Hormones are chemical messengers released by glands around the body – such as the pituitary, pineal, thyroid, testicles, ovaries and pancreas. The thyroid gland produces thyroid hormone, for instance. The testes produce testosterone, while the ovaries secrete oestrogen. Hormones are essential for our health and well-being, controlling, for example:
•metabolism, including the conversion of food into energy;
•some aspects of mood and emotions;
•reproduction and sexual function;
•growth and development.
Some cancers are especially sensitive to hormones’ growth-promoting effects. Oestrogen, for example, drives many cases of breast cancer, and testosterone often stimulates prostate cancer. So drugs that block these hormones are important treatments for breast, prostate and some other ‘hormone-sensitive’ (also called ‘hormone-dependent’) cancers.
Receptors and cancer
Hormones act by binding with specific ‘receptors’ on their target cells (see Figure 7.1). Imagine a cell is a car. The receptor is the ignition; the hormone is the key. When the key is slotted into the ignition, the engine can start and the car move. Similarly, when the hormone binds to the receptor, part of the cell’s internal machine starts and the cancer grows. This binding is specific: your key starts only your car; testosterone does not bind to oestrogen receptors, for example. Many of the body’s other messengers – such as the neurotransmitters that pass signals between nerves and from nerves to muscle – also act by binding to receptors.
Imagine you have a skeleton key that fits the ignition and switches on the engine. Some drugs act like a skeleton key. That is, the receptor cannot distinguish the drug (called an agonist) from the messenger produced by the body; both switch on the cell’s machinery. For example, your brain produces natural painkillers called endorphins (also known as endogenous opioids) that bind to specific receptors. Morphine, commonly used to treat severe cancer-related pain, binds to the same receptors as the endorphins and switches on the same pain-relieving pathways.
Imagine that you have another key. It fits the ignition, but will not turn, so the car will not start. While this key is in the lock, however, you cannot get the right key in. Some drugs operate in a similar way, binding to the receptor but not activating the cell’s machinery. These are antagonists. About 7 in every 10 breast cancers express oestrogen receptors. Drugs that block the oestrogen receptor are important treatments for early and advanced breast cancer.3 Anti-androgens (such as bicalutamide, cyproterone acetate and flutamide) attach to testosterone receptors, stopping the hormone from stimulating prostate cancer.
Receptor status
Because receptors are specific, a drug that interferes with hormones will work only if the cancer is sensitive to that hormone, so the cancer team will test a sample of the malignancy to see if it expresses receptors for the hormone. For example, oestrogen and progesterone stimulate the growth of some breast cancers, so the team will test for receptors for these two hormones and classify the malignancy as:
•oestrogen receptor positive (ER+) or negative (ER-);
•progesterone receptor positive (PR+) or negative (PR-).
Doctors call this the cancer’s ‘receptor status’.
As mentioned earlier, cancers are genetically very unstable and can change as they develop, so a primary breast cancer that is ER+ can produce ER- metastases and vice versa. One study found that the receptor status for breast cancer metastases differed from the primary malignancy in about 1 in 6 cancers (18 per cent) for oestrogen and almost half (45 per cent) for progesterone.65 The cancer’s receptor status can influence treatment, so it is worth discussing taking a biopsy of breast cancer metastases with your cancer team. Not all metastases can be sampled, however, as they might be inaccessible, for example.
Blocking hormones
Blocking the hormone that stimulates the malignancy’s growth or preventing its production can help treat hormone-sensitive cancers. For instance, many women with ER+ breast cancer take tamoxifen, which blocks oestrogen. Tamoxifen locks on to the oestrogen receptors. This means that oestrogen cannot stimulate the cancer cells’ growth and division. Tamoxifen can control advanced breast cancer, although resistance usually develops, and lowers the risk of early breast cancer coming back (recurring) after surgery or developing in the other breast. One study followed women with early breast cancer for 15 years. Over this time, taking tamoxifen for five years reduced the risk of death from breast cancer from a third (33 per cent) to a quarter (24 per cent). Taking tamoxifen for five years also reduced the risk of recurrence from about half (46 per cent) to a third (33 per cent).3
Most prostate cancers depend on testosterone to grow. Luteinizing hormone (LH) controls production of oestrogen and progesterone by the ovaries and testosterone by the testes (see below). Doctors might suggest drugs that block LH for some prostate and breast cancers. As mentioned previously (see pages 5 and 55), essentially chemotherapy works by directly killing cells or triggering apoptosis. Drugs that block hormones typically work at another stage in the cell cycle: they reduce cell proliferation.3
As we shall see in the next chapter, hormonal treatments might be combined with targeted treatments, such as trastuzumab (Herceptin), lapatinib (Tyverb) or everolimus (Afinitor).3 The combination allows the treatment to ‘attack’ the cancer on more than one front. Hormonal treatments can also help control some more advanced cancers, such as small visceral and bone metastases from breast cancer.3
The choice of hormonal treatment depends on your malignancy and other factors. For example, ovaries stop making oestrogen after the menopause, so LH blockers work for breast cancer in premenopausal women only. If the cancer no longer responds to a hormonal treatment, doctors describe it as ‘hormone refractory’.
Prostate cancer
In healthy men, an area of the brain called the hypothalamus releases gonadotropin-releasing hormone (GnRH). The hypothalamus is just above the pituitary gland, which lies behind the bridge of your nose. The pituitary controls the action of many other glands. The pulses of GnRH trigger the pituitary to release pulses of LH and follicle-stimulating hormone (FSH).
LH stimulates testosterone production in the testes, while testosterone and FSH trigger sperm production. Testosterone from the testes is released into the circulation and feeds back to the hypothalamus and pituitary gland, reducing production of GnRH, FSH and LH.66, 67
A group of drugs called GnRH analogues disrupt this ‘feedback’ loop3 (‘analogue’ means it is similar in shape to GnRH and so binds to the same receptor). GnRH analogues trick the body into acting as if levels of testosterone are high, so after an initial rise (flare), levels of testosterone fall dramatically. The flare can stimulate the tumour, which might lead to difficulty passing water and, in some people, result in spinal cord compression. As a result, the cancer team will probably prescribe a drug that blocks testosterone’s effect on the tumour and other tissues for two weeks before giving the GnRH analogue. You generally receive a GnRH analogue as an injection into the fat under your skin every month or once every three months.3
Aromatase inhibitors
Aromatase inhibitors are the main hormonal treatment for breast cancer in post-menopausal women. In addition to the ovaries, an enzyme in fat (called aromatase) makes oestrogen. Aromatase inhibitors lower oestrogen levels by blocking this enzyme. Aromatase inhibitors do not, however, stop the ovaries from producing oestrogen. The aromatase inhibitors, therefore, only lower oestrogen levels in women whose ovaries are not producing the hormone, such as those who have been through the menopause.
Side effects of hormone treatments
Hormones control some very basic aspects of our biology; after all, you cannot get much more basic than reproduction. For example, testosterone increases muscle strength, so blocking testosterone might trigger fatigue and weakness. (Men produce low levels of oestrogen, just as women produce low levels of testosterone.)
While side effects are common, in most people the benefits of hormone treatments outweigh the risks. In many cases some simple steps can help alleviate the discomfort – have a full and frank discussion with your cancer team.
During the natural menopause, for example, oestrogen levels fall. This means that drugs which block oestrogen can cause symptoms similar to the menopause, but, unlike the natural menopause, these symptoms can arise in men. About 7 in 10 women undergoing hormonal treatment for breast cancer and a similar proportion of men taking some drugs for prostate cancer experience hot flushes.
Tamoxifen, for example, might cause hot flushes, vaginal dryness, loss of libido and weight gain.3 In rare cases, tamoxifen seems to increase the risk of endometrial cancer and disorders of blood clotting (thromboembolic disease), so always tell your cancer team if you develop abnormal bleeding, such as from the vagina or gums. As tamoxifen affects blood clotting, you might stop treatment before an operation. In premenopausal women, tamoxifen can also weaken bones, leaving you more vulnerable to fractures.3
You can take steps to manage some of these side effects (see page 113). For example, taking drugs such as tamoxifen in the evening might reduce hot flushes (but never change your dose schedule without speaking to your cancer team first). Your cancer team can also suggest a variety of drugs that might alleviate hot flushes. Some people find hypnosis, acupuncture and yoga reduce flushes. A lubricant may alleviate vaginal dryness. Painkillers, weight loss, exercise and physiotherapy can reduce joint pain.3
In men with prostate cancer, GnRH analogues can cause hot flushes, impotence and weight gain. Some drugs can cause breast tenderness and growth in men (gynaecomastia) or damage your liver. Long-term treatment might weaken bones. Prostate cancer seems to increase the risk of diseases affecting the heart and blood vessels (cardiovascular system). Androgen deprivation appears to further increase the risk. So your cancer team might suggest treatments to protect your bones and cardiovascular system.3
Aromatase inhibitors can cause joint and muscle pains, loss of libido and weaken bones. Taking vitamin D and calcium supplements, and drugs that strengthen the skeleton (bisphosphonates), can help minimize the effect on bones. You might also need bone scans to monitor the effect on your skeleton.3 Other side effects are specific to each treatment, so speak to your cancer team and check out the information provided by cancer charities (see Useful addresses).
Remembering to take your treatment
Remembering to take your treatment can be challenging, especially if you have several drugs to remember (including for ailments other than the cancer), you feel depressed and demotivated or the drugs or cancer affect your memory (see the box ‘Cancer-related cognitive impairment’). Here are some ideas you might like to try.
•Ask your partner or carer to remind you to take your medicine.
•Keep a checklist and cross or tick each dose when you take it. Some apps track your medicine use. If you share this either electronically or by pinning up the list, your partner or carer only needs to remind you if you have forgotten.
•Leave yourself notes reminding you to take your treatment on the refrigerator, over your desk, next to the television, on the bathroom mirror, wherever works for you.
•Leave your medicines where they are easily seen, such as on the dining or bedside table or desk. Always keep medicines out of reach of young children, however.
•Speak to your cancer team if you have difficulties opening the packaging or swallowing tablets – there are often ways around these. If you have joint pain, for example, a pharmacist can repackage the medicines in containers that are easier to open. Liquid formulations of some medicines can help if you have difficulty swallowing.
•Try to take your treatment at the same times each day, which helps establish a routine and, in turn, helps you remember. You could use an alarm on a watch, phone or timer to remind you.
•Your routine might change on holiday, on a day out, at a birthday, wedding or if you are away on business. You might need to adjust your timings. Make sure you have sufficient supplies of all your medicines while away. Remember that you might not be allowed to take some painkillers into certain countries, so always check.
Some people feel that alarms are intrusive and remind them they are ill. If the alarm goes off in public, you might not want to explain about your cancer. You might feel irritated if carers remind you to take a medicine when you already have. Everybody is different, so find what works for you.
Intentionally refusing treatment
The practical steps given above can help if the person with cancer unintentionally forgets to take his or her medication, but sometimes people intentionally don’t take their medicine as suggested. Indeed, in one study, more than half (55 per cent) of those taking drugs – including tamoxifen – for breast cancer did not take their medicine as recommended, frequently or occasionally. About 4 in every 5 (83 per cent) of those who did not take their medicines said they forgot, but about 1 in 6 (17 per cent) reported that they intentionally did not take their medication.69
Cancer-related cognitive impairment
Some people with cancer find that it is hard to concentrate, focus or pay attention, which can linger after the initial treatment ends. Some report memory loss or difficulty remembering names, dates or phone numbers or with comprehension or understanding. Numerous factors linked to cancer and its treatment can cause or worsen cognitive impairment, including some chemotherapy drugs, hormonal therapy, certain forms of radiotherapy, stress, chemical changes produced by the cancer and brain tumours. Up to 3 in every 10 patients experience cancer-related cognitive impairment before chemotherapy. This rises to up to three-quarters during treatment – so-called ‘chemo-brain’ or ‘chemo-fog’. The symptom persists for several months after treatment for more than a third (35 per cent) of patients.68
Some people deliberately did not take their medication to avoid side effects, such as hot flushes. If side effects make you reluctant to follow the suggested regimen for taking your medicines, speak to the cancer team. Often there is a lot they can do to help.
Other people who deliberately missed their medication viewed themselves as having significantly less influence over their health and well-being than those who followed their cancer team’s advice.69 Perhaps some people feel that not taking a treatment helps re-establish a sense of control. Others might not fully appreciate the benefits of treatment, especially if they experience cancer-related cognitive impairment.
Obviously, a cancer treatment will not work unless you take it. So, if you are deliberately not taking your medicines, speak to your cancer team and explore the reasons underlying your reluctance. Ultimately, the choice is yours. During palliative care or in advanced cancer, for example, you might refuse a treatment or trade a less effective approach for one with fewer side effects. Nevertheless, self-help tips and, if necessary, supportive treatments can often manage side effects, so do not suffer in silence. If you feel you are not in control, try complementary or alternative medicine (CAM) or counselling instead of ignoring your team’s advice.
If you are caring for someone with cancer and you suspect he or she is not taking the medicines as suggested, you should gently and non-judgementally raise the issue with the person or the cancer team. You could save or prolong that person’s life.