Tamoxifen; Is it a cure for Breast Cancer?

Breast cancer (BC) is the most common cause of cancer amongst women around the globe with 1.5 million women being diagnosed with the disease in 2010 alone. Despite the high incidence rate, in western countries alone 89% of those diagnosed have passed the 5 year survival period upon their initial diagnosis. The World Health Organisation estimates a third of these cases could be decreased upon early detection and treatment of the disease thus 40,000 live could be saved per year.  Hence educating the general public of the disease as well as increasing the number of screening programmes for the disease will improve cancer mortality rate in the world.

However, treatment of BC is to be revolutionised with the discovery of preventative measures that were recently established through research data published in the Lancet Oncology with Professor Jack Cuzick of Queen Mary, University of London informing the BBC the evidence shown by the drugs Tamoxifen and Raloxifene is overwhelming and the drugs should be approved in the UK to be given as preventative therapy for women with high risk of BC. Both these drugs have already been approved by the FDA in the US to be given to women to prevent BC. Tamoxifen is more complex of the 2 drugs and is prominently known as a BC drug for years with fairly positive review. The drug itself may have other potential uses in other forms of cancer as well since it is also known to reduce inflammation involved in prostate cancer. However, it is essential to understand the workings of the drug and the pharmacokinetics to ensure patient safety as well as possible side effects short and long term.  Hence, what do we really know about Tamoxifen? Tamoxifen is an anti-oestrogen drug that has been used widely in the treatment of BC for over 30 years. However, its ability to prevent the disease emerged recently with much interest developed by the drug’s ability to prevent the side of effects like breast tenderness. The exact pathway by which the drug work is not very well understood but the general overview is well known. Tamoxifen is a selective oestrogen modulator hence works well amongst oestrogen positive BC patients. The metabolism of the drug is essential to understand the mannerism in which the drug coordinates annihilation of cancerous cells. It has also shown to reduce mortality and recurrence rate by 30% and 50% respectively although the response rate of the drug consists of a high degree of inter-individual variability due to its extensive metabolism within the liver as shown by the diagram shown below (Diagram 1);  

There are 2 common side effects with the use of Tamoxifen long term; increased risk of endometrial cancer and hot flashes. Hot flashes are the most commonly observed within BC patients leading to reduced quality of life resulting in patient non-compliance. The drug may also contribute to an increased risk of thromboembolic events as well as clinical depression which in turn leads to providing patients with secondary drugs of selective serotonin reuptake inhibitors (SSRI). However, clinicians need to prescribe these SSRI’s quite carefully since they may consist of anti-CYP2D6 activity which may result in reduced Tamoxifen efficacy. Tamoxifen is predominantly metabolized by cytochrome P450 (CYP) system to several primary and secondary sites of metabolism with some metabolites exhibiting more ant- estrogenic effects within BC cells than Tamoxifen. Tamoxifen-4-hydroxylation (T4H) part of the metabolic pathway has been given more attention due to the resulting metabolite of 4-hydroxy-Tamoxifen (4HT) is 30-100 fold more potent with anti-estrogenic properties. T4H is catalysed by CYP2D6 and other isoforms although the major metabolic pathways of Tamoxifen include N-demethylation and N-desmethyltamoxifen (NDT) catalysed primarily by CYP3A4 and CYP3A5 respectively. NDT is oxidised further to endoxifen and other metabolites. NDT is also hydroxylated by CYP2D6 enzyme forming endoxifen. Both 4HT and endoxifen have similar potencies in terms of anti-estrogenic activity while endoxifen targets ER-alpha for proteasomal degradation and its plasma concentrations in those patients receiving Tamoxifen therapy 5-10 fold higher than 4HT. NDT undergoes sequential metabolism to metabolite E exhibiting estrogenic activity in vitro. Tamoxifen is also metabolised by Flavin mono-oxygenases FMO1 and FMO3 resulting in Tamoxifen-N-Oxide(TNO) which can also be reduced by cytochrome P450 in vitro. It has also been shown TNO may be reduced to Tamoxifen by haemoglobin and NADPH-P450 oxireductase indicating TNO is enzymaticaly independent and dependent on Haemoglobin and NADPH-P450 suggesting TNO as a storage site for Tamoxifen in vivo cycles. Tamoxifen and its metabolites are inactivated by glucuronidation and sulfation via UGTs and SULTs respectively with Glucuronidation being more prominent. Approximately 75% of Tamoxifen dose is excreted via the biliary tract as glucuronides. The understanding of this metabolic pathway further will enable us to determine the preventative pathway involved in BC.

With the evolving understanding of Tamoxifen it is evident that the drug may have many more potential uses in the near future. For now though, it may be concluded that it is used as a preventable measure for BC as well as treatment of estrogen positive BC.