Q. I've been on tamoxifen for a couple of years, and now my doctor is switching me to an aromatase inhibitor. I understand how tamoxifen works, but this AI is a whole new thing... how does it work?
A. Aromatase inhibitors (pronounced aroma-tase: just like it looks) come in three basic flavors: Femara
® (letrozole), Arimidex
® (anastrozole), and Aromasin
® (exemestane). They're all known as third-generation AIs, meaning they're the third round of this type of drug to be developed-and the most successful so far.
AI's are the current drug of choice for postmenopausal women with ER- or PR-receptive (estrogen or progesterone receptive) breast cancer-either following a 2-3 year course of tamoxifen, or right out of the gate, post-surgery/chemo/radiation.
So, how does an AI work, exactly? Aromatase is an enzyme that turns the hormone androgen into estrogen. No aromatase = no estrogen. No estrogen = breast cancer cells can't grow (in women with hormone-receptive cancer). An aromatase inhibitor does exactly what it says: it inhibits the enzyme from doing its job. How? By binding itself, either temporarily (Arimidex, Femara) or permanently (Aromasin) to aromatase so that it becomes dysfunctional, and can't turn androgen into estrogen.
Tamoxifen works by preventing estrogen from binding to breast cancer cells and helping them grow. But an AI will actually reduce the amount of estrogen in your body by 90% to 95% - though only in postmenopausal women, which is why AIs are only recommended for women who've stopped having their period. Women whose ovaries are still active, who are still menstruating, produce too much estrogen for AIs to be effective. Thus, the decision for a woman having hormone therapy to start right in on an AI (vs. taking tamoxifen for awhile) may depend on whether her chemotherapy-induced menopause is permanent, or only temporary. If permanent, her doctor might start her on an AI right away. If temporary, and she remains pre-menopausal, she's not a candidate for an AI.
Q. How does the doctor decide whether I should take Aromasin, Arimidex, or Femara? Are they basically all the same, just made by different drug manufacturers?
A. They're all similar, but not exactly the same. Aromasin binds permanently to aromatase. Arimidex and Femara can bind with aromatase, then let go (this is called "reversible binding.") But they're so aggressive that their presence in your body means they will invariably shoulder any aromatase out of the way-kind of like that pushy person who always manages to get a seat in musical chairs.
Understand that all of these third-generation AIs are still very new, and results of long-term clinical trials are barely starting to come in. Some of the larger clinical trials include testing the effectiveness of tamoxifen vs. Arimidex (the ATAC trial, completed in 2005); Femara given after 5 years of tamoxifen vs. no further treatment after 5 years of tamoxifen (MA-17 trial, ended prematurely in 2003 when the results clearly showed Femara reducing recurrence risk significantly); and 5 years of Femara vs. 5 years of tamoxifen, head to head (the BIG trial, completed in 2005). All three trials showed the AI having a significant advantage over tamoxifen. Remember, all of these trials involve post-menopausal women, NOT pre-menopausal.
At this point, there's less data on Aromasin. One study, just completed this year, showed that women who take tamoxifen for 2-3 years, then switch to Aromasin for 2-3 years do better long-term than women who take tamoxifen alone for 5 years. Aromasin seems to extend tamoxifen's benefits. Another large trial, the TEAM trial, is comparing 5 years of Aromasin, taken right out of the gate (no tamoxifen) vs. tamoxifen followed by Aromasin. Results are expected next year.
WHEW With all that data, how DO physicians decide what to give you? Well, depends on your doctor. There's a lot of data comparing tamoxifen and AIs, but very little comparing the three AIs to one another, in terms of benefits and side effects. It's known that Femara inhibits (suppresses) 99% of aromatase in the body, while Arimidex and Aromasin trail by a couple of percentage points. For some doctors, that's reason enough to recommend Femara. On the other hand, it's been shown that Femara and Aromasin (but not Arimidex) can raise cholesterol levels, thus possibly increasing a woman's risk of heart attack and stroke very slightly; so women at risk for stroke or heart problems may be guided towards Arimidex.
Some researchers feel, however, that it is not possible to differentiate which of these drugs truly raise cholesterol and that this may be a problem of trial design - that the raising of cholesterol is probably a "class effect" seen in all three aromatase inhibitors.
Some doctors (mine, for example) feel that Arimidex, which is the "weakest" of the three, actually provides some added benefit by NOT suppressing as much aromatase. They feel that a tiny bit of estrogen in your body is better than none at all. They claim that it doesn't increase your risk of recurrence, and provides other health benefits. So they'll recommend Arimidex ahead of Femara or Aromasin.
As far as FDA approvals go, Arimidex is approved for women with breast cancer that hasn't metastasized past the lymph nodes (early stage disease). Femara is approved for women with early stage disease who've completed 5 years of tamoxifen. And Aromasin has FDA approval for women with early-stage cancer who've completed 2-3 years of tamoxifen; and for women with metastatic cancer who haven't responded to tamoxifen.
Q. Well, I can see why it's not a cut-and-dried decision, which one to take. Sounds like their benefits are pretty similar; but what about their side effects?
A. Actually, their side effects are pretty similar, too, with some minor differences. Many doctors will switch a woman from one AI to another to another based on her reaction to each one, choosing the one that ultimately gives her the fewest negative side effects.
Here are the side effects that are common to all AIs. Remember, YOU may not experience these; every woman's experience with a particular drug is hers and hers alone.
- joint and muscle pain;
- hot flashes;
- vaginal dryness, which can lead to yeast infections and painful intercourse;
- loss of bone density, leading towards osteoporosis;
- weight gain.
Of these side effects, joint, muscle, and bone pain are the most widely experienced and troublesome. About a third of women who take an AI don't (or barely) experience this side effect; about a third have stiffness and pain upon first getting up in the morning, but once they get going they're fine; and about a third have more frequent or severe pain. As many as 20% of the women in some studies stopped taking AIs because of pain. Which is a shame, because AIs have absolutely been shown to help prevent both breast cancer recurrence, and death from breast cancer.
If you start taking one AI and find the side effects bothersome, ask your doctor if you can switch to one of the others; you may have a better experience.
One of tamoxifen's side effects, risk of uterine or endometrial cancer, is notably absent in AIs: thankfully, none have been shown to lead to another cancer.
Q. And how long will I take whichever aromatase inhibitor it is I end up taking?
A. Just like tamoxifen, you'll take one pill every day. Studies have shown that it's important to take your AI regularly-even more important than it is to take tamoxifen regularly. Don't forget to take it, or let your prescription run out, or otherwise get caught short-taking that little white pill EVERY day is the only way to get its full benefit.
As for how long you'll take it - news at 11. At this point, all of us taking AIs are guinea pigs. (Physician's Note: Doctors might interject here that taking an FDA approved drug after an informed discussion with a licensed and treating physician does not meet their opinion of "guinea pig." Participating in important clinical trials can make a significant different in the way we treat breast cancer, so don't let fear of being a "guinea pig" dissuade you from making an otherwise informed choice about clinical trials). Is 5 years best for aromatase inhibitor use? Is 7 years better? How about 10 years? There just hasn't been sufficient data collected (yet) to draw hard and fast conclusions. You'll probably be on your AI for 3 years minimum, if you're switching over from tamoxifen; or for 5 years minimum, if you haven't taken tamoxifen. Beyond that, who knows? By 2 or 3 or 5 years from now, more studies will have been completed, and there'll be better data on which your oncologist can base his recommendations. Good luck!