This small study is a phase II trial, which means the treatment being studied was given to a small number of people to make sure it works and to study its safety. If the results from a phase II trial look promising, researchers will conduct phase III trials, which means the new treatment is given to a larger group of people (more than 1,000) to confirm that it works and to see whether it's more effective than commonly used treatments.
Hormonal therapy medicines either block the effect of estrogen on hormone-receptor-positive breast cancer cells or limit the amount of estrogen produced in the body. Over time, some hormone-receptor-positive, advanced-stage breast cancers that responded to hormonal therapy stop responding.
In this small study, researchers found that giving estradiol, a form of estrogen, to 66 post-menopausal women being treated for advanced-stage, hormone-receptor-positive breast cancers that had stopped responding to aromatase inhibitors (a type of hormonal therapy) was effective on about 30% of the cancers.
The researchers split the women into two groups:
About 30% of the women in each group got benefits from the estradiol (19 women total). But the group that got the higher dose of estradiol had more side effects and the side effects were more severe.
Seven of the cancers that grew during estradiol treatment were treated again with an aromatase inhibitor. Three of the cancers responded to the aromatase inhibitor, even though before the estradiol treatment the cancers had stopped responding to aromatase inhibitors. This suggests that alternating the type of hormonal therapy medicine may cause some hormone-receptor-positive cancers that stop responding to hormonal therapy to start responding again.
Since the benefits were the same with both levels of estradiol, the researchers said the low dose of estradiol makes more sense.
Three kinds of hormonal therapy medicines are used often to treat women diagnosed with hormone-receptor-positive, advanced-stage breast cancer: aromatase inhibitors, Faslodex (chemical name: fulvestrant), and tamoxifen.
Aromatase inhibitors work by lowering the amount of estrogen in the body. The aromatase inhibitors are:
Faslodex and tamoxifen work by blocking the effects of estrogen on breast cancer cells.
If you're being treated for hormone-receptor-positive, advanced-stage breast cancer and the cancer has stopped responding to hormonal therapy medicine, consider discussing this study with your doctor. Using estradiol to treat breast cancer isn't routinely done in this situation, and most of the cancers in this study didn't respond to estradiol. Still, as you and your doctor consider your treatment options, the results of this study make it reasonable to consider whether treatment with estradiol might make sense for you.
You can find more information about the different types of hormonal therapy and how and when they're used to treat both early- and advanced-stage breast cancer in the Breastcancer.org Hormonal Therapy section.
Patients with endocrine-resistant breast cancer had identical efficacy and fewer adverse events when treated with low-dose versus standard-dose estradiol, according to results of a small randomized clinical trial.
Both doses of the estrogen led to a total clinical benefit rate of about 30%, but patients randomized to the low dose had about half as many adverse events.
Moreover, a small subset of patients reacquired sensitivity to endocrine therapy after treatment with estradiol, investigators reported in the Aug. 19 issue of the Journal of the American Medical Association.
"We found that estrogen treatment stopped disease progression in many patients and was much better tolerated than chemotherapy would have been," Matthew J. Ellis, MD, PhD, of Washington University in St. Louis, said in a statement.
The findings provided confirmation of the paradox of hormone receptor-positive breast cancer: Some tumors that become unresponsive to estrogen-lowering therapy respond to treatment with estrogen.
The earliest evidence of the paradox came from studies demonstrating the efficacy of diethylstilbestrol (DES) as treatment for breast cancer. However, the benefits were limited to postmenopausal women, suggesting that the decline in estrogen levels associated with menopause sensitized cancer cells to DES.
Some patients responded to intermittent therapy, which led to repeated disease regression with reintroduction of DES, the authors noted.
Following the introduction of tamoxifen, DES was withdrawn from the U.S. market. Estradiol, at the recommended dose of 30 mg/d, became an infrequent substitute for DES in the treatment of endocrine-resistant breast cancer.
Laboratory studies showed that prolonged estrogen deprivation had a priming effect on breast cancer cells, which underwent estradiol-induced apoptosis, the authors continued. Moreover, unopposed estrogen was associated with a reduced risk of breast cancer in the Women's Health Initiative, further stimulating interest in low-dose estrogen therapy for breast cancer.
Seeking to evaluate the efficacy and tolerability of estradiol in advanced breast cancer, Ellis and colleagues performed a phase II clinical trial involving 66 postmenopausal women with advanced, aromatase inhibitor-resistant, hormone receptor-positive breast cancer.
The patients were randomized to 30 or 10 mg/d of estradiol.
The primary endpoint was total clinical benefit, defined as response or stable disease for at least 24 weeks. Secondary outcomes included toxicity, progression-free survival, time to treatment failure, and quality of life.
The authors reported that nine of 32 patients (28%) in the standard-dose group benefited from treatment, as did 10 of 34 (29%) in the low-dose group.
Adverse events (egrade 3) occurred significantly more often with standard-dose estradiol (34% versus 18%, P=0.03).
Using PET imaging, the authors explored potential predictors of response to estradiol. They found that an estradiol-stimulated increase in fluorodeoxyglucose F 18 e12% had an 80% positive predictive value for response.
Seven patients who subsequently progressed during estradiol therapy were retreated with an aromatase inhibitor. Two had a partial response and one had stable disease, suggesting the cancer had become resensitized to anti-estrogen therapy.
"This raises the possibility of alternating therapy to induce repeated regressions," Ellis said in an interview. "That should be evaluated in a prospective clinical trial. Additionally, the optimal dose and duration of therapy need to be determined."
The study "is particularly intriguing" because the lower dose of estradiol was associated with fewer adverse events with no loss of efficacy compared with standard-dose therapy, Pamela N. Munster, MD, of the University of California San Francisco, and John T. Carpenter, MD, of the University of Alabama at Birmingham, said in an editorial.
"The comparable efficacy in the setting of significant differences in toxicities between two doses supports further testing of low-dose estrogen in patients with breast cancer resistant to aromatase inhibitors," they concluded.
The study was supported by the National Cancer Institute and the AVON Foundation.
Co-author Barry A. Siegel, MD, disclosed financial relationships with Radiology Corporation of America, Cardinal Health, DMS Imaging, GE Healthcare, PETNET Solutions, Philips Medical Systems, and Siemens.
Carpenter disclosed relationships with AstraZeneca, Novartis, GlaxoSmithKline, Ortho Biotech, Genentech, Lilly, Amgen, and MGI Pharma.
Primary source: JAMA Source reference: Ellis MJ, et al "Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer" JAMA 2009; 302(7): 774-80.
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