A low dose of generic estradiol is as effective and safe as a conventional high dose for treatment-resistant, advanced estrogen receptor-positive breast cancer, according to results of a randomized phase II clinical trial.
The data were presented at the San Antonio Breast Cancer Symposium (SABCS) in December 2008.
Before the discovery of tamoxifen in the 1970s, doctors used estradiol, a naturally occurring form of estrogen, to treat some hormone-sensitive breast cancers. Given in high doses of 30 milligrams (mg) or 15 mg, estradiol kills breast cancer cells. Because women sometimes had severe side effects—including blood clots, nausea and bloating—doctors stopped using estradiol after they found tamoxifen was as effective but caused fewer side effects.
Today, aromatase inhibitors are a gold standard treatment for metastatic breast cancer in postmenopausal women. Aromatase inhibitors work by dramatically lowering the level of natural estrogen, which can fuel cancer growth. The medicines in this family approved for metastatic breast cancer are anastrozole (brand name: Arimidex), letrozole (brand name: Femara) and exemestane (brand name: Aromasin).
Over time some cancers that initially respond to aromatase inhibitors stop doing so. Researchers in this study tested the theory that cancers that begin growing again may do so because they became "super sensitive" to estrogen. In this environment, these "super sensitive" cancers grow in the presence of low levels of estrogen that remain in women taking aromatase inhibitors. The researchers theorized that higher doses of estrogen might kill these "super sensitive" cells, making the cancer cells again respond to aromatase inhibitors.
To study their theory, the researchers tested the standard dose of estradiol against a lower dose, in the hopes the lower dose would be just as effective as the higher dose but prompt fewer side effects.
The 66 postmenopausal participants were assigned randomly to one of two study arms:
Arm 1 received 30 mg of estradiol daily, the standard dose.
Arm 2 received 6 mg of estradiol daily, the dose under study.
Thirty-four women received the 6 mg dose and 32 women received the 30 mg dose. All participants had been treated previously with an aromatase inhibitor. The medicine had either worked for six months or more for the metastasis, or it stopped working to prevent metastasis of the first breast cancer (adjuvantly) after two years or more.
Doctors stopped estradiol treatment if the cancer progressed and switched participants back to an aromatase inhibitor.
Up to one-third of participants benefited from estradiol treatment, with 25 percent in the high-dose arm and 29 percent in the low-dose arm having at least six months of stable disease, or no growth or progression of the cancer.
Three participants had progression of the cancer after successful treatment with estradiol and switched back to an aromatase inhibitor; in one case so far, the cancer responded.
The independent committee reviewing this study closed the 30 mg arm after finding the 6 mg dose was just as effective as the 30 mg dose and had fewer side effects.
What Does This Study Mean for Me?
This small study shows that a low dose of generic estradiol may be useful for hormone-sensitive metastatic breast cancer that progresses after treatment with an aromatase inhibitor; however, this study is too small for the findings to be applied to day-to-day practice. Instead, the findings suggest another promising avenue for treating metastatic breast cancer.
If you have the type of breast cancer studied in this clinical trial, are postmenopausal and have been treated with an aromatase inhibitor that stopped working, you might want to discuss this trial with your healthcare team, or ask whether similar studies may be available to you. You should understand the benefits and risks before embarking on estradiol therapy.
Ellis, MJ et al. A randomized phase 2 trial of low dose (6 mg daily) versus high dose (30 mg daily) estradiol for patients with estrogen receptor positive aromatase inhibitor resistant advanced breast cancer. Presented at the 31st Annual San Antonio Breast Cancer Symposium. Abstract 75.