I have been taking tamoxifen for nearly 2 weeks, and so far so good with regards to side effects (still early days). If you’re premenopausal, and have had surgery for an invasive, oestrogen receptor-positive (ER+) breast cancer, it is recommended that you take tamoxifen for 5 years. There is very robust evidence that it improves your chance of survival (albeit by very small margins in my case) and it can reduce the risk of getting cancer in the other breast by up to 50%. I was very resistant to taking it as I’d heard all sorts of horror stories about side effects such as hot flushes, night sweats, vaginal dryness, menstrual irregularities, weight gain, blood clots and endometrial (womb) cancer. Some women experience the menopausal symptoms really badly. I was already in the perimenopause so I wasn’t sure whether my night sweats would get worse or just stay the same. I’m also not too keen on having a dry fanny! So far the night sweats are no worse and I’m reserving judgement on the other…
I have a PhD in pharmacology, so if I have to take a medication I need to research its mechanism of action and really understand what it’s doing to my body. The pharmacodynamics (what the drug does to the body) and pharmacokinetics (what the body does to the drug) of tamoxifen are mind boggling to me. I’m sure that not everyone shares my fascination for how drugs work, but my, this is an interesting one! This is my attempt to understand how tamoxifen works. Buckle in, it’s quite a ride! Feel free to skip this post if science makes your brain hurt…
1962 search for a contraceptive
Tamoxifen was initially developed as a safe contraceptive, but funnily enough it ended up having exactly the opposite of the desired effect, and actually made women ovulate, rather than stopping ovulation. Unbeknown to its manufacturer ICI (now AstraZeneca) it was to become the first non-toxic targeted treatment for breast cancer, thanks in large part to collaboration between researchers and the enthusiasm of a young post-doc, VC Jordan, in examining its anti-tumour effects with some oh-so-elegant science.
Jordan discovered that tamoxifen was something known as a SERM (selective oestrogen-receptor modulator), which means that it blocks oestrogen receptors in some tissues (such as breast tumours) and stimulates them in others (such as the uterus and bones). One thing which I hadn’t appreciated about oestrogen receptors is that there are two types in question here, ERα and ERβ. When oestrogen binds to either of these ER, what happens inside the cell depends on a variety of little helpers which send messages to turn the cell’s genes on or off. In breast tumour cells, tamoxifen blocks the oestrogen receptors and this causes the cells to die (apoptosis – makes me imagine the cells going “pop!” and dying). Other tissues have little helpers which send different messages to the cell’s genes, depending on the cell type and the balance between ERα and ERβ. So in breast tumour cells tamoxifen blocks the effects of oestrogen, but in other tissues it can act like oestrogen itself.
My genes are different from yours
The intricacies of the human body never cease to fascinate and amaze me. Another thing which has got me thinking is the fact that my body does things to the drug, which may be different to what another person’s body does to the same drug. We all have different versions of our genes (polymorphisms) so which variety of a particular gene I have determines what happens to tamoxifen inside my body. Tamoxifen needs to be chomped on by the liver before it can even do its business (it’s the active metabolites which do the work – tamoxifen on its own seems rather inactive), and some people’s livers seem to do this job better than others. The other thing is that my oestrogen receptors will not be exactly the same as another woman’s, so it’s hard to predict whether the tamoxifen will be a wonder drug for me or whether it will just give me loads of side effects with few benefits. That said, on paper the benefits certainly have me convinced that it’s worth a try.
The fascination doesn’t stop there. Tamoxifen is also useful in preventing recurrence of oestrogen receptor negative cancers, although the way it does this is very confusing. I spent almost a whole day trying to get my head around this, and I have to say, I am still rather bemused. Suffice to say that tamoxifen seems to have other actions as well as its action on the oestrogen receptor. It does something funny to mitochondria (the powerhouses which fuel our cells) which makes tumour cells more likely to go pop and die (apoptosis). At the same time it has strange effects on cholesterol metabolism which seems to protect against cancer. Paradoxically, while plenty of studies show that tamoxifen increases nasty oxygen free radicals which damage cells (which is what you want to kill a tumour cell, but not what you want if the cell is healthy as it can cause it to malfunction), it also has antioxidant properties (and we all know that is a good thing). Tamoxifen also has direct effects on DNA, a mechanism by which it is thought to be good for treating cancers other than breast cancer.
If you’re worried about taking tamoxifen there is a very helpful NHS tool which can help you decide whether to take it or not. It calculates the effect which taking tamoxifen should have on your survival. https://breast.predict.nhs.uk/tool
Even though my calculated 15 year survival benefit of taking tamoxifen for 5 years comes out at less than 1%, survival is not the only point of taking it. I’m not at all keen on going through all the investigations, uncertainty and mastectomy which cancer in my “good” breast would mean. If it reduces the chances of that by 30-50% then it’s worth a punt. I will let you know if it turns me into even more of a perimenopausal wild thing than I already am!!
- Goodsell DS. The molecular perspective: tamoxifen and the estrogen receptor. Oncologist. 2002;7(2):163-164.
- Jordan VC. Tamoxifen: a most unlikely pioneering medicine. Nat Rev Drug Discov. 2003;2(3):205-213.
- Shagufta, Ahmad I. Tamoxifen a pioneering drug: An update on the therapeutic potential of tamoxifen derivatives. Eur J Med Chem. 2018;143:515-531.
- Yang G, Nowsheen S, Aziz K, Georgakilas AG. Toxicity and adverse effects of Tamoxifen and other anti-estrogen drugs. Pharmacol Ther. 2013;139(3):392-404.