A long time in writing, the tale of tamoxifen and the other ‘hormone blockers’ used in the treatment of breast cancer.
I often make reference to “the many years ago when the surgeon was King.” At that time, certain alternate-thinking surgical types realised that if the ovaries were taken out of women who had breast cancer, the cancers had less chance of returning. So started the pharmaceutical race of finding medicines that could do what surgery did, minus the pain. Cancer research was considered to be a hopeless career choice, but a series of events put the right people, in the right place, at the right time to recognise a unique opportunity to advance cancer therapeutics.
The history is important
In about 1962, around the fabulous time of “free love”, a drug was launched as a post-coital contraceptive pill. Unfortunately, it was thought to have an anti-oestrogen effect but it actually increased oestrogen levels in young women when first used, having a fertility effect.
The failed/foiled plot
ICI 46,474, the anti-oestrogenic trans isomer of a substituted triphenylethylene, was discovered in the laboratories of Imperial Chemical Industries (ICI) Ltd Pharmaceuticals Division, now AstraZeneca. The team – Dora Richardson (chemist), Michael J. K. Harper (reproductive endocrinologist) and Arthur L. Walpole (head of reproduction research) – was tasked with developing a post-coital contraceptive during the early 1960s.
The compound was apparently a classical oestrogen in the mouse vagina (animal experiments…I hate them) but an anti-oestrogen in rat testis. Who knew? The question was what was the pharmacology of ICI 46,474 in humans: an oestrogen or an anti-oestrogen?
Headline news: A failed post-coital contraceptive. ICI 46,474 was not a contraceptive in humans. The drug induced ovulation and could potentially be used as a pro-fertility agent.
So ICI 46,474 was re-launched as a fertility drug.
At this stage, a very clever scientist, Dr Craig Jordan, noticed that it had an affect on breast cancer; unfortunately, he had no CV because he had no publications.
His mentor gave him the following advice: “Tell them the story so far; each paper should take no longer than two weeks to write-up and link together a series of studies with a theme.” And so, the ugly duckling was reinvented as tamoxifen, the first targeted therapy for breast cancer.
Tamoxifen ruffled its feathers with many articles over the last 40 years and finally it has been recognised for the swan, it truly is.
Transformation
The transition from the use of tamoxifen as a palliative therapy for advanced cancer to adjuvant therapy (after cancer treatment) had started. The initial clinical studies of tamoxifen were focused entirely on its application as a treatment for metastatic breast cancer.
The efficacy of tamoxifen was the same as that of high-dose oestrogen therapy (diethylstilboestrol 15mg daily), but the advantage of tamoxifen was fewer serious side effects.
The origins of targeted therapy – many fancy therapies exist today for breast cancer treatment (traztuzamab), melanoma and other cancers – started in the 1970s by challenging cytotoxic chemotherapy with an alternative approach to treatment, which was achieved by adapting the pharmacological principles of the drug receptor theory to cancer care.
Before we look at other medicines, let’s recap: tamoxifen is not an anti-oestrogen. I often hear: “I am not taking my tamoxifen because then I’ll have no hormones, and will dry up like an old prune.”
Pros and cons
Tamoxifen has both positive and negative oestrogen affects. In fact, some of the reasons why women don’t want to take it is because of the positive oestrogen affects. Tamoxifen is like a tap that has a central lever; left for cold and right for hot, so you can get cold and hot water from the same faucet.
If young women take it without contraception, they can fall pregnant, but it is mostly heart protective and good for arteries, and bare in mind more women are likely to die of heart disease than breast cancer. It is good for your bones; hip fractures and need for emergency surgery in oesteoporotic women is more dangerous for clots (DVTs) than our dear friend ‘tam’.
Does tam welcome menopause into your life?
Yes, tam and other breast cancer medicine are supposed to put you into menopause, and menopause is not for sissies. Ask Charl, the husband of a menopausal witch surgeon.
Menopause is a phase of life, no different to being a toddler or a teenager with rampant hormones and acne. This too shall pass. Going through life phases are different for each person – different problems, different symptoms and different solutions. There is no “one size fits all”.
Menopause is not a light switch that is suddenly turned off, and your hormones don’t just dry up like a tap. One produces hormones from fat, so that muffin top (I have one too), that bootylious booty and Madonna-thighs, are producing oestrogen. Food and drink, especially alcohol, can be a source of oestrogen.
Age and menopause is supposed to result in weight gain. This is true, but not a given. When one is three and bouncing around the whole day, one can have three meals a day, including sweets and snacks. But as we age and bounce around less, the old adage ‘input versus output’ applies. Meaning we can’t eat three meals a day and snacks, and not exercise.
Tam has no calories but if it changes your metabolism to menopausal, you need to eat less and exercise more. As for hot flushes, night sweats, vaginal dryness, and dry skin, they can be managed with a variety of supplements, creams, lotions and potions, and prescription medications. Below is a vaguely helpful table with many blanks, that needs to be filled in by your oncology team.
Don’t be a tit; take your tam (TYT)
I also hear the comment: “I can’t take tam as I don’t want to get uterine, cervical or ovarian cancer.” There is no association with tam and ovarian cancer (associated with BRCA), no association with tam and cervical cancer (associated with HPV virus) and the risk for uterine cancer is 1%; it is more dangerous to be on the roads.
Tam is the contraceptive pill against cancer sperm. You can have unprotected sex and not get pregnant; you can be on the pill and get pregnant. The risk, though, is very small.
If you have had an invasive breast cancer there is always a chance of a single cell (cancer sperm) escaping and lying dormant – to wake up later, like a little sleeping terrorist – and whereas the attack may be local and manageable, it could also be a suicide bomber out to do a 911. And once a cancer comes back elsewhere – remember it can’t kill you while in the breast – you are always actively fighting the war with big guns such as drugs and radiation, and bombs like chemo.
Other hormonal therapies
Endocrine therapy is currently used as a treatment modality for all stages of hormone receptor-positive breast cancer.The majority of breast cancers are stimulated by oestrogen. As a consequence, the objective of hormonal therapy is to deprive the
tumour of hormone-induced growth stimuli, either
by blocking the oestrogen receptor or inhibiting oestrogen synthesis.
There are a number of different treatment options: selective oestrogen receptor modulators (SERMs), e.g. tamoxifen. They bind to the oestrogen receptor site, inhibiting the activation of oestrogen-responsive genes and blocking oestrogen from binding.
Aromatase inhibitors (AIs) act to block the conversion of androgens into oestrogens by inhibiting or inactivating the activity of aromatase thus causing oestrogen deprivation in postmenopausal women. These drugs are more of hormone blockers and have different side effects, also manageable, such as joint aches.
Ovarian ablation and/or suppression are considered part of the current standard adjuvant endocrine therapies for premenopausal women with breast cancer. These often involve injections and switch off hormone production. The endocrinology of the postmenopausal breast is unusual in that oestrogen levels may be substantially higher in the breast tissue than in the circulation. Additionally, breast cancers are able to concentrate oestrogen from the circulation against a gradient, and to synthesise oestrogen.
There are a variety of endocrine medicines used in the treatment of breast cancer. Your oncology team, with you, will decide which is the best option, for how long you need to be on them for and whether you need to change from one to another.
Like tam started as an ugly duckling and has grown into a beautiful swan, think of yourself before as the duckling, and now glide beautifully (exercise), safely (take your meds) and regally as a swan does.
References:
1. Hayes DF, Robertson JFR. Overview and concepts of endocrine therapy. In: Robertson JFR, Nicholson RI, Hayes DF, eds. Endocrine Therapy of Breast Cancer. London, England: Martin Dunitz; 2002:3-10.
2. Robertson JF. Oestrogen receptor down regulators: new anti-hormonal therapy for advanced breast cancer. Clin Ther. 2002;24
(suppl A):A17-A30.
3. NCCN Practice Guidelines in Oncology.
Available at: http://www.nccn.org.
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