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Femara, Arimidex and Aromasin: The Aromatase Inhibitors
 
 
What are they?

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+



How do they work?

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.




When are they used?

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.




How are they taken?

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.




Is one better than the other?

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.




Margaret
(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.”




What are their side-effects?

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:

  • Hot flashes ("hot flushes")
  • Nausea, vomiting, constipation, loss of appetite.
  • Hair thinning. (For further information, CLICK HERE)
  • Osteoporosis. This is a potentially serious side-effect, especially if the agents are being used over several years as part of the adjuvant treatment of early breast cancer. There is more information on osteoporosis and its management HERE. The most serious consequence of osteoporosis is bone fractures, especially in the spine and hips. The overall risk of these happening in the ATAC Trial (see below) was 7.1%. Because of this risk, all women likely to be taking aromatase inhibitors for more than 12 months should have bone mineral density measurement as a baseline, and then at regular intervals, probably 2nd yearly, and should also follow all the preventative measures outlined HERE
  • Rashes
  • Muscle and joint discomfort. This is quite common (around 20%) but variable in intensity. In the worst cases, women typically say something like "I feel like I'm suddenly very old and creaky. All my joints are stiff. My hands are stiff, especially in the morning. I find it hard to get my knees to get going when I stand up." This problem seems to be at its worst about the second month of treatment and then eases off. Sometimes a change from one aromatase inhibitor to another will cause less problems.
  • Fluid retention
  • Mood disturbance
  • Sexual dysfunction, including loss of libido and vaginal dryness
  • Thrombophlebitis (inflammation with clotting in the surface veins of the limbs) (less common than with tamoxifen)
  • Fatigue
  • Dizziness

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.




What if I forget to take it one day?

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.



Adjuvant treatment of early breast cancer: Are these drugs alternatives to tamoxifen?

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:
  • Fewer recurrences of breast cancer
  • Improved disease-free survival
  • Fewer hot flashes (also called hot flushes)
  • Less vaginal bleeding
  • Less cancer of the lining of the womb (endometrial cancer)
  • Less blood clotting (thromobotic) events
  • More arthritis
  • More bone fractures from osteoporosis during the period of five years that the drugs were administered, but not after they were ceased
  • No difference in overall survival

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 placebo-controlled trial investigated whether postmenopausal women with hormone-receptor-positive tumors, who have completed five years of tamoxifen therapy, would benefit from further treatment with letrozole ("Femara"). This trial shows a reduction of breast cancer events from 5.9% in the placebo arm to 2.9% in the letrozole arm at a median follow-up time of 2.4 years. This translates to about 1 event per 100 women treated per year. This trial also shows a small benefit in overall survival but only in women whose lymph nodes were involved at the time of surgery. Further data on long-term effects will be confused, however. The reason is that the trial organizers felt that the trial should be closed to allow women on the placebo arm to take letrozole if they wished to. Long term data on the original target of the trial, which was to have been five years of letrozole treatment, will now never be known.
Aromatase Inhibitors after tamoxifen - the Italian Experience
At the San Antonio Breast Cancer Symposium in December 2003, the results were presented of an Italian study in which 448 women were randomly assigned either to continue their tamoxifen after the second year, or to switch a that point to the aromatase inhibitor, Arimidex. The patients were treated between 1998 and 2002 so the median time of follow-up is quite short at just 2 years. However, these preliminary results show that women who switched treatment had around half as many recurrences and new breast cancers.
The Intergroup Exemestane Study
In this study, published in the New England Journal of Medicine in March, 2004, 4742 postmenopausal women who had undergone excision of primary breast cancer and were then treated with tamoxifen for two to three years were randomized to either continue the tamoxifen, or switch to exemestane ("Aromasin").
The group of women who had been assigned to switch to the aromatase inactivator
exemestane had significantly longer disease free survival than women who continued to receive tamoxifen. This means that those on exemestane had fewer recurrences and fewer new primary breast cancers, but as yet there is no evidence that they LIVE longer ("overall survival").
Again this trial is supporting the fact that the aromatase inhibitors appear to be superior to tamoxifen in preventing breast cancer recurrence when used as adjuvant treatment in women who have passed the menopause.






The Breast International Group (BIG) 1-98 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:
1) five years of tamoxifen alone versus five years of letrozole ("Femara") alone; 2) the sequence of tamoxifen for two years followed by letrozole for three years; 3) the sequence of letrozole for two years followed by tamoxifen for three years.
Among the 4003 patients in the letrozole group, 84.0% remained alive and disease-free at five years compared with 81.4% of the 4007 patients in the tamoxifen group. The reduction in rates of recurrence was seen for both local (breast) recurrences and distant recurrences. Tamoxifen was associated with more venous thrombosis and embolism (clots), and more vaginal bleeding, leading to more endometrial abnormalities (changes in the lining of the womb) and endometrial biopsies. Letrozole was associated with more bone fractures, elevation of cholesterol (though this was usually mild) and more heart attacks and strokes, though these events were very rare with both treatments.
Professor Richard Gelber of Harvard Medical School and Statistician for the trial said, "The first results of BIG 1-98 demonstrate clear superiority of letrozole compared with tamoxifen to reduce the risk of breast cancer recurrence (especially in distant metastatic sites) for postmenopausal women following surgery for breast cancer which contains hormone receptors in the tumor cells.
The two drugs are well tolerated, but letrozole therapy compared with tamoxifen is associated with increased risks of bone fractures, hypercholesterolemia, and deaths without breast cancer recurrence due to cerebrovascular accident or cardiac causes. This finding, which is not associated with compromised overall survival, requires additional attention, because previous studies of the cardiovascular risk of the aromatase inhibitors have not focused properly on this aspect. Until additional information becomes available, aromatase inhibitors should be used with caution, especially in patients at elevated risk for cardiovascular disease."





Why shouldn't all women on adjuvant tamoxifen switch to Arimidex or Femara?

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.






ASCO RECOMMENDATIONS ON AROMATASE INHIBITORS IN ADJUVANT THERAPY

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.
MY ADVICE:
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.
Recently in a clinical trial called BOLERO-2 it was shown that women whose disease is resistant to Arimidex or Femara may get particularly good control with a combination of Aromasin and a new drug, everolimus ("Afinitor"). The main side-effects were soreness around the lips and mouth ("stomatitis") and high blood sugars ("hyperglycaemia"). Afinitor is already available in Australia for kidney cancer but not as yet for breast cancer. We hope that will change during 2012.






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Copyright © 2014, Professor Richard Kefford AM MB BS PhD FRACP. All rights reserved.