LOW DOSE ESTRADIOL FOR BREAST CANCER TREATMENT

August 25, 2009 – Metastatic breast cancer that has become resistant to an aromatase inhibitor could benefit from treatment with estradiol.

In a new phase 2 randomized study of 66 patients, clinical benefit rates of 28% and 29% were found in patients treated with 6 mg and 30 mg daily doses of oral estradiol, respectively.

Because low-dose (6-mg) estradiol had less toxicity and fewer effects on quality of life, it was recommended for further study by the investigators, whose new paper is published in the August 19 issue of the Journal of the American Medical Association.

All of the patients had been treated with aromatase inhibitors, which reduce levels of estrogen, for at least 24 weeks, and all had acquired resistance to these agents.

Using estradiol, the most potent of the 3 estrogens naturally produced in the body, as a treatment is paradoxical because the study participants' breast cancers were hormone-receptor-positive and thus stimulated by estrogen.

"The women in the study had all experienced a relapse while on estrogen-lowering drugs, and their disease was progressing," said lead author Matthew J. Ellis, MD, PhD, in a press statement, "so they were faced with undergoing chemotherapy. We found that estrogen treatment stopped disease progression in many patients and was much better tolerated than chemotherapy would have been," added Dr. Ellis, who is an oncologist with the Siteman Cancer Center at Washington University and Barnes-Jewish Hospital in St. Louis, Missouri.

Estradiol May Resensitize Some Tumors

Estrogens have been recommended as treatment for breast cancer since 1960 but have fallen out of favor clinically in recent years because of the emergence of a variety of antiestrogen agents and the use of chemotherapy, according to an editorial accompanying the study.

Nevertheless, this study and at least 1 other suggest that "sustained clinical benefit can be achieved by alternating between inhibitory and stimulatory estrogen-receptor modulation," write the editorialists, Pamela N. Munster, MD, from the University of California, San Francisco, and John T. Carpenter, MD, from the University of Alabama at Birmingham.

Indeed, in the current study, estradiol treatment not only stopped disease progression in about a third of patients, but in some patients, metastatic tumors became resensitized and again responded to antiestrogen treatments, say the editorialists.

About 40,000 women die of metastatic breast cancer each year, and estrogen therapy could potentially help thousands of women, said Dr. Ellis, noting that the therapy costs less than a dollar a day.

Study Details

Study participants, who had metastatic breast cancer that had been treated with an aromatase inhibitor and who had progression-free survival (≥24 weeks) or relapse (after ≥2 years), were randomized to either 6 mg (n = 34) or 30 mg (n = 32) of estradiol. Patients at high risk for estradiol-related adverse events were excluded.

Patients were examined after 1 and 2 weeks, and every 4 weeks thereafter, for clinical and laboratory toxicities and flare reactions. Tumor radiological assessment occurred every 12 weeks. At least 1 measurable lesion was evaluated for response.

The primary end point in the study, clinical benefit rate (defined as tumor response plus stable disease at 24 weeks), was achieved in 9 of 32 patients (28%; 95% confidence interval [CI], 18% - 41%) in the 30-mg group and in 10 of 34 patients (29%; 95% CI, 19% - 42%) in the 6-mg group.

An estradiol-stimulated increase in fluorodeoxyglucose F-18 uptake (≥12% prospectively defined), measured by positron emission tomography/computed tomography, was predictive of response (positive predictive value, 80%; 95% CI, 61% - 92%). However, it was possible to assess these estrogen-induced "flares" in only 46 patients (70%).

Seven patients with estradiol-sensitive disease were retreated with aromatase inhibitors at estradiol progression (2 of whom achieved partial response and 1 of whom achieved stable disease), suggesting resensitization to estrogen deprivation, report the authors.

The adverse-event rate (≥grade 3) was higher in the 30-mg group (11/32 [34%]; 95% CI, 23% - 47%) than in the 6-mg group (4/34 [18%]; 95% CI, 5% - 22%; P = .03).

The adverse effects associated with the 30-mg dose of estradiol led to treatment discontinuation in 4 of 32 patients; only 1 patient withdrew from therapy at the 6-mg dose, and that was for personal reasons.

Low Dose is Intriguing

Up until 1971, when tamoxifen was introduced, high doses of estrogens were one of the "few nonsurgical options for the breast cancer treatment," write the editorialists. Clinical trials at that time indicated that tamoxifen and high-dose estrogen in postmenopausal woman with advanced breast cancer had similar results, but that the adverse effects of estrogen were worse, they note.

The new study is "intriguing" because clinical benefits were observed at low doses, with reduced toxicities.

"These findings suggest that in contrast to the toxicities observed with the 30-mg dose in this study and reported in previous studies, a lower dose of 6 mg of estrogen can be administered with acceptable toxicities and fewer profound effects on quality of life," write the editorialists.

The editorialists also note that it is very likely that the resistance to aromatase inhibitors seen in the study was likely acquired rather than de novo. They believe that the likelihood stems from the long median time from initial diagnosis (82 months in the 30-mg group; 90 months in the 60-mg group).

The study was supported as individual cancer-center supplements from an Avon Foundation and National Cancer Institute Partners for Progress Award. The authors have disclosed no relevant financial relationships.

JAMA. 2009;302:774-780 and 797-798. Abstract