Finding the Right Combination

For ER-positive breast cancer, researchers look to find which drugs work best, how they should be sequenced, and how long they should be taken.

Many women develop breast tumors that are sensitive to estrogen—a female hormone that feeds a tumor’s growth and development. So for the past 15 years, researchers have experimented with drugs that either lower the production of estrogen in the body or keep a tumor from exploiting it. What hasn’t been clear is which drugs work best, how they should be sequenced, or how long they should be taken.

On Thursday, during the San Antonio Breast Cancer Symposium, researchers presented the latest data from ongoing studies that try to clarify how these drugs should be used. Most of the research compares tamoxifen—one of the oldest and best known breast cancer drugs—to newer drugs called aromatase inhibitors. Whereas tamoxifen blocks estrogen, aromatase inhibitors—known by the brand names Arimidex (anastrozole), Aromasin (exemestane), and Femara (letrozole)—decrease the amount of estrogen in the body.

The New England Journal of Medicine

Studies have already found that women with early breast cancer who take tamoxifen for five years may reduce their risk of recurrence by about 50 percent, but that still leaves a lot of women who will once again face cancer. So scientists want to know whether aromatase inhibitors will improve that number, either when used as an alternative to, or in sequence with tamoxifen. In 2005, in the , researchers reported that one aromatase inhibitor, Femara, did a better job of reducing recurrence than tamoxifen in a study of 8,000 women. Data from this trial presented in San Antonio last year reported a recurrence risk among women taking Femara that was about 19 percent lower, and survival was 13 percent better.

This study, called BIG 1-98, compared four different combinations: five years of tamoxifen, five years of Femara, two years of Femara followed by three years of tamoxifen, or two years of tamoxifen followed by three years of Femara. Women who switched to tamoxifen after Femara did as well as women who just took the aromatase inhibitor the entire time.

So far, using an aromatase inhibitor for five years—as opposed to using it in sequence with tamoxifen—hasn’t improved outcomes, says Eric Winer, MD, director of breast oncology at the Dana-Farber Cancer Institute in Boston. While aromatase inhibitors have reduced recurrences, Winer said, so far “this has not seemed to translate into big differences in survival.”

On Thursday, scientists reported that recently released BIG 1-98 results were probably inaccurate because many women scheduled to take tamoxifen for five years switched medications mid-way through the study. These women were given the option of switching to Femara after the 2005 analysis found that women taking Femara were faring better. About one in four women chose to make that switch. The option to switch drugs complicated the statistical analysis, making it difficult to compare tamoxifen to Femara because some women in the “tamoxifen” group had actually taken both drugs. “We don’t know what would have happened had they stayed on tamoxifen,” said Meredith Regan, ScD, a statistician with the study. To try to account for that issue, the study investigators used statistical adjustments to estimate what might have occurred had 25 percent of the women not switched. In San Antonio, Regan presented the results: women taking Femara had an overall survival about 17 percent higher than those taking tamoxifen.

Other studies described last year in San Antonio evaluated different brands of aromatase inhibitors. Researchers from Great Britain presented the only study so far to compare another aromatase inhibitor drug, Aromasin, to tamoxifen. In that study, researchers divided almost 10,000 women into two groups. Half received tamoxifen and half Aromasin. Last year, the researchers reported that women who took Aromasin were 11 percent less likely to have a recurrence. Three years into the study, women taking tamoxifen were switched to Aromasin after results from a similar trial suggested that women fared better when they switched to Aromasin after two to three years of tamoxifen.

In San Antonio this year, scientists reported whether the women who initially started on Aromasin did better than the women who switched later from tamoxifen. “There is no difference whatsoever,” said researcher Daniel Rea, MD, of the University of Birmingham, either in the likelihood of cancer recurring or in survival. In fact, the results were close to identical.

Another study examined whether being premenopausal at diagnosis made a difference in outcomes (all women were menopausal during the study, either naturally or because of treatment). Premenopausal women who took tamoxifen for five years, followed by Femara, were less likely to have a recurrence than women who took only tamoxifen.

Even with the new data, studies of aromatase inhibitors alone or in various combinations with tamoxifen have been difficult to interpret, Winer says. All the drugs in question have strengths and weaknesses to consider in terms of costs and side effects, and none has emerged markedly worse than the others. For example, tamoxifen may better protect a woman’s cardiovascular system—not a small consideration, as women with breast cancer today are likely to need a healthy heart for years to come.

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This article is a part of ’s 2009 San Antonio Breast Cancer Symposium coverage. To read more articles from SABCS 2009, visit sabcs2009.curetoday.com.