The STAR (Study of Tamoxifen and Raloxifene) trial, one of the largest breast cancer prevention trials ever conducted, showed that five years of Evista is as effective as tamoxifen in lowering risk of developing breast cancer, giving high-risk women a new option for prevention
For the past two generations, a member of Evelyn Smith DeMille's family has died of breast cancer at a young age-her aunt at 41, then her younger sister at 38. "I have a daughter who will be 21 in August," DeMille says. "There is a good chance we have a genetic predisposition."
DeMille originally signed up for the Breast Cancer Prevention Trial (BCPT) in the early 1990s. After the BCPT was completed, she signed up for the STAR (Study of Tamoxifen and Raloxifene) chemoprevention trial rather than taking the five-year course of tamoxifen that was offered to her. "I see this study as a step along the way to prevent breast cancer for all women," DeMille says.
Effectiveness Without the Toxicity
The STAR trial, one of the largest breast cancer prevention trials ever conducted, enrolled nearly 20,000 postmenopausal women with a high risk of breast cancer, including DeMille. Participants received either daily Evista® (raloxifene) or tamoxifen for five years. The trial, conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) and sponsored by the National Cancer Institute, showed that Evista works as well as tamoxifen in lowering the risk of breast cancer in this high-risk population. Although participants in the STAR trial were required to have at least 1.67 percent risk of developing a breast cancer in the next five years which is considered high risk-the average was closer to 4 percent.
While both drugs appear to reduce the risk of developing invasive breast cancer by half, fewer side effects were associated with Evista than with tamoxifen, making it a better choice for some women. Data show that the group on Evista had 36 percent fewer uterine cancers and 29 percent fewer blood clots. Although both drugs increase the risk of blood clots, only tamoxifen is associated with uterine cancers, especially of the endometrium (lining of the uterus). Tamoxifen also increases the risk of cataracts, a long-term side effect not associated with Evista.
"Findings of raloxifene being equally effective with fewer side effects provide women with another option," says Worta McCaskill-Stevens, MD, STAR's program director. "It allows them to have a choice of an agent that has fewer blood clots, endometrial cancers and cataracts."
While both drugs prevented invasive breast cancers, tamoxifen also protects against non-invasive breast cancers—ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS)—whereas Evista does not. In situ cancers, though not usually classified as cancer, are confined in the milk ducts and do not reach the fatty or connective tissue of the breast."These non-invasive entities can be picked up by screening mammograms," says Dr. McCaskill-Stevens. "They are not life-threatening diseases." But while most in situ cancers are DCIS, LCIS comprises 10 percent of cases and is considered a high risk factor for invasive cancer. (Watch for the Fall issue of CURE, which will feature non-invasive breast cancer.)
Whether or not the positive data with Evista will encourage more high-risk women to take chemopreventive agents is still unanswered. Although long-term tamoxifen trials prove the drug reduces risk by half, women may choose not to take the drug for prevention. A 2004 study by Beth Israel Deaconess Medical Center in Boston found that many women, even those at high risk for the disease, feel the side effects and risks outweigh the possible benefit. STAR researchers hope the trial results will initiate conversation between patients and primary care physicians about chemoprevention and give them another choice in addition to tamoxifen.
“I think we have a lot of education to do on breast cancer risk and agents available,” Dr. McCaskill-Stevens says.
Doing Double Duty
Like tamoxifen, Evista is a selective estrogen receptor modulator (SERM), which helps prevent estrogen from binding to cancer cells and inhibits cancer cell growth. As a SERM, Evista also stops the thinning of bone tissue and increases the amount of good tissue, thus lowering the risk of bone fracture. Approved for treating and preventing osteoporosis in postmenopausal women in 1997, Evista is currently prescribed to nearly half a million postmenopausal women for bone health.
Doctors hope that because of the dual benefit and fewer side effects, more high-risk women will use Evista. Currently, tamoxifen is the only FDA-approved drug for the prevention of breast cancer, but Eli Lilly and Company, the maker of Evista, intends to file the drug for approval for the reduction of invasive breast cancer risk in postmenopausal women by the end of the year. STAR researchers have also been in talks with FDA officials about the study’s implications.
For Some, Tamoxifen Still the Best Choice
D. Lawrence Wickerham, MD, associate chairman of the NSABP and the study’s protocol officer, expects women will be using Evista to lower their breast cancer risk in the near future, but an in-depth conversation between patient and doctor on the risks and benefits is essential, he says, because Evista is not for everyone.
Dr. Wickerham says that since tamoxifen and Evista are chemically similar, women who have already had five years of tamoxifen would not be good candidates for Evista. Tamoxifen provides the maximum benefit for breast cancer prevention at five years, so following tamoxifen with Evista would increase the risk of side effects without any additional benefit. Women who have taken tamoxifen and are looking for agents to improve bone health should find alternatives, such as Fosamax® (alendronate) or Actonel® (risedronate).
Because Evista has not been tested in premenopausal women, tamoxifen is still the only choice for this group. The same holds true for breast cancer survivors.
Experts say some women probably shouldn’t be on either drug, including those with a high risk of blood clots, stroke, uncontrolled high blood pressure or uncontrolled diabetes.
While DeMille has completed five years of Evista, she’s continuing with her annual mammograms, the STAR trial’s follow-up tests and hopes to participate in new prevention clinical trials. “I try to do as much as I can to volunteer for research studies, to push the envelope and help find the answers.”
Final results from the STAR trial will be presented at the American Society for Clinical Oncology annual meeting next month.
For more information on the STAR trial, go to http://www.nsabp.pitt.edu/STAR/Index.asp.
Editor's note: On September 14, 2007, the FDA approved Evista (raloxifene) for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer.