Global Health Challenges

What is PCOS?

Polycystic ovary syndrome (PCOS) is an endocrine disorder which features amenorrhea, hyperandrogenaemia, and enlarged ovaries with multiple cysts (Sirmans & Pate, 2013). PCOS has shown to be present in over 10% of women of childbearing age and in severe cases causing infertility (March et al, 2010). More than 50% of women with PCOS are obese (Butterworth, Deguara & Borg, 2016). To improve quality of life for these women many lifestyle altercations are required however this only works to an extent (Harris-Glocker et al, 2010). For women with a body mass index (BMI) of over 40kg/m² or a BMI of over 35kg/m² with an obesity related condition which would be improved with weight loss (such as diabetes type 2 or high blood pressure), bariatric surgery is a solution (nhs.uk, 2017). Pathophysiology mechanisms of PCOS in relation to amenorrhea (the absence of menstruation) will be considered along with current drug interventions. How bariatric surgery affects the fertility of PCOS patients will also be discussed in further depth.

How PCOS leads to amenorrhea  

PCOS patients who are obese exhibit impaired ovulation and decreased pregnancy rates relative to PCOS patients at healthy BMI’s (Tziomalos and Dinas, 2018). The basic lesion of PCOS is an endocrinological disturbance within the ovary, which has been associated with excess androgens and other extra-ovarian hormonal abnormalities such as hyperinsulinemia, hirsutism and increased LH:FSH ratio (Palomba, 2018) as seen in figure 1. However individually these endocrinological associations with PCOS do not explain the pathogenesis, suggesting there are wider causes and contributions to the mechanism pathway (Palomba, 2018). 

The pathophysiology of PCOS is not yet fully understood however Rotstein (2013) proposes that hyperandrogenaemia is causing an arrest in antral follicle development, which leads to anovulation and so there is no corpus luteum, resulting in subfertility or amenorrhea (Rotstein, 2013) (figure 1). A more recent study by Butterworth, Deguara & Borg (2016) suggests that insulin resistance and hyperinsulinemia are the key pathophysiological mechanisms (Butterworth, Deguara & Borg, 2016). Although the complex interaction between environment, genetics and lifestyle have heavy impacts on fertility, the exact aetiology is still unknown (Butterworth, Deguara & Borg, 2016). Intrauterine androgen exposure is in question as a contributing factor of anovulation, as Dumesic et al (2018) has shown that pregnant women with PCOS have elevated testosterone, but it is not yet clear if the foetus is exposed to the increased androgen levels (Dumesic et al, 2018). A study investigating the aromatase activity of the placenta would provide insight and potentially confirm if intrauterine androgen exposure directly contribute to anovulation of PCOS patients (Palomba, 2018). If this mechanism is more understood then a suitable intervention may be able to prevent foetal androgen exposure. 

To combat subfertility, the first-line drug therapy used to induce ovulation is oral anti-oestrogen clomiphene citrate (CC) or letrozole (Balen et al, 2016). CC works by blocking hypothalamic and pituitary oestrogen receptors, it also induces a discharge of FSH which triggers regular ovulation (Homburg and Filippou, 2016). Insulin resistance is a common feature of PCOS, there has shown to be a correlation between insulin resistance and CC resistance (Kar, 2012). In such cases of insulin resistant PCOS patients, letrozole was a suitable alternative (Kar, 2012). Letrozole is an aromatase inhibitor which acts by reducing oestrogen production by blocking androgens which would balance the androgen levels, preventing the subfertility (Kar, 2012). As figure 1 portrays, metformin is also a common drug used to reduce hyperinsulinemia and ameliorate hyperandrogenism in obese and non-obese patients (Sam and Ehrmann, 2017). For PCOS patients with insulin resistance, studies reveal that metformin has been successful in inducing regular ovulatory cycles and efficient weight loss (Sam and Ehrmann, 2017). Although not all PCOS patients display insulin resistance therefore metformin drug is specific to PCOS patients with insulin resistance.  

CC, letrozole and metformin are effective treatments to induce ovulation however drugs are metabolised differently in patients therefore its effectiveness will vary (Roque et al, 2015). Lifestyle modification remains to be the best first step treatment for amenorrhoeic PCOS patients before resorting to pharmacological ovulation induction (Hashim, 2016). For patients who find lifestyle changes to be ineffective and do not benefit from drug therapy may then consider bariatric surgery.

Reproductive considerations for bariatric surgery 

Infertility has shown to be a key reason for PCOS patients seeking bariatric surgery (Christ and Falcone, 2018). PCOS patients were found more proactive in seeking treatment for infertility when compared to amenorrhoeic women without PCOS (Hashim, 2016). Bariatric surgery is a successful management strategy for morbid obesity, however there are limited studies on its effect on patients who exhibit PCOS (Skubleny et al, 2016). PCOS patients are already predisposed to glucose abnormalities and ultimately type 2 diabetes, dyslipidaemia and eventually cardiovascular disease. (Malik and Traub, 2012). Bariatric surgery can be a powerful tool to prevent these fatal consequences and also possibly ameliorate PCOS features (Malik and Traub, 2012). There are three types of bariatric surgery procedures which are most commonly performed (figure 2). These include; Laparospic roux-en-Y Gastric Bypass (LRYGB), Laparospic sleeve gastrectomy (LSG) and Laparospic adjustable gastric banding (LAGB) (Malik and Traub, 2012). 

LRYGB has shown to be most effective especially in cases of diabetic patients, where weight loss and glucose control was successful even after a five year follow up (Dicker et al, 2016), however fertility of these patients were not considered in this paper. Jamal et al (2012) highlighted 10 participants who exhibited PCOS and infertility, after a LRYGB procedure the outcomes resulted in menstrual irregularities corrected with a regular cycle of 82% of patients without the need of hormonal treatment or in vitro fertilisation (IVF) (Jamal et al, 2012). Also 60% of their patients had achieved a successful pregnancy within three years postoperative without any pregnancy induced or postpartum complications (Jamal et al, 2012). Malik and Traub (2012) identified in their study a 68% success rate for LRYGB procedures after a 4 year follow up, though this was with limited data and a small sample size (Malik and Traub, 2012). Doblado et al (2010) highlighted a PCOS patient aged 29, LAGB enabled the patient to achieve a successful pregnancy using in vitro fertilisation (IVF). Hughes (2014) described that LAGB has shown to be the least effective as after a three year follow up, patients often lost an average of only 16% of thei­­r weight whereas LRYGB enabled a 32% average weight loss (Hughes, 2014). LSG is the newest procedure and so there is limited published results, though results do indicate a higher success rate over LAGB (Malik and Traub, 2012). George and Azeez (2013) found success with LSG where results showed the procedure resolved menstrual dysfunction in 100% of PCOS patients and hirsutism and radiological evidence of PCOS was resolved in 80% of patients (George and Azeez, 2013). Although, George and Azeez (2013) did not have a follow up record therefore it is difficult to determine the long term results from this experiment. 

A recent meta-analysis study conducted by Skubleny et al (2016) identified a sample of 2130 obese female patients. 45.6% of these patients exhibited PCOS however after bariatric surgery (mainly LRYGB) there was a significant decrease of PCOS to only 6.8% postoperatively at a one year follow up (Skubleny et al, 2016). Long term data is still limited to confirm if the decreased PCOS symptoms would remain permanently attenuated (Skubleny et al, 2016). The evidence for improvement in fertility after bariatric surgery is still limited but trends do indicate high success rates.

Hopes for the future 

The exact relationship between PCOS and amenorrhea remains unknown however strong indications are that hyperandrogenaemia and hyperinsulinemia are key pathophysiology mechanisms (Butterworth, Deguara & Borg, 2016). Lifestyle altercations and drug therapies are effective treatments, however they only work to an extent for some patients (Roque et al, 2015). Several studies indicate that bariatric surgery improves diagnostic features of PCOS in patients (Christ and Falcone, 2018). Though limitations in these studies are substantial, as there are many criteria of infertility which were not mentioned. Infertility is multifactorial where PCOS is a frequent cause (Butterworth, Deguara & Borg, 2016), however almost none of the studies mentioned patient age nor lifestyle choices such as smoking and alcohol intake which all affect fertility. As most studies show amelioration of PCOS postoperatively, the current criteria for bariatric surgery remains to require a BMI of over 35kg/m² with a condition such as diabetes or hypertension. Infertility should also be considered as a condition for bariatric surgery as there are clear increases in pregnancies postoperatively (Malik and Traud, 2012). A more detailed study on PCOS patients who experience infertility, and an analysis on their age, environmental impacts and genetics would provide further insight into the ambiguity of how bariatric surgery affects fertility of PCOS patients. 

References 

Balen, A.H., Morley, L.C., Misso, M., Franks, S., Legro, R.S., Wijeyaratne, C.N., Stener-Victorin, E., Fauser, B.C., Norman, R.J. and Teede, H. (2016). The management of anovulatory infertility in women with polycystic ovary syndrome: an analysis of the evidence to support the development of global WHO guidance. Human reproduction update, 22(6), pp.687-708.

Butterworth, J., Deguara, J. and Borg, C. (2016). Bariatric surgery, polycystic ovary syndrome, and infertility. Journal of obesity, 2016.

Christ, J. and Falcone, T. (2018). Bariatric Surgery Improves Hyperandrogenism, Menstrual Irregularities, and Metabolic Dysfunction Among Women with Polycystic Ovary Syndrome (PCOS). Obesity surgery, pp.1-7.

Dicker, D., Yahalom, R., Comaneshter, D.S. and Vinker, S. (2016). Long-term outcomes of three types of bariatric surgery on obesity and type 2 diabetes control and remission. Obesity surgery, 26(8), pp.1814-1820.

Doblado, M.A., Lewkowksi, B.M., Odem, R.R. and Jungheim, E.S. (2010). In vitro fertilization after bariatric surgery. Fertility and sterility, 94(7), pp.2812-2814.

Dumesic, D.A., Oberfield, S.E., Stener-Victorin, E., Marshall, J.C., Laven, J.S. and Legro, R.S. (2015). Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocrine reviews, 36(5), pp.487-525.

George, K. and Azeez, H. (2013) August. Resolution of Gynaecological Issues After Bariatric Surgery-A Retrospective Analysis. In Obesity Surgery Vol. 23, No. 8, pp. 1043-1043

Harris-Glocker, M., Davidson, K., Kochman, L., Guzick, D. and Hoeger, K., 2010. Improvement in quality-of-life questionnaire measures in obese adolescent females with polycystic ovary syndrome treated with lifestyle changes and oral contraceptives, with or without metformin. Fertility and sterility, 93(3), pp.1016-1019.

Hashim, H.A., 2016. Twenty years of ovulation induction with metformin for PCOS; what is the best available evidence?. Reproductive biomedicine online, 32(1), pp.44-53.

Homburg, R. and Filippou, P. (2016). Treatment of WHO 2: Clomiphene Citrate. Ovulation Induction: Evidence Based Guidelines for Daily Practice, pg15.

Hughes, V. (2014). A gut-wrenching question. Nature, 511(7509), p.282.

Skubleny, D., Switzer, N.J., Gill, R.S., Dykstra, M., Shi, X., Sagle, M.A., de Gara, C., Birch, D.W. and Karmali, S. (2016). The impact of bariatric surgery on polycystic ovary syndrome: a systematic review and meta-analysis. Obesity surgery, 26(1), pp.169-176.

Jamal, M., Gunay, Y., Capper, A., Eid, A., Heitshusen, D. and Samuel, I. (2012). Roux-en-Y gastric bypass ameliorates polycystic ovary syndrome and dramatically improves conception rates: a 9-year analysis. Surgery for Obesity and Related Diseases, 8(4), pp.440-444.

Kar, S. (2012). Clomiphene citrate or letrozole as first-line ovulation induction drug in infertile PCOS women: A prospective randomized trial. J Hum Reprod Sci. ;5(3):262-5.

Malik, S.M. and Traub, M.L. (2012). Defining the role of bariatric surgery in polycystic ovarian syndrome patients. World journal of diabetes, 3(4), p.71.

March, W.A., Moore, V.M., Willson, K.J., Phillips, D.I., Norman, R.J. and Davies, M.J., (2009). The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Human reproduction, 25(2), pp.544-551.

Nhs.uk. (2017). Weight loss surgery. [online] Available at: https://www.nhs.uk/conditions/weight-loss-surgery/ [Accessed 1 Nov. 2018].

Palomba, S. ed.  (2018). Infertility in Women with Polycystic Ovary Syndrome: Pathogenesis and Management. Springer.

Roque, M., Tostes, A.C., Valle, M., Sampaio, M. and Geber, S., 2015. Letrozole versus clomiphene citrate in polycystic ovary syndrome: systematic review and meta-analysis. Gynecological Endocrinology, 31(12), pp.917-921.

Rotstein, A. (2013). Polycystic ovarian syndrome (PCOS) | McMaster Pathophysiology Review. [online] Pathophys.org. Available at: http://www.pathophys.org/pcos/ [Accessed 26 Oct. 2018].

Sam, S. and Ehrmann, D.A., 2017. Metformin therapy for the reproductive and metabolic consequences of polycystic ovary syndrome. Diabetologia, 60(9), pp.1656-1661.

Sirmans, S., and Pate, K. (2013). Epidemiology, diagnosis, and management of polycystic ovary syndrome. Clinical epidemiology, 6, 1-13. doi:10.2147/CLEP.S37559

Tziomalos, K. and Dinas, K., (2018). Obesity and Outcome of Assisted Reproduction in Patients With Polycystic Ovary Syndrome. Frontiers in endocrinology, 9, p.149.

Not all microorganisms cause disease, however pathogens are disease causing microorganisms. The reason why exposure to some microorganisms but not other result in pathology has many explanations and will be discussed in the context of commensals, bacterial adaptation, over active immune responses, and probiotics.

The gut microbiota protects from pathogens and shapes the immune response, exhibiting a symbiotic relationship known as commensalism. This is where one species benefits whilst the other is unaffected. It is crucial for the immune system to be able to distinguish between pathogens and commensals as patients affected with HIV, burn victims or patients on immune suppressant drugs (e.g transplant patients) and cancer therapy are most vulnerable to opportunistic commensal-induced infections.

Candida Albicans is an ascomycete fungus which grows on mucosal membranes of the mouth and urogenital tracts in 50% of healthy patients as commensals however can cause pathology under certain circumstances. Candida Albicans have the ability to interconvert between a yeast and fungal form depending on environmental conditions. When under starvation at 37 degrees or pH at 7 they start to form Hyphae. The yeast form can adhere to and colonise the host epithelial tissues, whilst the fungal form is adapted to spreading within the blood stream. The yeast converts back to the hyphal form which can then invade host tissue, causing damage. Mutants where Candida Albicans have been unable to convert to the hyphal form have prevented from causing disease.

High exposure to antibiotics can kill commensals within the gut. Clostridium difficile is a bacterium that can infect the bowel and cause diarrhoea, it takes advantage of the lack of commensals within the mucosa and produces toxins to degrade connective tissue. Bowel disease is a chronic remitting inflammatory disorder where the host epithelial barrier integrity is reduced in addition to the absorption of nutrients. Chronic inflammation in the gut results in a compromised epithelial layer with reduced mucosal layer and so commensals invade through the epithelial layer. In healthy patients IL-10 and T-reg cells are produced to prevent commensal-induced inflammation in addition to IgA antibodies, when this system fails for immunocompromised patients then pathology occurs. 

The host can detect pathogens via the secretion systems they use to transport virulence proteins out of the cell however both pathogens and commensals use secretion systems. As a result bacteria have adapted and evolved to lose a certain secretion system from the cells membrane to enable invasion of the host immune response and cause pathology. Bpp5 in Bordetella pertussis has genes missing in the middle of the type 6 secretion system (T6SS) locus. This strain has shown to cause pneumonia in sheep. This may have occurred due to reduced competition of other bacterial species from the loss of the T6SS. Illustrating how certain members of a species can be disease causing other members of the same species are not able to do so.

The immune response must proceed with caution to prevent over response to commensals which can also result in pathology. Tumour necrosis factor alpha (TNFa) is a cell signalling cytokine which under standard conditions would not cause pathology. During standard innate immune response macrophages are activated by damage-associated molecular patterns (DAMPs) and pathogen associated molecular patterns (PAMPs). TNFa is produced which then recruit and activate neutrophils and NK cells to the infection site. This causes tissue swelling, heat and induces fever. Immune cells have evolved to function well at higher temperatures but microbes are not able to function in this condition, hence fever is induced to make an uninhabitable environment. These innate cells reinforce each other, inducing a stronger response. Initiation of the adaptive immunity results in pathogen killing, T cells require 2 signals to respond to pathogens, signal 1 communicates antigen specifics presented by dendritic cells whilst signal 2 stimulate PAMPs to upregulate B7 to T cells on antigen presenting cells via CD28. Signal 1 without signal 2 means the T cell is recognising itself or food. The infection site must then be resolved because if PAMPS cannot be cleared they can then act as toxins and so a systemic infection occurs.If the pathogen is not being killed easily or quickly enough especially in cases for Immunocompromised and elderly patients with downgraded IL-10, they will have sustained immune activation, and so more TNFa continues to be produced. Increasingly high levels of TNFa can inhibit heart contractions, cause cachexia, reduce blood pressure, and as a final result: septic shock, organ failure then death. Toll-like receptor four (TLR4) is a pattern recognition receptor for lipopolysaccharide, polymorphisms in TLR4 are associated with increased susceptibility to sepsis. 

Probiotics such as Lactobacillus casei are live bacteria and yeasts that help restore the natural balance of bacteria in gut. Without probiotics, antibiotics have the ability to wipe out the protective gut bacteria such as lactobacillus and so resulting in vulnerability to pathogens. Probiotics are thought to directly kill or inhibit growth of pathogenic microorganisms. Probiotics also enhance gut-specific IgA responses, which are often defective in children with food allergens however Lactobacillus GG was effective in prevention of early atopic disease in children at high risk. At birth, the  gastrointestinal (GI) tract is sterile, but in the first months and years of life a rapid sequential colonisation occurs until a stable indigenous gut microflora is established. Simultaneously, the T-helper-2-dominant immunity of neonates is intensified in atopic individuals, with the subsequent expression of atopic disease. Dietary antigens also strongly affect the neonatal GI system, induction of oral tolerance, IgA production, as well as generation of transforming growth factor which suppresses T-helper-2-induced allergic inflammation. Oral lactobacilli in atopic children enhance transforming growth factor ß and IL-10 production in vivo, findings from clinical and experimental studies suggest that these anti- inflammatory cytokines have a crucial role in prevention of pathology. 

It can be concluded from this discussion that pathology occurring due to exposure to some microorganisms but not others is simply circumstantial. Certain bacteria have adapted to remain undetected by the immune system and so able to cause pathology. If the patient is immunocompromised then many commensals – such as clostridium difficle and Candida albicans – can take the opportunity to cause pathology. TNFa induces a working immune response optimal when localised, but when systemic results in pathology. Probiotics are strains of bacteria which can prevent pathology caused by atopic disease. These examples display circumstantial evidence of how exposure to certain microorganisms can result in pathology. 

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

Beniey, M., Haque, T. and Hassan, S., 2019. Translating the role of PARP inhibitors in triple-negative breast cancer. Oncoscience, 6(1-2), p.287.

Cancer Research UK. (2019). Breast cancer statistics. [online] Available at: https://www.cancerresearchuk.org/health- professional/cancer-statistics/statistics- by-cancer-type/breast-cancer#heading- Four [Accessed 20 Oct. 2019].

Cadoo, K. A., Fornier, M. N., & Morris, P. G. (2013). Biological subtypes of breast cancer: Current concepts and implications for recurrence patterns. Quarterly Journal of Nuclear Medicine and Molecular Imaging, 57, 312–321.

Emens, L.A., 2018. Breast cancer immunotherapy: facts and hopes. Clinical Cancer Research, 24(3), pp.511-520.

Evans, D.G.R., Warwick, J., Astley, S.M., Stavrinos, P., Sahin, S., Ingham, S., McBurney, H., Eckersley, B., Harvie, M., Wilson, M. and Beetles, U., 2012. Assessing individual breast cancer risk within the UK National Health Service Breast Screening Program: a new paradigm for cancer prevention. Cancer Prevention Research, 5(7), pp.943-951.

Fu, S., Chen, X., Lo, H.W and Lin, J., 2019. Combined bazedoxifene and paclitaxel treatments inhibit cell viability, cell migration, colony formation, and tumour growth and induce apoptosis in breast cancer.” Cancer letters 448 (2019): pp.11-19.

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.

Park, A. (2017). https://time.com. [online] Time. Available at: https://time.com/4645337/nearly-half-of- women-with-breast-cancer-report- serious-side-effects/ [Accessed 17 Oct. 2019].

World Health Organization. (2019). Breast cancer. [online] Available at: https://www.who.int/cancer/prevention/di agnosis-screening/breast-cancer/en/ [Accessed 18 Oct. 2019].