WASHINGTON, DC—Updated results from the National Surgical Adjuvant Breast and Bowel Project's landmark Study of Raloxifene and Tamoxifen (STAR) confirm that both tamoxifen and raloxifene reduce the risk for breast cancer in high-risk women.
But too many eligible patients are choosing neither option, say oncologists who hope the new findings will persuade more high-risk women to take the drugs as a cancer chemopreventive.
After a median follow-up of 81 months, tamoxifen appears to reduce the risk of invasive breast cancer by 50%, compared with that for untreated women, reported D. Lawrence Wickerham, MD, Associate Chairman of the National Surgical Adjuvant Breast and Bowel Project (NSABP) and Chief of the Section of Cancer Genetics and Prevention at Allegheny General Hospital in Pittsburgh, speaking here at the AACR Annual Meeting.
Raloxifene appears to be associated with about a 38% reduction in risk, he said.
However, the superiority of tamoxifen comes at a cost—“significantly more endometrial cancers, hysterectomies for benign disease, thomboembolic events, and cataracts than raloxifene.”
The bottom line, Dr. Wickerham said, is that both drugs are good choices for chemoprevention: “These data are good news for postmenopausal women who want to reduce their risk of breast cancer,” a step toward eliminating breast cancer in high-risk women, he said.
Original STAR Findings
STAR, also known as NSABP Protocol P-2, compared the two selective estrogen-receptor modulators (SERMs) raloxifene and tamoxifen in 19,747 healthy, postmenopausal women with an elevated risk for breast cancer.
More than 70% of participants had one or more first-degree relatives with a history of breast cancer.
Original results, after 47 months of follow-up, showed that both drugs reduced the risk of breast cancer by about 50% compared with historical data on untreated women (Vogel VG et al: JAMA 2006;295: 2727-2741).
This is comparable to the 50% reduction in risk seen with tamoxifen versus placebo in the Breast Cancer Prevention Trial (Fisher B et al: JNCI 1998;90:1371-1388), the researchers noted.
But raloxifene appeared to carry fewer risks of side effects, with lower rates of endometrial cancer and thrombolembolic events.
Updated STAR Findings
In the latest reported results, at 81 months of follow-up, or 21 months after 60 months of daily treatment, differences emerged between the drugs in terms of efficacy and toxicities, Dr. Wickerham said.
In the updated analysis, which was published online simultaneously to his talk on April 19 in the AACR journal Cancer Prevention Research, patients in the raloxifene group had a 1.24 relative risk of invasive breast cancer compared with those in the tamoxifen group.
Put another way, raloxifene retained approximately 76% of tamoxifen's effectiveness, or was associated with a 38% reduction in the risk of invasive breast cancer, compared with untreated women, he said.
Patients in the raloxifene group had a 1.22 relative risk for noninvasive breast cancer versus tamoxifen-treated patients. This means that raloxifene was about 78% as effective as tamoxifen in preventing noninvasive cancers, Dr. Wickerham said.
The updated toxicity analysis showed that raloxifene was associated with several significant advantages over tamoxifen: a 45% reduction in invasive uterine cancer, an 81% reduction in uterine hyperplasia, a 25% reduction in thromboembolic events, a 55% reduction in hysterectomy, and a 20% reduction in cataracts.
There was a nonsignficant 16% reduction in mortality rates in the raloxifene arm.
Raloxifene's significant advantage in terms of toxicity appeared to translate into a higher rate of adherence, Dr. Wickerham said.
A total of 39.8% of patients in the tamoxifen group dropped out vs 27.4% in the raloxifene arm.
Dr. Wickerham disclosed relationships with AstraZeneca and Eli Lilly.
Study discussant Gabriel N. Hortobagyi, MD, Chair of Breast Medical Oncology at the University of Texas M. D. Anderson Cancer Center, said, “There is no longer any doubt about the effectiveness of these agents.
“Here are two relatively inexpensive drugs that lower the incidence of breast cancer by about 50%, with side effects that are modest. [Yet] only 5% to 20% of the tens of thousands of women” who could benefit from the drugs use them, he said.
“Only bilateral prophylactic mastectomy is more effective [in lowering breast cancer risk]. We need to reassess why we are not using these drugs more broadly.”
In what seemed like a metaphor for the underuse of the agents, the hall looked like a ghost town during the late-breaking talk and discussion. Only about 200 of the meeting's thousands of attendees peppered the 7,600-seat room.
At a news conference afterward, Scott M. Lippman, MD, Chair of the Department of Thoracic/Head and Neck Medical Oncology at M. D. Anderson Cancer Center and Editor-in-Chief of Cancer Prevention Research, offered an explanation, saying that the late-breaking presentation was not included in the program materials and therefore many attendees did not hear about it in time. (The session had been included, though, for at least a few days before the meeting in the Online Proceedings and Itinerary Planner.)
Additionally, Dr. Lippman speculated, the talk beforehand was on a far different topic, so there would be little overlap in audiences. (That was “The Cancer Genome” Plenary Session, chaired by Arul Chinnaiyan and featuring Bert Vogelstein, Laura van'T Veer, Levi Garraway, and Stephen Chanock, which filled the same hall, the largest at the meeting.)
Dr. Hortobagyi said a “misunderstanding of side effects” is one of the main reasons that raloxifene and tamoxifen are underused in the prevention of breast cancer.
“It was reported that tamoxifen increased the risk of endometrial cancer three-fold,” but the absolute risk “is very, very small,” he said.
Judy E. Garber, MD, Director of the Cancer Risk and Prevention Program at Dana-Farber Cancer Institute in Boston and AACR President-Elect, noted that in the Breast Cancer Prevention Trial, the total risk for endometrial cancer among women taking tamoxifen for five years was only 1.25%: The absolute number of affected patients is “minuscule,” she agreed.
Dr. Garber said she is completely mystified about the underuse of raloxifene as it does not raise endometrial cancer risk “at all.”
Another reason more women may not be taking the drugs is because their primary-care physicians may not be bringing up the choice, Dr. Lippman said.
“Primary-care physicians should be bringing up these options with every high-risk woman,” he said.
Dr. Hortobagyi said the reputation of SERMS was harmed by results of the Women's Health Initiative, which linked hormone replacement therapy with an increased risk of breast cancer,
“Raloxifene and tamoxifen were lumped together with hormone-replacement therapy,” when in reality, HRT and SERMs have “opposite effects on breast cancer,” Dr. Hortobagyi said.
So Which Drug for Which Patients?
So which patients should be taking which drug to decrease their risk for breast cancer?
Given its greater efficacy, tamoxifen may be a better choice if women are at very high risk of breast cancer, Dr. Hortobagyi said.
If women are not at risk for blood clots or uterine cancer, both drugs are good breast-cancer prevention options, Dr. Lippman said.
For postmenopausal women who are at risk for osteoporosis, raloxifene might be a better choice as it offers a “two-for-one benefit,” he said, referring to its indication as treatment for osteoporosis.
As for why raloxifene's effectiveness would wane over time, Dr. Wickerham said that drug has a “short half life” in the body, compared with tamoxifen.
“The antitumor activity of raloxifene depends on taking the pill,” he explained.
The study included only postmenopausal women. but tamoxifen has a proven track record in premenopausal women as well, Dr. Hortobagyi noted.
In the one-third of premenopausal women who have had a hysterectomy and therefore a risk of uterine cancer that is “close to nonexistent” and no history of blood clots, tamoxifen may be considered, he said.
Asked about age alone as an indication, Dr. Hortobagyi said he probably wouldn't give either drug to a woman in her 60s who is otherwise healthy based on her being at high risk because of age alone.
Both drugs cost about $140 a month or $8,500 for the five years of treatment recommended to prevent breast cancer. In comparison, treating one case of early breast cancer can easily cost $50,000 to $120,000, according to Dr. Hortobagyi.