Chemoprevention Is No Magic Bullet
What the science says about tamoxifen and raloxifene
Posted June 27, 2013
The Telegraph recently reported that, “More than 500,000 women at risk of breast cancer because of their family history should take tamoxifen as preventive measure.” The story is based on a new set of guidelines from the National Institute for Health and Care Excellence in the UK recommending chemoprevention drugs to women who have not been diagnosed with breast cancer but are considered to be high-risk. The new guidelines, hailed as “historic” and a "game changer," even suggest that the drugs tamoxifen and raloxifene may be appropriate for women of moderate risk.
The promise to reduce the risk of getting breast cancer by 40 to 50 percent sounds great, but the actual (absolute) figures are far less impressive – less than 2 percent— and these drugs promote blood clots, cancers, cataracts, and other harms. Before jumping on the bandwagon, it’s important to read the fine print and ask some tough questions.
The Drugs In Question
The two drugs making the headlines, tamoxifen and raloxifene, are selective estrogen receptor modulators, or SERMs. Tamoxifen, the most famous of the SERMs, manufactured by AstraZeneca, has been used for decades in the US to treat women diagnosed with a type of breast cancer known as estrogen receptor (ER) positive. About 75 percent of breast cancers fall into the ER positive category because they grow, in part, in response to estrogen. Blocking the effects of estrogen on breast tissue using SERMs, or other mechanisms, can reduce the risk of breast cancer development. Women in the US whose 5-year risk of developing breast cancer is more than 3 percent fit the guidelines for recommended use of one of these drugs. The typical duration is every day for five years.
While SERMs do appear to reduce the risk of breast cancer in women at elevated risk, the reduction is quite small.
The study that earned tamoxifen its FDA approval in 1998 reported that taking the drug every day for five years reduced the number of invasive breast cancers by almost 50 percent . In the study of more than 13,000 women there were about half the number of invasive breast cancers in the tamoxifen group after 7 years of follow-up compared to the placebo group. But in absolute numbers, the reduction was much smaller. Only 4.25% of women in the placebo group developed breast cancer compared to 2.48% in the tamoxifen group, a reduction of only 1.77 percent. In other words, most of the women did not develop breast cancer regardless of whether or not they took the drug.
The other SERM, raloxifene, had similar outcomes in terms of risk reduction. The drug was initially approved for osteoporosis, but women taking the drug also appeared to have a lower incidence of breast cancer compared to those on the placebo. Eli Lilly, the manufacturer, started promoting raloxifene off-label , telling doctors that it had results similar to tamoxifen for breast cancer prevention. AstraZeneca sued Lilly for illegal marketing practices, but so many women were already using raloxifene off-label that the lack of FDA approval for breast cancer was fairly inconsequential. Not long after, the National Cancer Institute got involved in a large study called the STAR trial to compare the effects of tamoxifen and raloxifene.
The STAR trial assessed nearly 20,000 postmenopausal women who were at an increased 5-year risk of breast cancer. About 9700 women were randomly assigned to each comparison group, with one group taking tamoxifen and the other raloxifene. At the end of the study there were about equal numbers of invasive breast cancers, 163 cases in the tamoxifen group and 168 cases in the raloxifene group. On average, 1.7 percent of the study participants got breast cancer after taking the SERMs. There was no placebo group, but the number of breast cancers developed coincided with the results of the earlier tamoxifen study. The FDA approved raloxifene in 2007 for use in high-risk postmenopausal women to reduce breast cancer risk.
Side effects of the SERMs have been consistent across studies. These include increased risk of endometrial and uterine cancers, stroke, cataracts, bone loss, and blood clots as well as hot flashes, joint pain, and other menopausal symptoms . Since the risk reduction for breast cancer is small, these side effects contribute to concern among some advocacy groups that the risks associated with taking chemoprevention drugs such as the SERMs may outweigh the benefits. A recent study of more than 83,000 women published in The Lancet reported that 42 women would need to be treated with SERMs to prevent one breast cancer in the first 10 years of follow-up. The rest would not have their risk for breast cancer reduced but they would still deal with the increased risk of these and other side effects. The study also reported that while the SERMs do reduce the risk of breast cancer in some women at elevated risk, the duration of the effect is unknown .
"Duration of effect" is an important factor in terms of risk reduction and side effects. A study that made the headlines last year after it was presented at the San Antonio Breast Cancer Research Symposium, the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) trial , compared the results of tamoxifen use for ten years instead of five. The study enrolled nearly 13,000 women with early breast cancer who had already completed five years of tamoxifen. Half of the women were randomly assigned to the group to continue the drug to 10 years and the other half stopped taking it at year five (control group). There was no placebo to compare the effects to patients who did not take tamoxifen.
Continuing tamoxifen to year ten produced a reduction in recurrence and mortality. The absolute reduction in recurrence between the two groups was 3.7%. There was no difference in mortality in years 5 through 9, but by year 10 there was an an absolute mortality reduction of 2.8%. The lack of linear progression in mortality reduction is not explained, but longer usage of the drug led to an increased risk for pulmonary embolism and doubled the risk for death from endometrial cancer.
Current protocols from the US Preventive Services Task Force recommend considering the use of SERMs for risk reduction in women who are at an increased breast cancer risk (i.e., those who have a five-year risk of developing breast cancer that is at least 3 percent or more based on risk assessment models that take into account a variety of factors), but are against it for women who are not high-risk. The report qualifies its recommendation for use, however, by saying that, “Most women identified as “high risk” will not develop breast cancer, and the majority of breast cancer cases will arise in women who are not identified as having increased risk. The reality is that most women who get breast cancer have none of the known risk factors.
With so much still unknown about what causes breast cancer, it may not be wise to pin the hope of prevention on drugs that work for a small percentage of women, while also putting them at risk for other diseases and poor health outcomes.
Reading Between The Lines
One woman, a physician, told me that she got a high grade premalignancy with high potential for progression to endometrial cancer, underwent three D&C’s, and ultimately had a complete hysterectomy due to her 4.8 years on tamoxifen. Her side effects won’t count in any of the statistics though because she did not develop an all out cancer. In her research the physician found that the risk of endometrial cancer persists 15 years after taking tamoxifen, is related to the length of exposure, is higher in women who form polyps while taking the drug, and is higher in women over age 50, women like her. “The horrible irony of developing a new primary cancer by taking a recurrence prevention medication and being a compliant patient,” she says, “leaves me with a sense of betrayal, but not exactly sure by whom.”
Neither tamoxifen nor raloxifene are currently licensed for preventive use in the UK. And although both drugs were approved in the US to reduce the risk of developing breast cancer in high-risk women who have been treated for breast cancer, the drugs are not widely accepted in the US for breast cancer prevention in healthy women . Furthermore, if women take the drugs for five or ten years to prevent breast cancer, they may instead be faced with a host of other health problems while becoming immune to the potential benefits of the drugs as treatment should they develop an ER positive breast cancer later on. Some doctors say that the risks of tamoxifen-related effects are negligible . But it cannot be understated that, " careful consideration of risks and benefits is needed to identify women who are most likely to benefit from these drugs ."
Promoting cancer prevention drugs for women who do not yet have breast cancer may be putting the cart before the horse. It is not possible to predict the type of breast cancer a person may develop at some point in the future. Primary prevention of breast cancer requires eliminating cancer promoters, and unnecessary radiation and harmful drugs. No matter how hard we might wish for one, there is no magic bullet.
Dr. Gayle Sulik is the author of Pink Ribbon Blues: How Breast Cancer Culture Undermines Women's Health. More information is available on the author's website .
© 2013 Gayle Sulik, PhD ♦ Pink Ribbon Blues on Psychology Today