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SERMs: Underused and under the radar
Two of cancer prevention’s biggest successes have been slow to get adopted.
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The selective estrogen receptor modulators tamoxifen and raloxifene have been shown to reduce the risk for breast cancer in women at high risk by as much as 50%. With an accumulation of years of clinical trial data testing both drugs, a high rate of efficacy in the target population and highly favorable adverse effects profiles, these two drugs are considered two of the bigger success stories among chemopreventive methods.
“I have worked with tamoxifen for 20 years and raloxifene for almost a decade, and I don’t think that it is an exaggeration to say that tamoxifen is probably the most important cancer drug yet to be discovered,” said Victor G. Vogel, MD, director of the Geisinger Cancer Institute at the Geisinger Health System, Danville, Pa. “Published estimates indicate that it has saved about 6 million lives worldwide.
“However, despite four large trials worldwide, and despite all the years of experience using the drug to treat breast cancer, there has been no uptake, either in North America or in Europe, for using tamoxifen to reduce breast cancer risk,” Vogel told HemOnc Today.
Recently approved raloxifene (Evista, Lilly) may share the same fate. Women at high risk for breast cancer, whether due to age, family history or prior breast abnormalities, have two options to lower their chances for developing the disease, yet a majority of these women have either never heard of these drugs or choose not to take them.
“Unfortunately, these breast cancer trials were run by oncologists, and healthy women don’t see oncologists,” said Gabriel N. Hortobagyi, MD, chair of breast medical oncology at The University of Texas M.D. Anderson Cancer Center.
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Photo by John Everett |
For this and other reasons, oncologists and breast cancer experts are trying to clarify the role of tamoxifen and raloxifene for the prevention of breast cancer among primary care physicians and OB/GYNs who see at-risk women, and educate the public to empower those women at risk to seek treatment.
Established efficacy
Tamoxifen, which was already used as a treatment for ER-positive breast cancer, was approved by the FDA for the prevention of breast cancer in high-risk women in 1998. The drug works as an anti-estrogen in the breast, but research has shown that is has estrogenic effects in the uterus and bone.
The approval was based on the results of the National Surgical Adjuvant Breast and Bowel Project’s Breast Cancer Prevention Trial, which included 13,388 women who were either aged 60 years or older, aged 35 to 59 years with a 5-year predicted risk for breast cancer of 1.66% or more, or had a history of lobular carcinoma in situ. The patients were randomly assigned placebo or 20 mg tamoxifen per day for 5 years.
Although the results were positive, with the risk for invasive breast cancer reduced by 49% and noninvasive breast cancer by 50%, they were somewhat overshadowed by an increased risk for uterine cancer and thrombosis. Women taking tamoxifen developed uterine cancer twice as often as women on placebo. In addition, the trial did not show that tamoxifen decreased the risk for breast cancer death.
“Tamoxifen got FDA approval for prevention in 1999, and following that, there was never any increase in its use for that indication,” Vogel said. “Ten years after that trial was published, it is still only being used for treatment of cancer, with virtually nothing being done for risk reduction.”
Raloxifene, a second-generation selective estrogen receptor modulator (SERM), was originally approved by the FDA in 1997 for the prevention of, and in 1999 for the treatment of, osteoporosis in postmenopausal women. Unlike tamoxifen, raloxifene works as an anti-estrogen in the breast and the uterus. Almost immediately after the approval of tamoxifen in 1998, the Study of Tamoxifen and Raloxifene (STAR) trial commenced, comparing the two drugs head-to-head in a randomized, double blind fashion.
Published in 2006, initial results from STAR indicated that raloxifene was as effective as tamoxifen in preventing breast cancer in postmenopausal women, but had fewer adverse effects on the uterus and conferred a lower risk for thromboses. In late 2007, the FDA approved raloxifene for the prevention of breast cancer in postmenopausal women with osteoporosis and those at high risk for invasive breast cancer.
In May 2009, ASCO released updated clinical practice guidelines about the use of these two drugs in women at high risk for breast cancer (see sidebar).
“With the results of the STAR trial complete, and longer follow-up from the IBIS trial, which examined postmenopausal women using tamoxifen for prevention, ASCO felt that it was time for an update,” said Kala Visvanathan, MD, associate professor of oncology and epidemiology at the Sidney Kimmel Comprehensive Cancer Center, Baltimore. “We concluded that both tamoxifen and raloxifene have use in preventing hormone-positive cancers, at least in the short term. Tamoxifen was useful in both pre- and postmenopausal women, while raloxifene was an option only in postmenopausal women.”
Not catching on
Most recently, long-term follow-up results from STAR were presented at the 2010 American Association for Cancer Research Annual Meeting in Washington, D.C. The results showed that after 81 months of follow-up, both drugs were still highly effective methods for preventing breast cancer in high-risk women. Tamoxifen is slightly more effective with increased adverse effects; raloxifene is slightly less effective with fewer adverse effects.
“Just like tamoxifen, the use of raloxifene has not increased in the 4 years since the publication of the STAR results,” said Vogel, who was a researcher on the trial. “Its use has remained essentially flat. It is still used primarily for osteoporosis management.”
Even when educated about tamoxifen, women have been found to shy away from it. In February, a study published in Breast Cancer Research and Treatment found that after viewing a tailored decision-aid, women were able to gain a good understanding of tamoxifen’s risks and benefits, but few indicated interest in taking the drug.
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In the study, Fagerlin and colleagues enrolled 632 women with a 5-year predicted risk for breast cancer of 1.66% or more and showed them each an individualized decision-aid discussing the risks and benefits of tamoxifen. Although 29% of women said that they would seek out additional information on tamoxifen, only 6% believed that they would take the drug.
Obstacles to use
The experts interviewed by HemOnc Today believe that there are multiple reasons why women may not want to take tamoxifen and raloxifene in a preventive setting.
“Women often know of someone who has been treated with tamoxifen for breast cancer,” Visvanathan said. “It may have been a family member or a friend, but these women may confuse the use of tamoxifen in the treatment setting — where it may or may not have worked — with its use in the preventive setting.”
In addition, convincing someone to take a medication that may result in side effects is difficult when the disease is not yet present.
“When you talk about cancer prevention, you are talking about treating healthy people,” Hortobagyi said. “Healthy people, with no symptoms, have a much lower tolerance for toxicities.
“If you tell me I have heart disease, and I am gasping for breath all day, I may be willing to take a medication with side effects,” he said. “If you tell me I may get heart disease in 20 years and you want to give me a medication that may cause pimples, impotence or diarrhea, I will probably be less motivated.”
However, not everyone who takes tamoxifen or raloxifene will experience the side effects that are most widely discussed, Hortobagyi said. In fact, most women who take SERMs do not experience any side effects.
“Of those who do have them, most of the time they are mild and indistinguishable from those experienced during menopause,” he said. “If the side effects are truly disruptive, we can try to remedy them. If that doesn’t work, you stop using the drug, and within hours or days, the side effects go away.”
In addition, when compared with the effects of medications used to treat diseases in other specialties, the effects of SERMs are comparable, if not better.
“I have often said to patients, ‘If I told you this was cholesterol, you would tell me to give you a statin,’” Vogel said.
Hortobagyi, who takes a statin every day, could relate. “Half the adults in the country are on a statin. … I have muscle aches and joint pain every day because of them, and even though I am not at high risk, I take it because I know it is for a good cause.”
Unlike cholesterol, which can be measured once a statin is started, it is impossible to prove to high-risk women that SERMs are lowering their breast cancer risk.
“We do not have a marker that we can point to,” Hortobagyi said. “We give patients the drugs and can’t monitor that their risk has decreased.”
Educating PCPs, OB/GYNs
Unlike women who choose not to take the drug after weighing the benefits and risks, some women may not take it because they are not aware that they are at high risk or because they have never heard of these drugs.
Hortobagyi said although he has discussed SERMs at various cancer-focused meetings, these meetings do not expose internists and OB/GYNs, the practitioners who see patients before a cancer diagnosis, to this important information.
Those PCPs who are familiar with SERMs may not have the time or inclination to identify patient candidates for the drugs, Vogel added.
Holly Pederson, MD, is a medical breast specialist at Cleveland Clinic, but an internist by training. Part of her day-to-day function is to conduct breast cancer risk assessments on patients and counsel them on chemoprevention with raloxifene and tamoxifen.
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“Many doctors, while they may be familiar with the medications and their indications, fail to risk stratify appropriate patients for consideration of the medication,” Pederson said. “There are a number of patients that may benefit from either medication, but it is familiarity with both identifying those patients and determining who would be best served where a greater lack of understanding comes in to play.”
Several different breast cancer risk models and assessments exist for indentifying women at high risk, each taking slightly different factors into consideration. Also complicating matters is the fact that a woman’s risk for breast cancer can change throughout her lifetime, meaning multiple risk assessments may be necessary over time.
“Plus, different trials used different models of risk, with slightly different definitions of ‘high risk,’” Visvanathan said.
This can make the process seem confusing and overwhelming, Pederson said. Unlike certain hospital systems, such as Cleveland Clinic or Mayo Clinic that offer high-risk breast screening programs and counseling, practitioners at large do not have many outlets for the referral of patients who may be at high risk.
“This is a 45-minute discussion about the pros and cons of the drugs. That, plus the risk assessment, possibly using up to three different models, plus taking a medical history and a family medical history together with making a recommendation about tamoxifen or raloxifene, is an involved process,” Pederson said. “Even after that, it is also a commitment to follow that patient for at least 2 years with regular mammography or maybe a screening breast MRI. It is a lot more than the average practitioner may want to take on.”
A simple algorithm would be an ideal solution to helping PCPs and OB/GYNs identify at-risk patients.
“Unfortunately, there is no such thing that you can just put online for use because a lot of these decisions, in addition to the risk assessments, come down to clinical decision-making,” Pederson said.
For example, Pederson said she will typically not offer preventive medication to patients who continue to smoke because of the increased risk for blood clots.
“It can be a judgment call,” she said. “But, in a nutshell, a woman with a positive family history of breast cancer under the age of 50 — even if that history is in an extended or second degree relative — or a family member with ovarian cancer at any age, at least warrants that patient receiving consideration for risk assessment.”
Dropping the ball
“We have examined about 40,000 women in clinical trials looking at SERMs as a prevention of breast cancer,” Hortobagyi said. “There is clearly overwhelming evidence that using tamoxifen and raloxifene for extended periods of time, for 5 years, reduces the risk of breast cancer by 50%. If your baseline is high enough, that is a meaningful reduction.”
Visvanathan agreed. “We are not getting this information to the people who need it. Additional updates need to be given to OB/GYNs and internists. We need to target specific groups with educational information, and give them easy access to that information,” she said
“We are not implying that tamoxifen or raloxifene should be put in the drinking water,” Hortobagyi said. “But we have to get physicians to start to identify women at higher risk. There are tools available free online and they are easy to use. If we were doing this right, we could potentially save several thousand lives every year.” – by Leah Lawrence
For more information:
- Fagerlin A. Breast Cancer Res Treat. 2010;119:613-620.
- Visvanathan K. J Clin Oncol. 2010;27:3235-3258.
- Vogel VG. Cancer Prev Res. 2010;3:696-706.
- Vogel VG. JAMA. 2006;295:2727-2741.