Antiestrogen Combo New Standard for Metastatic Breast Cancer?

Drug Combination Extends Survival by 6 Months

Ron Zimmerman

December 07, 2011

December 7, 2011 (San Antonio, Texas) — Women with metastatic breast cancer have extended survival if their physicians simply combine anastrazole (Arimidex, AstraZeneca) and fulvestrant (Faslodex, AstraZeneca), a study presented here at the 34th Annual San Antonio Breast Cancer Symposium shows.

Women taking the 2 drugs in combination lived more than 6 months longer than women who took the drugs sequentially, according to the researchers who presented their findings.

"This will likely change the standard of care," said coauthor Kathy Albain, MD, from Loyola University Medical Center in Chicago, Illinois.

Study coauthor Rita Mehta, MD, from the University of California at Irvine, said the study's results are particularly exciting because in more than a decade, "these patients have not had a new treatment that gave them an overall survival benefit."

Anastrozole is an aromatase inhibitor that works by decreasing estrogen in a patient, which is the hormone that fuels breast cancer. Fulvestrant binds to estrogen receptors, blocking estrogen's effect on cancer cells. Anastrozole is taken in pill form and fulvestrant is injected.

Both drugs are already used to treat breast cancer, although they are not typically given in combination. Researchers reason that the different modes of action of the 2 drugs make the combination effective against hormone-receptor-positive breast cancer, which accounts for more than half of all breast cancers. A majority of deaths from breast cancer occurs among women in this group.

"If we take away [both] estrogen and the estrogen receptor, the 2 together should be better than just doing 1 at a time, said Dr. Mehta.

This study involved 707 postmenopausal women with hormone-receptor-positive metastatic breast cancer who were randomized to either sequential or combination therapy. Half of the women received the standard regimen, which is to start with anastrozole, and when the disease progresses, to switch to fulvestrant. The other half of the study group was assigned to receive the 2 drugs in combination. The anastrozole dosage was the same in both study groups — 1 mg daily. Those in the combination group also received a 250 mg injection of fulvestrant every 28 days, after an initial set of injections (500 mg on day 1 and 250 mg on day 14) to establish a base level of fulvestrant in their bloodstreams.

Women treated with the standard regimen survived a median of 41.3 months; those treated with the combination survived a median of 47.7 months.

The combination produced its greatest result in women who had not previously been treated with tamoxifen. About 60% of patients in each study group were tamoxifen-naïve; in this subset of women, those treated with the standard regimen survived a median of 39.7 months, and those treated with the combination survived a median of 47.7 months.

The study authors caution that the effect of previous tamoxifen use is unclear. "We need to better understand other possible factors, since the prior tamoxifen factor could be a false lead from an unplanned analysis," said Dr. Mehta. She suggests that a next step for researchers should be "to try the combination at even earlier stages of breast cancer to test whether long-term cures could be increased at those stages."

Adverse effects were similar in both groups, although some women in the combination group suffered the most severe adverse effects (1 stroke and 2 pulmonary embolisms).

This combination has already found its way into physicians' practices. C. Kent Osborne, MD, director of the Dan L. Duncan Cancer Center at the Baylor College of Medicine in Houston, Texas, told Medscape Medical News that he currently uses fulvestrant in combination with aromatase inhibitors at his clinic. "I combine the 2 at progression to an aromatase inhibitor because studies have shown that [fulvestrant] works best in a low-estrogen environment."

Although fulvestrant, 250 mg, was used in this study, an AstraZeneca spokesperson told Medscape Medical News that the US Food and Drug Administration has now approved a 500-mg dose after results of another phase 3 study showed that the higher dose reduces risk for disease progression by 20% compared with the 250-mg dose. That study also showed that the side effect profile of the higher dose was similar to that of the lower dose. A 250-mg dose is recommended for patients with moderate liver impairment.

The study trial was funded by the National Cancer Institute and AstraZeneca. Dr. Osborne has disclosed no relevant financial relationships.

34th Annual San Antonio Breast Cancer Symposium (SABCS): Abstract SWOG S0226. Presented December 7, 2011.

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