There are three of these drugs currently in use in Australia in the treatment of breast cancer that is hormone sensitive (positive for the oestrogen receptor ("ER+") and/or progesterone receptor ("PR+"): letrozole ("Femara"), anastrozole ("Arimidex"), and exemestane ("Aromasin"). All are available on the Australian Pharmaceutical Benefits Scheme (PBS) for women after the menopause for adjuvant therapy of early breast cancer and for management of metastatic ("secondary") breast cancer that is ER+ and/or PR+
These drugs lower the levels of the active circulating female sex hormone, oestrogen, to almost zero. They are only used when the main source of oestrogen, the ovaries, have ceased producing the hormone, which happens naturally after the menopause. After the menopause, oestrogen is mainly produced in the fat tissue of the body and in tumour tissue itself by the action of an enzyme called “aromatase”. This enzyme acts on circulating steroid hormones called “androgens” which are produced in the adrenal glands, fat tissue and muscle (See Figure). Aromatase converts the androgens into active oestrogen. The aromatase inhibitors block this enzyme virtually completely, thus depriving the body, and breast cancer cells, of active oestrogen. Letrozole and anastrozole are both synthetic non-steroid molecules, whereas exemestane is itself a steroid molecule.
The aromatase inhibitors do not block the production of important adrenal hormones, like the androgens themselves and cortisone.
Aromatase inhibitors are used in post-menopausal women with advanced, or metastatic, breast cancer which is positive for the presence of the oestrogen receptor (ER)and/or progesterone receptor (See Figure). Presence of these receptors on the surface of breast cancer cells indicates that the cancer is "hormone sensitive". Over 70% of breast cancers are hormone sensitive.
They may also be indicated in adjuvant therapy of early breast cancer that is hormone sensitive (see below), but only in women who have been through the menopause. They do not work before the menopause because the ovaries produce too much estrogen.
Arimidex: 1 mg tablets taken once daily, before or after food.
Femara: 2.5 mg tablets taken once daily, before or after food.
Aromasin: 25 mg tablets taken once daily after food.
The evidence for superiority of one over the other is slight. Claims to the contrary are mainly drug-company propaganda. Arimidex or Femara are currently considered the first choice in the treatment of ER +ve metastatic breast cancer. Clinical trials show them to be superior to tamoxifen in tumour response rates and time to tumour progression. Aromasin is only licensed in Australia for use in ER + metastatic breast cancer after the drug tamoxifen has failed to work.
Aromasin is the only one that will give responses after failure of one of the other aromatase inhibitors, because it works slightly differently to cause irreversible inhibition of the enzyme.
(Not her real name or picture).
“I was found to have spots on the bone scan and lung after having had three months of new, progressive discomfort in my lower back. A biopsy of the lung nodules showed secondary breast cancer which was positive for the oestrogen receptor. I was commenced on Femara, together with monthly injections of another drug called Aredia, which strengthens bone and prevents fractures and pain. That was two years ago. My bone scan has returned almost to normal and the CAT scan I had of my chest last month showed no evidence of the secondaries. I have had absolutely no side-effects whatsoever. Femara is a miraculous drug.”
These drugs were generally well tolerated across all studies as first-line and second-line treatment for advanced breast cancer. Approximately one-third of the patients treated can be expected to experience mild adverse reactions. The most frequently reported adverse reactions in the clinical trials were hot flushes, nausea and hair thinning. Many adverse reactions can be attributed to the normal consequences of oestrogen deprivation (e.g. hot flushes, hair thinning).
My own experience is that side-effects are extremely uncommon, and I have certainly not seen them in one-third of my patients ? more like one-in-ten.
Reported side-effects include:
These drugs do not interfere with other medications.
They should not be taken by women who are still having their menstrual periods, during pregnancy or breast-feeding.
Don’t worry: just take it the next day as normal. The drug lasts in the blood-stream for around 2 days. But try to be regular with the daily dosing.
The aromatase inhibitors are being increasingly used in preference to tamoxifen in post-menopausal women.
The main trial in early breast cancer is the ATAC (Arimidex, Tamoxifen, Alone or in Combination) Trial. In this trial, over 9000 women were randomised in a double-blind fashion (neither the women nor the investigators knew who was getting what, to avoid any sort of bias). They received either tamoxifen, anastrazole or both drugs together. The study shows that, with over 8 years of median follow-up time, in the anastrazole-only arm, when compared to the other two arms of the trial, there were statistically significant data to support:
Remember that the trial was confined to post-menopausal women with an average age of 65. Also, remember that tamoxifen has a 30-year track-record of safety.
The end-point of most relevance in these studies of adjuvant treatment in early breast cancer is overall survival and so far there is no evidence of this in the ATAC Trial, which has the longest period of follow-up of any of the adjuvant studies of aromatase inhibitor drugs. Anastrazole is now on the Australian Pharmaceutical Benefits Scheme (PBS) for use in post-menopausal women with early breast cancer that is hormone sensitive. Some chemists don't seem to know this. If, in Australia, you are charged around $200 for your prescription don't pay it! The chemist has made a mistake!
Adjuvant treatment of early breast cancer: Is it useful to take an Aromatase Inhibitor after tamoxifen?
The MA-17 Trial.
This study involves more than 8000 postmenopausal women (800 in Australia and New Zealand) with early, hormone-sensitive breast cancer and is testing the following five year treatment plans:
Firstly, these drugs are contraindicated in pre-menopausal women, and probably of uncertain efficacy in women who have just gone through menopause.
These drugs deprive the body completely of oestrogen and that may have serious long-term effects, especially on bone density (see my notes on osteoporosis.) There also continue to be reservations about the possible long-term effects on cholesterol metabolism, cardiovascular health, sexual health and mental function (cognitive effects). We have thirty years of experience with tamoxifen.
Another factor is that of "keeping your powder dry". If we use up all the treatment options in trying to prevent recurrence we may be deprived of very effective and useful therapies in the event of that recurrence occurring.
The American Society of Clinical Oncology (ASCO) has recommended (November 15th 2004) that postmenopausal women who are receiving adjuvant hormone therapy as part of the management of early breast cancer, should receive an aromatase inhibitor. This is based on the clinical trials summarised above. It is based principally on small improvements in reducing tumour recurrence, rather than any substantial data concerning improvements in long term survival. ASCO states that aromatase inhibitor therapy is appropriate as initial treatment for women with contraindications to tamoxifen. For all other postmenopausal women, there are two options:
1. five years of aromatase inhibitor treatment, or
2. sequential therapy consisting of tamoxifen (for either two to three years, or five years) followed by aromatase inhibitors for two to three, to five years.
The optimal duration and sequencing of hormonal adjuvant therapy is still unknown, but it should be for at least 5 years.
I will be discussing this with each of my patients at their regular follow up visits.
Meanwhile, for anyone taking tamoxifen: stay on it until next you see your Oncologist. For anyone about to come to the end of their five years on tamoxifen: discuss the whole matter with your Oncologist before ceasing it.
As summarised above, it should be stressed that the long term effects of taking aromatase inhibitors for five years are still not known, and special monitoring for osteoporosis is strongly recommended.
TREATING METASTATIC BREAST CANCER WITH AROMATASE INHIBITORS
Anti-oestrogen drugs (tamoxifen and the aromatase inhibitors) are extremely useful in treating metastatic (secondary) breast cancer that is oestrogen receptor positive. Your oncologist may use these sequentially - if one stops working a switch will be made to one of the others. Disease control can be achieved in certain patients for years in this way.
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