Large trials testing drugs to prevent breast cancer (chemoprevention) date back to the 1990s, when tamoxifen was first evaluated in this setting. Tamoxifen is a selective estrogen receptor modulator (SERM). SERMs block the effects of estrogen in breast tissue by binding to the estrogen receptors in breast cancer cells leaving no room for estrogen to attach to the receptor. If estrogen can’t attach, it is unable to signal the cell to grow and multiply. The initial, large-scale breast cancer chemoprevention trial was the National Surgical Adjuvant Breast and Bowel Project (NSABP) Breast Cancer Prevention Trial (P-1), initiated in 1992. P-1 randomized approximately 14,000 women who had a risk of at least 1.66% of developing breast cancer in the upcoming 5 years to 5 years of tamoxifen or placebo. Risk was assessed using the Gail model, which is a tool designed by scientists at the National Cancer Institute (NCI) and the NSABP to estimate a woman’s risk of developing invasive breast cancer, both in the next 5 years and in her lifetime (assuming she lives to age 90). Factors included in this tool include current age, age of menarche (first menstrual period) and first live birth, number of first degree relatives with breast cancer, and whether or not a woman has had breast biopsies in the past with or without atypical cells. In the P-1 trial, 5 years of tamoxifen reduced the risk of breast cancer by almost 50%. Tamoxifen also led to a 32% reduction in the risk of fractures due to osteoporosis however the risk of strokes, blood clots, uterine cancer and cataracts were increased in the tamoxifen group. As a result of this trial, the FDA approved tamoxifen for breast cancer chemoprevention in women aged 35 and older with a 5-year breast cancer risk of 1.67% or higher.
Evista (raloxifene) is a SERM that was initially FDA approved to treat osteoporosis. In the Study of Tamoxifen and Raloxifene (STAR) trial, 5 years of tamoxifen was compared to 5 years of raloxifene in approximately 20,000 postmenopausal women who had a risk of at least 1.66% of developing breast cancer in the upcoming 5 years. The Gail model was also used to assess risk in this trial. While raloxifene was less effective than tamoxifen in preventing breast cancer, it was better tolerated, with less risk of clotting events or uterine cancer. This trial led to the FDA approval in 2007 of raloxifene for breast cancer chemoprevention in postmenopausal women at increased risk of breast cancer.
For premenopausal women at increased risk of breast cancer, the only currently available chemoprevention option is tamoxifen. In postmenopausal women, however there are 2 FDA-approved options: tamoxifen and raloxifene with efficacy as well as toxicity differences. So, how does one choose? Recently, a benefit/risk index has been proposed to help women and their physicians decide which drug is better for them based on their individual characteristics. Based on this index, postmenopausal women with a uterus had a better risk/benefit ratio with raloxifene, while the ratio was similar for the two drugs in women without a uterus.
The FDA approved options for chemoprevention utilize SERMs. There are, however, recent data supporting the use of an aromatase inhibitor (AI) for chemoprevention in postmenopausal women. AIs work differently than SERMs: AIs stop the production of estrogen in post-menopausal women by blocking the enzyme aromatase, which turns male hormones produced by the adrenal glands into small amounts of estrogen in women. This means that less estrogen is available to stimulate breast cancer cells. The MAP.3 trial randomized approximately 4500 postmenopausal women with a Gail model 5-year breast cancer risk of 1.66% or greater to aromasin (exemestane) or placebo. With 3 years of follow-up, exemestane reduced the incidence of invasive breast cancer by 65%. Of course, this trial begs the question of whether an AI is better or worse than a SERM, and at present there are no data to answer that question in the area of chemoprevention. AIs can have a detrimental effect on bone density, and this was also seen in the MAP.3 trial. A safety substudy showed that 2 years of aromasin worsened age-related bone loss despite supplementation of calcium and vitamin D.
Despite the availability of chemoprevention options, overall acceptance of them by women has been lukewarm at best. A recent study looked at the use of tamoxifen in the US for chemoprevention of breast cancer and found it to be extremely low. In 2000, only 0.2% of US women between 40-79 years took tamoxifen for prevention, while in 2005, the prevalence was 0.8%. There are many potential explanations for these results. Physicians may be reluctant to prescribe tamoxifen, and women may be reluctant to take it. Numerous studies have shown that when women who are at high risk of developing breast cancer are offered tamoxifen, relatively few accept it, possibly due to concern about potential side effects, particularly uterine cancer, blood clots and cataracts. Also the lack of a measurable effect that patients and their physicians can measure likely limits acceptance. This can be best understood by comparing the infrequent use of tamoxifen to prevent breast cancer to the widely accepted use of statins to prevent heart disease. With the statins, lowering of cholesterol is a measurable effect that patients and their physicians can use to assess the benefit of the drug in an individual patient. Unfortunately, there is no such comparable surrogate effect for breast cancer prevention.
Many question also remain as to whether the benefits of tamoxifen outweigh the risks in a healthy woman who may never be destined to get breast cancer. If a woman’s risk of getting breast cancer in the next 5 years is 2%, then that means her risk of not getting breast cancer in that time interval is 98%. The lack of acceptance of chemoprevention is extremely frustrating to researchers in the field. Breast cancer is the second leading cause of cancer-related death in US women, and we now have options to reduce the incidence, but these options are underutilized. While there are certainly legitimate reasons that a woman may choose to not take a chemopreventive drug, eligible high-risk women deserve to be aware of the data and available options and with their health care provider, to weigh the potential risks and benefits based on their individual situation.