered. For instance, can the administration process be improved? Fu et al (2019) administered bazedoxifene to mice through a tube and then paclitaxel via injection in stomach. For human trials, could there be an easier administration process? Side effects in animal models were not mentioned therefore human trials would being more insight. Although rare, TNBC in males can occur and it is worth investigating whether the treatments Fu et al (2019) describes are also relevant to males. Scientific research is driven by asking and answering questions, the more we understand the better we can solve the issues society are facing. We owe it to TNBC patients to do our very best to raise awareness, increase our knowledge, and make the most of their quality of life.
In little dishes Fu et al (2019) shows cancer cells and the effect of bazedoxifene, paclitaxel and a combination of both. The purple markings are cancer cells (from the 4T1 line). DMSO shows the cancer where no additional drugs are preventing its growth. The B1 is bazedoxifene and clearly reduces the amount of cancer cells as does P0.05 which is paclitaxel. However, in combination (B1+P0.05) there is such little cancer cells left that we cannot see any purple with our eyes. Confirming that bazedoxifene and paclitaxel combined is effective in fighting cancer cells. To ensure the validity of what Fu et al, (2019) have claimed to find, statistical analysis is used. Essentially this is just a way to confirm results did not occur randomly by chance but there is real correlation. Rest assured Fu et al (2019)’s results can be trusted as their data analysis came back significant, meaning that there is a genuine cause behind their experiments, and we can use this data to explore further.
What is the future for TNCB treatments?
Bazedoxifene and paclitaxel is already a clinically approved treatment, meaning it is on the market and being used by patients. Therefore, combined bazedoxifene and paclitaxel will be quick to bring to market as a treatment for TNBC patients unresponsive to immunotherapy and PARP inhibitors.
Fundamentally what this means is that TNBC patients may have another opportunity to fight their battle against cancer. To answer the question in the title of this article: “Do we finally have an effective treatment?” – perhaps. Results are certainly promising for TNBC as Fu et al (2019) has showed us.
The exact mechanism of how bazedoxifene works on TNBC remains unknown, I believe this area of research is the next step from what Fu et al (2019) along with extending their work further to clinical human trials. Additionally, the more we understand how something works normally, the better we can solve problems when it goes wrong. Fu et al (2019)’s research is not a magic solution; it has given us a start but there are still many questions to be asked and answered. For instance, can the administration process be improved? Fu et al (2019) administered bazedoxifene to mice through a tube and then paclitaxel via injection in stomach. For human trials, could there be an easier administration process? Side effects in animal models were not mentioned therefore human trials would being more insight. Although rare, TNBC in males can occur and it is worth investigating whether the treatments Fu et al (2019) describes are also relevant to males. Scientific research is driven by asking and answering questions, the more we understand the better we can solve the issues society are facing. We owe it to TNBC patients to do our very best to raise awareness, increase our knowledge, and make the most of their quality of life.
References
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Ibrahim, Y.H., García-García, C., Serra, V., He, L., Torres-Lockhart, K., Prat, A., Anton, P., Cozar, P., Guzmán, M., Grueso, J. and Rodríguez, O., 2012. PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple- negative breast cancer to PARP inhibition. Cancer discovery, 2(11), pp.1036-1047.
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