National Cancer Institute NCI Cancer Bulletin: A Trusted Source for Cancer Research News
April 20, 2010 • Volume 7 / Number 8

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Long-term Follow-up Confirms Breast Cancer Risk Reduction with Raloxifene

Study of Tamoxifen And Raloxifene logo

The drugs raloxifene (Evista) and tamoxifen both substantially reduce the risk of breast cancer in women at high risk for the disease, but raloxifene causes fewer and less-severe side effects, according to the long-term results of a large breast cancer prevention trial presented yesterday at the American Association for Cancer Research (AACR) annual meeting in Washington, DC.

The findings, from the NCI-supported Study of Tamoxifen and Raloxifene (STAR) trial, were mostly consistent with the trial’s initial results published in 2006; findings that eventually led to FDA approval of raloxifene to reduce the risk of breast cancer in postmenopausal women at increased risk. With nearly 3 more years of follow-up data on the more than 19,000 women who participated in the study, raloxifene was modestly less effective than tamoxifen at reducing the incidence of both invasive and noninvasive breast cancer, but was markedly safer and had a substantially lower risk of rare side effects, including endometrial cancer.

The updated STAR findings and the overall data on both tamoxifen and raloxifene—both of which are in a class of drugs known as selective estrogen receptor modulators, or SERMs—for breast cancer prevention are “good news for women,” said Dr. D. Lawrence Wickerham of the National Surgical Adjuvant Breast and Bowel Project, the NCI cooperative group that led the trial. “Among postmenopausal women with increased breast cancer risk, there are now two options to reduce that risk,” he said.

“I think these data are particularly good news for the primary care community,” said Dr. Judy Garber, director of the Cancer Risk and Prevention Program at the Dana-Farber Cancer Institute, during a press briefing. Particularly given their heavy use of and comfort with raloxifene to prevent and treat osteoporosis, for which it is also approved, she said, the results should “encourage primary care physicians to discuss raloxifene [for breast cancer risk reduction] more often.”

Dr. Wickerham acknowledged that the idea of taking a drug to prevent or reduce cancer risk, often called chemoprevention, has been a tough sell. “Chemoprevention is still in its infancy,” he said. “These STAR data are an important step toward bringing chemoprevention to the same level as that seen in areas like preventive cardiology,” he continued, where drug therapy is commonly used to treat heart disease precursors such as high blood pressure and high cholesterol.

Tamoxifen has been approved for breast cancer risk reduction since 1998, following the findings from the Breast Cancer Prevention Trial (BCPT), which showed a nearly 50 percent reduction in breast cancer risk among women at increased risk who took tamoxifen for 5 years compared with those who took a placebo. But tamoxifen has never caught on as a cancer prevention agent. The drug’s low uptake has often been attributed to concerns about its potential side effects, namely increased risk of endometrial cancer and dangerous blood clots.

But the potential risks of tamoxifen and raloxifene have been overstated, said Dr. Gabriel Hortobagyi, chair of the Department of Breast Medical Oncology at the University of Texas M. D. Anderson Cancer Center, during the briefing. In the BCPT, for example, even though women taking tamoxifen had a significantly increased risk of developing endometrial cancer, the risk was still less than 1 percent.

Like tamoxifen, raloxifene had been shown to decrease breast cancer risk in clinical trials. Consequently, STAR was launched to test the two drugs head-to-head in postmenopausal women who are at an elevated risk of breast cancer (based on the commonly used NCI Breast Cancer Risk Assessment Tool). On average, the women in STAR had a 15 percent increased lifetime risk of breast cancer. Participants were randomly assigned to take one of the drugs every day for 5 years.

Tools to Aid Clinician Decision Making

To help clinicians discuss breast cancer chemoprevention options with patients at the University of Pennsylvania Abramson Cancer Center, Dr. Armstrong and her colleagues are developing decision-support tools to disseminate to primary care practices. These tools will allow clinicians to take information from a patient’s health-risk appraisal, looking at factors such as family health history and reproductive risks, and link it with a decision-support tool built into the center’s electronic medical record system.

The approach is being piloted in several clinical settings and is expected to be rolled out more widely next year. The hope, said Dr. Armstrong, “is that we can get to a point where we can say that these are the women who will receive the greatest benefit from raloxifene or tamoxifen; they are way over the threshold for absolute benefit and should be offered the medication.”

If such an approach can be shown to reduce breast cancer mortality, she continued, “I think it will produce a significant impetus for health care providers to be more innovative about how we can really individualize what we do for our patients.”

When the initial STAR findings were published, with a median follow-up of 47 months, both drugs were equally effective in reducing the risk of invasive breast cancer. But the updated results show that raloxifene’s effectiveness appears to wane over time. With a median follow-up of 81 months, raloxifene was about 76 percent as effective as tamoxifen at reducing invasive breast cancer risk. For noninvasive breast cancer, which includes conditions known as ductal carcinoma in situ and lobular carcinoma in situ, tamoxifen was initially shown to be modestly more effective than raloxifene. That finding held true with the longer follow-up, but the gap narrowed, with raloxifene proving to be about 78 percent as effective as tamoxifen.

Raloxifene’s side-effect profile remained far superior, with a 45 percent reduced risk of endometrial cancer and a 25 percent lower risk of serious blood clots compared with women who took tamoxifen.

The findings add to “the evidence that supports the long-term benefits of these drugs,” said Dr. Katrina Armstrong, co-director of the Cancer Control Program at the University of Pennsylvania Abramson Cancer Center in Philadelphia. What’s needed now, Dr. Armstrong continued, “is an active effort to understand the barriers to use [of raloxifene and tamoxifen] and the implementation of clinical decision-support tools to help providers identify women who are eligible to take them and make decisions about their use.” (See the sidebar.)

In essence, she continued, it comes down to getting health care providers, namely primary care physicians, “to be comfortable doing risk stratification and prescribing preventive medications without having a biomarker like cholesterol” to guide those decisions.

“Even 12 years after tamoxifen was approved by the FDA for breast cancer risk reduction,” said Dr. Katherine Lee, co-director of the High Risk Clinic at the Cleveland Clinic Breast Center, “[many clinicians] are still very reluctant to have that conversation” with patients about taking raloxifene or tamoxifen. “I see high-risk women every day. So they will hear about chemoprevention from me; and tamoxifen and raloxifene are your current options for risk reduction,” Dr. Lee said.

Part of the reluctance, she agreed, comes back to concerns about side effects, both on the part of the clinician and the patient. But there is also another key difference between drug therapy for blood pressure or cholesterol and drug therapy for cancer prevention, she stressed: a hard endpoint that both clinicians and patients can follow. “Doctors like to follow numbers,” said Dr. Lee, who was also an investigator on the STAR trial. “With raloxifene or tamoxifen, there are no numbers. You can’t tell whether a patient is improving upon her risk. It’s far more complex.”

—Carmen Phillips