April 21, 2010 (Washington, DC) — Long-term data from the landmark Study of Raloxifene and Tamoxifen (STAR) confirm that both drugs reduce the risk for breast cancer.
"There is no longer any doubt about the effectiveness of these agents," said Gabriel Hortobagyi, MD, chair of breast medical oncology at the University of Texas M.D. Anderson Cancer Center in Houston.
Only bilateral prophylactic mastectomy is more effective" in decreasing breast cancer risk, he pointed out.
However, only an estimated 5% to 20% of "the tens of thousands" of eligible women in the United States agree to start taking these drugs, Dr. Hortobagyi said.
"We need to reassess why we don't use these drugs more broadly," he added.
Dr. Hortobagyi was speaking here at the American Association for Cancer Research (AACR) 101st Annual Meeting, acting as a discussant for the STAR long-term results. These results were presented by D. Lawrence Wickerham, MD, from Allegheny General Hospital in Pittsburgh, Pennsylvania, and published online April 19 in Cancer Prevention Research.
STAR compares raloxifene and tamoxifen, both selective estrogen-receptor modulators (SERMs), in postmenopausal women with an elevated risk for breast cancer.
"More than 70% of the study participants had 1 or more first-degree relatives with a history of breast cancer," Dr. Wickerham explained.
The results were good news: both agents continue to prevent breast cancer at 81 months or, put another way, after 60 months of daily treatment plus another 21 months of follow-up.
Compared with earlier 47-month data, these long-term data show that "differences had begun to emerge" between the 2 drugs in terms of efficacy and toxicities, said Dr. Wickerham. Still, "both drugs represent an important step in preventing breast cancer," he summarized.
Empty Hall a Metaphor
The results were reported and discussed in a late-breaking presentation that had been added to a plenary session, which was housed in one of the largest halls of the Walter Washington Convention Center.
Although the meeting had a reported 17,000 attendees, comprised of scientists, clinicians, and industry representatives, the 7,500-seat hall was almost entirely empty — only about 200 people sat in the cavernous space.
The entire scenario seemed like metaphor for the experience of breast cancer chemoprevention agents in the United States: impressive data but poor reception.
Tamoxifen has not been "widely used for breast cancer prevention, in large part because of the increased risk for endometrial cancer and thromboembolic events associated with its use," the STAR authors write in their paper.
The reasons for the lack of use of raloxifene in chemoprevention are less clear.
"It's a mystery," said Judy Garber, MD, director of the Cancer Risk and Prevention Program at Dana-Farber Cancer Institute in Boston, Massachusetts, and president-elect of the AACR. She was speaking at an AACR press conference about the STAR results, and especially championed the use of raloxifene for postmenopausal women at elevated risk for breast cancer.
"Raloxifene does not cause endometrial cancer at all," she emphasized in an interview with Medscape Oncology.
Empty Hall Explained, New Data Described
The lack of an audience for the STAR presentation had some explanations.
As a late-breaking presentation, it was not included in the meeting materials; thus, meeting goers could not schedule it ahead of time. AACR is also a burgeoning meeting, with growing numbers of presentations that compete for attendees' attention.
At the STAR press conference, Scott Lippman, MD, from the M.D. Anderson Cancer Center and editor-in-chief of Cancer Prevention Research, noted that the professional audience that is most important to educate about SERMs and breast cancer chemoprevention is not oncologists, but primary care physicians.
"It's a crime not to have a discussion [about chemoprevention] between a primary care provider and a woman at risk for breast cancer," said Dr. Lippman.
That discussion can now include the long-term data from STAR, he added.
In the trial, which is also known as the National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol P-2, more than 19,000 postmenopausal women with an elevated risk for breast cancer were randomized to either raloxifene or tamoxifen.
In initial reporting of results at 47 months, there was no significant difference between the 2 trial groups in the incidence of invasive breast cancer, the primary end point. Both drugs had an estimated decreased incidence [of invasive breast cancer] of approximately 50%, compared with untreated women (JAMA. 2006;295:2727-2741).
In the new report, with a median follow-up of 81 months, the STAR study authors write that "raloxifene no longer appears to be as effective as tamoxifen in preventing primary invasive breast cancer."
However, long-term raloxifene retained 76% of the effectiveness of tamoxifen in preventing invasive disease, "which represents as much as a 38% reduction in invasive disease (compared with an untreated group)," write the authors.
Raloxifene is also about 78% as effective as tamoxifen in preventing noninvasive disease, they report.
Dr. Wickerham addressed the issue of the waning of raloxifene's preventative powers over time, and suggested that it is because raloxifene is less potent.
He observed that raloxifene has a "short half life" in the body, compared with tamoxifen, which has a relatively long half life. "The antitumor activity of raloxifene depends on taking the pill," said Dr. Wickerham.
However, the superiority of tamoxifen at 81 months "comes with a cost," write the STAR authors: "significantly more endometrial cancers, hysterectomies for benign disease, thromboembolic events, and cataracts."
But this risk for endometrial cancer with tamoxifen needs to be kept in perspective, Drs. Garber and Hortobagyi said during the STAR press conference.
In another study, the Breast Cancer Prevention Trial (BCPT), which compared SERMs and placebo, the total risk for endometrial cancer among women taking tamoxifen for 5 years was 1.25%, said Dr. Garber. "It's a very small total risk," she said.
On the basis of the STAR results, which women should take which SERM to decrease their risk for breast cancer?
"For postmenopausal women with elevated risk, these results should encourage widespread acceptance of raloxifene for breast cancer risk reduction, especially in women with an intact uterus who also face a risk of osteoporosis and facture," write the STAR authors, referring to raloxifene's indication as treatment for osteoporosis.
"The results should also promote greater acceptance of tamoxifen (given its greater efficacy) by premenopausal women who are at a very high risk of breast cancer," they add.
Convincing women to take tamoxifen might be a harder sell, suggested another expert in chemoprevention for breast cancer.
"What women tend to do is equate the risk for breast cancer and uterine cancer," Mary Daly, MD, chair of the Department of Clinical Genetics at Fox Chase Cancer Center in Philadelphia, Pennsylvania, told Medscape Oncology.
Theories About Raloxifene and Tamoxifen
In his presentation at AACR and in an interview with Medscape Oncology, Dr. Hortobagyi discussed 4 major factors that he believes have negatively affected the uptake of the raloxifene and tamoxifen for the prevention of breast cancer.
First is the "misunderstanding of side effects," he said. "It was reported that tamoxifen increased the risk of endometrial cancer 3-fold." But the absolute numbers of affected patients was "miniscule," he explained.
Second is the "total ignorance of the data" and the missed message that "help was available."
Third is the confusing "mix" of osteoporosis and breast cancer prevention messages that accompanied data from the raloxifene clinical trials, such as Multiple Outcomes of Raloxifene (MORE). In addition, bisphosphonates, which are "very strong drugs," came onto the market at about the same time, said Dr. Hortobagyi. He also believes that Eli Lily, the makers of raloxifene, did not invest in marketing the drug as much as the bisphosphonate makers.
Last, the results from the Women's Health Initiative were damaging, despite their lack of relevance to SERMs. "Our belief that estrogens will keep you young forever was disrupted," he said. "Raloxifene and tamoxifen were lumped together with hormone replacement therapy," he continued, explaining that the fact that all were "hormonally related" was enough to create confusion. The irony is that hormone replacement therapy and SERMs had "opposite effects on breast cancer in reality," said Dr. Hortobagyi.
Dr. Wickerham reports being a consultant to Eli Lilly and receiving honoraria from AstraZeneca.
Cancer Prev Res (Phila Pa). Published online April 19, 2010. Abstract
American Association for Cancer Research (AACR) 101st Annual Meeting. Special plenary session. Presented April 19, 2010.
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