Policy on Pills for Prevention

Introduction

Since its founding in 1990, Breast Cancer Action has emphasized the need to find the root causes of breast cancer so that we can truly prevent the disease. Abundant evidence indicates that the genesis of many cases of breast cancer lies with our toxic environment. Yet by far the focus of national resources devoted to breast cancer prevention has been on the development of drugs to lower the incidence (new cases) of breast cancer, rather than to finding the disease’s environmental triggers. This BCA policy describes the efforts to bring new medical products to the market to reduce breast cancer incidence in healthy women, as well as the problems created by this approach, and explains why the organization opposes a pills-based approach to breast cancer prevention.

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The Tamoxifen for Prevention Trial — BCPT P-1

In the early 1990s, the National Cancer Institute (NCI) undertook a long-term study of tamoxifen (trade name Nolvadex), a hormonal treatment that had been shown to reduce the risk of recurrence in women with breast cancer, to see if it lowered breast cancer incidence in healthy women with a high risk of developing the disease.1 The Breast Cancer Prevention Trial P-1 (BCPT P-1), which started in 1992, was halted before its planned conclusion because of the significant reduction in breast cancer incidence found in women treated with tamoxifen compared to the placebo control group. Participants were informed of the findings and which group they had been randomized to, and those in the placebo group were offered the opportunity to begin taking tamoxifen or enter a new trial that was comparing tamoxifen with another drug, raloxifene, that showed potential to reduce breast cancer incidence as well.

Soon after BCPT P-1’s termination in 1998, the Food and Drug Administration (FDA) approved tamoxifen for use in high-risk healthy women to lower the risk of breast cancer. Manufacturers and other proponents of tamoxifen at the FDA hearings lobbied strongly to have the drug described as “preventing” breast cancer. Prevention refers to protecting individuals or populations from the development of disease. Because a portion of those taking tamoxifen develop breast cancer, even if at lower rates, women’s health advocates, including BCA, argued successfully that it could not be labeled as preventing breast cancer but rather as lowering risk.

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Treating Risk as Disease — Tamoxifen and Disease Substitution

Tamoxifen has significant side effects. Milder effects include hot flashes and vaginal dryness. The more severe risks include endometrial cancer, pulmonary emboli (blood clots in the lung), stroke, deep vein thrombosis, and cataracts. After many years of study, the drug was found to significantly increase the risk of uterine sarcoma, an uncommon and dangerous form of cancer of the uterus.2

Despite years of direct-to-consumer advertising by AstraZeneca, tamoxifen’s manufacturer, utilization of tamoxifen by healthy women to reduce breast cancer risk has remained relatively low.3

In preventive medicine, only very minimal risks are considered acceptable — such as those from vaccination or vitamins. The prevalence and severity of tamoxifen’s side effects led to coining a new term, “disease substitution.”4

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Study of Tamoxifen and Raloxifene — STAR Trial (BCPT P-2)

Since the FDA approved tamoxifen’s use by healthy women, a number of other drugs have been and continue to be studied as possibly safer alternatives to tamoxifen. Raloxifene (trade name Evista), in the same class of drugs as tamoxifen, has been compared to tamoxifen in a clinical trial (“STAR” or BCPT P-2) of healthy women at high risk for breast cancer. Raloxifene’s manufacturer, Eli Lilly, hoped that its product would prove more popular as a “prevention” pill than tamoxifen, since many postmenopausal women were already taking it for its approved use to increase bone density (even though it is ineffective in reducing hip fracture and marginally effective in reducing spinal fractures).5

Raloxifene has been widely prescribed to healthy women to lower breast cancer risk for many years now, even though it has not been approved for this by the FDA (such treatment is termed “off-label use”). Eli Lilly, raloxifene’s manufacturer, was fined $36 million for illegally promoting the drug to doctors as a breast cancer preventative.

Results from the STAR trial found that the two drugs are equivalent in reducing invasive breast cancer risk. Raloxifene is portrayed by the NCI as being safer than tamoxifen, but the published results show that the differences between most of their side effects are not statistically significant.6 The exceptions were that raloxifene users had fewer deep-vein blood clots and cataracts than tamoxifen users. Women had taken the treatments for an average of only three years at the time the study was ended.

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Aromatase Inhibitors for Healthy Women — The Next Prevention Frontier

Aromatase Inhibitors (AIs) are the other main class of drugs being tested to lower breast cancer risk in postmenopausal women. Three AIs are currently approved for the treatment of breast cancer by the FDA, and they are listed in the accompanying chart (see below). These drugs block aromatase — an enzyme that converts the hormone androgen into estrogen — which is the primary source of estrogen for postmenopausal women. They are being evaluated as replacements for tamoxifen or raloxifene in healthy, high-risk postmenopausal women.

There is limited research on AIs in postmenopausal women with early stage, estrogen-positive breast cancer. The drugs have prompted concern because they cause serious side effects, including increased risk of osteoporosis and bone fractures, joint and muscle pain, high cholesterol,  and cognitive problems. Ongoing trials are looking at whether adding a bisphosphonate drug to an AI will lower osteoporosis risk. Bisphosphonates, which are used to treat osteoporosis, also carry the risk of serious side effects, including osteonecrosis of the jaw.

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Chemoprevention — A Bad Idea for Public Health

Research on the so-called breast cancer prevention medications7 has been problematic in three major areas: lack of long-term follow-up for safety, comparative studies that do not include a placebo group, and misleading reporting of findings. These studies appear to be designed to promote sales of products without clear evidence of safety to large populations of women.

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Lack of Long-term Data

Studies of breast cancer “prevention” medications have focused on the specific goal of achieving lowered breast cancer incidence. Ending trials early is becoming increasingly common and is controversial.8 While the breast cancer benefit may be clear, at least in the short term, the clinical benefit — particularly for healthy women — is compromised because the extent of harmful side effects is unknown, as is the long-term survival benefit.

Most breast cancer develops over a period of a decade or longer. When a trial is stopped after several years, we cannot derive information about the persistence of the protective benefit. Does the medication actually prevent cancer or delay its development?

Study sizes are too small, and follow-up too short, to reveal rarely occurring adverse outcomes and long-term safety or to assess the possibility that risks continue to develop after cessation of treatment. We have no way to determine overall survival in the study groups. In order to make informed decisions about medical treatments, we need sound data to consider risks and benefits together.9

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Absence of Placebo Controls

The STAR Trial compared raloxifene directly to tamoxifen without use of a placebo group. The decision to not include a placebo control group was heavily criticized at the beginning of the trial and eliminated the possibility of knowing how taking either drug compares to taking no drug at all. The practice of running studies that compare one drug against another — without providing a control group to determine whether no treatment is as good as the treatment being evaluated — is prevalent in chemotherapy trials. This practice assumes that one of the drugs is a highly regarded treatment and that denying that treatment would be unethical.

BCA believes that tamoxifen’s benefits for healthy women have not been shown to outweigh the drug’s risks. Accordingly, we believe that a placebo control group should be included in all so-called prevention drug trials. Apparently the National Cancer Institute does not intend to use placebo control groups in breast cancer “prevention” trials going forward.

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Misleading Statistics

A third major problem with the “prevention” medication studies has been misleading reporting of results. It has become common practice to make public announcements of results prior to peer-reviewed publication. Such announcements, and even journal articles, often couch statistical findings in the most positive manner and create a media outpouring that is almost always exaggerated and misleading.

Because breast cancer is a relatively rare occurrence in women, including those at high risk, differences in incidence portrayed using “relative risk” tend to appear much larger than absolute risk differences.10 An example of this comes from the preliminary findings from the STAR trial, which found both raloxifene and tamoxifen reduced breast cancer incidence by 50 percent. Maryann Napoli, of the Center for Medical Consumers, explains what this means:

Of the 9,700-plus women in each drug group, about 167 got breast cancer. This translates to 1.7 percent, whereas 3.4 percent would be expected to develop breast cancer had they not taken a drug. (Hence the 50 percent reduction in breast cancer incidence). Another way of saying the same thing is: 98.3 percent of women will not get cancer if they take raloxifene or tamoxifen, whereas if they take no drug, 96.6 percent of women will not get cancer (an absolute difference of 1.7 percent). Obviously, much more research is needed to determine who is at high risk for breast cancer.11

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Prevention Creep — Danger Ahead

Most of the so-called breast cancer prevention pill types were initially used as treatments for advanced breast cancer, then to treat women with early breast cancer, and finally considered to lower risk in women without symptoms. Currently the official line is to market these drugs to women with a high risk of developing breast cancer — a bit less than a 2 percent chance over five years. Eric Schneider, a medical and public health professor at Harvard, has referred to this process as “prevention creep.”12

A concerted campaign is now underway in the medical community to boost the number of people taking drugs to lower their risk for cancer. The American Association for Cancer Research’s (AACR) Chemoprevention Working Group advocates “widespread implementation of chemoprevention of cancer.”13 They propose a broad educational promotion directed at physicians and “society as a whole” to accomplish this. The centerpiece of this educational campaign is to correct the “misperception” that healthy people should not be treated with possibly harmful drugs.

We need an intensive educational effort to convince people that absence of clinical symptoms may not guarantee that one is “healthy,” and that a more sophisticated understanding of risk factors can be used constructively to develop interventions that have the potential to provide better health.14

The AACR chemoprevention campaign is particularly troubling in an era when the FDA is led by people who favor accelerated approval of chemoprevention drugs, have close relationships with drug manufacturers, and support product liability changes that would protect drug companies from suits initiated by injured patients.15

Women deserve to be fully informed about the benefits and risks of breast cancer “prevention” drugs prior to making a decision about whether or not to take them. At present, individuals are making decisions under conditions of uncertainty.

Breast Cancer Action, while clearly understanding the large numbers of women at risk for developing breast cancer, does not advocate using drugs to treat risk. It is difficult to imagine a drug powerful enough to actually reduce the risk of breast cancer that will not have serious side effects. Moreover, the focus on pills for prevention of disease diverts resources from finding and eradicating environmental causes of, as well as effective treatments for, breast cancer.

The mission of Breast Cancer Action (BCA) is to carry the voices of people affected by breast cancer to inspire and compel the changes necessary to end the epidemic. We believe access to information is vital; we encourage people to participate fully in decisions relating to breast cancer; and we recognize that structural changes in society are needed to accomplish our mission.

Adopted by the Breast Cancer Action Board of Directors in July 2006.

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Hormonal Treatments Studied for Reducing Breast Cancer Risk

Selective Estrogen-Receptor Modulators (SERMs):
Generic Name Brand Name Manufacturer
Tamoxifen Nolvadex AstraZeneca
Raloxifene Evista Eli Lilly
Aromatase Inhibitors:
Generic Name Brand Name Manufacturer
Anastrozole Arimidex AstraZeneca
Exemestane Aromasin Pfizer
Letrozole Femara Novartis

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1 Tamoxifen is one of a class of drugs called selective estrogen receptor modulators (SERMs) that inhibit cancer growth. By attaching themselves to estrogen receptors in cells, SERMs prevent natural estrogens from entering those cells. SERMs are termed “selective” because in some receptors they block estrogen, and in others they act as estrogens.

2 Tamoxifen is officially listed as a cancer-causing agent on the list of carcinogens reported by the U.S. Department of Health and Human Services.

3 Joy Melnikow, et al., “Preferences of Women Evaluating Risks of Tamoxifen,” Cancer 103 (10), May 15, 2005, pp. 1996-2005.

4 Adriane Fugh-Berman and Samuel Epstein, “Tamoxifen: Disease Prevention or Disease Substitution?” The Lancet 340: November 7, 1992, pp. 1143-45.

In a 2005 report of women in the BCPT P-1 trial who continued to be followed for an average of seven years, 126 in the tamoxifen group and 114 in the control group had died (not a statistically significant difference). While the greater number of deaths in the treatment group was not mentioned in the discussion of mortality outcomes in the published study, the numbers were shown in one of the figures in the article: Bernard Fisher, et al., “Tamoxifen for the Prevention of Breast Cancer: Current Status of the National Surgical Adjuvant Breast and Bowel Project P-1 Study,” Journal of the National Cancer Institute, 97 (22), November 16, 2005, pp. 1652-62.

5 Maryann Napoli, “Media Hype the New Findings for Evista as an Anti-Breast Cancer Drug,” HealthFacts 31 (5), May 2006, p. 4.

6 Victor G. Vogel, et al. for the NASBP, “Effects of Tamoxifen vs. Raloxifene on the Risk of Developing Invasive Breast Cancer and Other Disease Outcomes,” JAMA, published online June 5, 2006, pp. E1-E15.

7 Other drugs have been mentioned as candidates for prevention pills. For some time, aspirin and other pain-killers, particularly COX-2 inhibitors (such as Vioxx and Celebrex), were thought about as possible breast cancer prevention pills, but the revelation that Vioxx and related drugs caused deaths from cardiovascular events removed them from further consideration. Statins, a class of cholesterol lowering drugs, have been studied as a potential chemoprevention pill, but there is no evidence to substantiate their effectiveness in lowering breast cancer risk.

8 Victor M. Montori, et al., “Randomized Trials Stopped Early for Benefit — A Systematic Review,” JAMA 294 (17), November 2, 2005, pp. 2203-09.

9 John Bryant and Norman Wolmark, “Letrozole After Tamoxifen for Breast Cancer — What is the Price of Success?” New England Journal of Medicine 349 (19), November 6, 2003, pp. 1855-57.

10 Relative risk is the probability of developing a given effect if a drug is used, divided by the probability of developing that effect if no drug is used. Absolute risk measures the number of people who experienced a particular effect on a drug in the relation to the total number of people who were treated.

11 Maryann Napoli, op cit.

12 Shannon Brownlee, “The Perils of Prevention,” New York Times, March 16, 2003.

13 “Prevention of Cancer in the Next Millennium: Report of the Chemoprevention Working Group to the American Association for Cancer Research,” Cancer Research 59, October 1, 1999, pp. 4743-4758.

14 Ibid. p. 4743.

15 “Cancer Prevention Drugs: Fast Approval Not in the Public’s Interest,” HealthFacts 28 (7), July 2003, pp. 1-2.

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