Postmenopausal women who have survived breast cancer may have a new way to prevent recurrences, according to the results of a recently released study.
The international study of 5,187 postmenopausal women found that the drug letrozole, when taken after completing five years of tamoxifen therapy, cut breast cancer recurrences by almost half. These results were so significant that the study was stopped early to get the news to women as quickly as possible.
Numerous institutions participated in this study, including the University of Maryland Medical Center's Greenebaum Cancer Center (GCC). Katherine H. Tkaczuk, M.D., Director of the GCC's Breast Evaluation Program, was the local principal investigator for the study. Dr. Tkaczuk, along with research nurse Nancy Tait, enrolled six patients in this trial.
Letrozole is one of a new class of drugs known as aromatase inhibitors, which work by reducing body levels of estrogen in postmenopausal women.
In fact, this class of drugs (aromatase inhibitors) was discovered and developed at the University of Maryland Medical Center by Angela Brodie, Ph.D., who heads a GCC research program and is a professor of pharmacology at the University of Maryland School of Medicine. Brodie was the one who developed the basic chemistry/pharmacology of these drugs.
Below, Barry Meisenberg, M.D., Deputy Director of Clinical Affairs and head of the GCC's division of Hematology/Oncology, discusses the implications of the recent study.
Can you tell us briefly about the study and the results?
The study aimed to answer a specific question: Does additional hormonal therapy after tamoxifen improve the outcomes?
All the women in this study had some form of surgery and sometimes radiation. Their local cancer was treated with either surgery or lumpectomy and radiation. All of the tumors were hormone receptor positive (estrogen-receptor positive breast cancer) so that qualified them for tamoxifen.
Previous studies of tamoxifen have shown that five years appears to be the best duration. The standard of care has been five years. This study looked at a different class of drugs that inhibit estrogen formation in different ways to see if adding that to tamoxifen would give a superior outcome. Half the patients in the trial received the agent letrozole once a day and half received a placebo.
Early results are monitored in case there's a difference in the outcome. There was an independent statistical board that looks at differences in outcome. If they see a large enough difference (between the placebo and people receiving the drug) they have the authority and the ethical obligation to close the study early and notify all the women who are on placebo so they have the option of taking the active drug. That's what happened in this case.
The findings specifically were that there was a reduction in the recurrence rate of breast cancer over this period of time. It was a reduction of about 42 percent, which is large. The average person in this study was on therapy only for 2 ½ years, before these differences were appreciated and the study closed early.
Why is letrozole only indicated for postmenopausal women?
Because premenopausal women have a very high production of estrogen in their ovaries and this kind of therapy might not be appropriate since it shuts down the peripheral production of estrogen.
The study was designed just for postmenopausal women because they are the ones where the estrogen production is occurring primarily in tissues other than the ovary. Also, previous studies had shown that the aromatase inhibitors had good activity against more advanced forms of breast cancer in postmenopausal women.
Why is letrozole only effective with estrogen-sensitive breast cancer?
Because estrogen-sensitive breast cancers use estrogen as a growth factor. So if you have a breast cancer that doesn't use estrogen as a growth factor, then inhibiting estrogen production binding (tamoxifen) or production (aromatase inhibitors) has no effect.
Who is the best candidate for letrozole treatment?
Postmenopausal women with hormone receptor positive breast cancer who have been on tamoxifen for the currently recommended dose of five years. These women now have an alternative therapy to consider. The breast cancer has to be hormone sensitive; otherwise, letrozole is not beneficial.
In this study, the women had been off tamoxifen for no more than three months before beginning letrozole. But could women who have been off tamoxifen for two or even three years also benefit? Could letrozole have the same protective effect for women who stopped taking tamoxifen years ago?
It's unknown. Like all good studies, this study raises more questions than it answers. It's also unknown if you actually need the full five years of tamoxifen. Maybe if you use letrozole as a follow-up you only need three years. We also don't know how long a patient needs to be on letrozole. The average person on this study was on it for 2 ½ years.
What are the long-term side effects?
We don't know what the long-term side effects are for prolonged letrozole use. According to the study, the side effects were low-grade hot flashes, which you would expect with estrogen deprivation, arthritis and muscle pain (more frequent in the letrozole group). There was a slight increase in osteoporosis (new diagnosis of osteoporosis) during the course of the study, but it wasn't a huge difference. But this [was] only after 2 ½ years. What would it be after five or ten years? We don't know.
The other concern would be, we know that estrogen appears to play some role in maintaining cardiovascular health. So what's the net effect of deprivation of estrogen for prolonged periods of time?
The study raised many questions that we don't know the answers to.
A chief question that every patient would have is, "Is this an appropriate therapy for me?"
There is no uniform answer to that question. Every woman in this situation should have a discussion with their physician and the decision based upon their individual risk for recurrence. Some women are already taking aromatase inhibitors instead of tamoxifen after their surgery and the results of this study were not applicable to them.
For women who are at low risk, it might not be worthwhile to take this medication. Whereas for women who are at the higher risk, it may well be worth the side effects because they continue to be at high risk even after finishing tamoxifen. We have to do risk profiling and figure out which women remain at high risk and should get this therapy and which women should not.
What else has letrozole been used to treat?
Letrozole is not a new medication. The therapy was already available for treatment of advanced disease (metastatic breast cancer). Letrozole has been shown to be better than tamoxifen for patients with metastatic breast cancer. But this new study opens up the therapy for women who have not yet had metastatic breast cancer.
Could letrozole be a replacement for tamoxifen?
This study did not evaluate that question. There has been another study done of a different aromatase inhibitor called Arimidexd and the results are promising but not fully mature. So right now we are not recommending that women already on tamoxifen stop and switch to one of these drugs.
Is letrozole offered at the Greenebaum Cancer Center?
Yes, it can be prescribed and filled anywhere. Women who would like more information about letrozole as a possible treatment can call the Greenebaum Cancer Center for a consultation at the Breast Evaluation Program at 1-800-492-5538.