Online Exclusive - July 10, 2009
Recently, the
Journal of Clinical Oncology (JCO) published
ASCO’s Clinical Practice Guideline Update on the Use of Pharmacologic Interventions Including Tamoxifen, Raloxifene, and Aromatase Inhibition for Breast Cancer Risk Reduction. ASCO first published a guideline on this topic in 1999 and previously updated it in 2002. This update was led by Kala Visvanathan, MD, MHS, of the Johns Hopkins Medical Institutions.
The guideline is intended for clinicians seeing women who have not previously had breast cancer. The guideline examines whether tamoxifen, raloxifene, aromatase inhibitors, and/or fenretinide reduce the risk of breast cancer in women who take it and, if so, which of them is most effective. A major contribution of this guideline is the discussion of what constitutes effective and responsible communication by physicians of these issues to women who are eligible for these agents.
Although the guideline reviews four agents/categories of agents, it finds that women who have learned they are at increased risk of breast cancer may be eligible to consider using tamoxifen and raloxifene, but not the other agents. Women at high risk are defined as those identified by risk assessment models and include women with lobular carcinoma in situ (LCIS). The benefit of tamoxifen and raloxifene is only in reducing ER-positive invasive breast cancer, not ER-negative breast cancer. The guideline stresses the need for research into developing agents for reducing the risk of the latter.
The guideline notes that there are insufficient data on how taking any of these agents affects mortality. Breast Cancer Risk Reduction Expert Panel member Barnett S. Kramer, MD, MPH, of the National Institutes of Health, explained, “the seminal Breast Cancer Prevention Trial and the other trials that followed have periodically come under criticism because, although they clearly show that tamoxifen and raloxifene decrease the incidence of breast cancer, they have not shown that the decreased incidence translates into a lower risk of death from breast cancer. However, the very diagnosis of breast cancer, and the morbidity incurred by treatment, are so life-changing that breast cancer incidence is a major health outcome in and of itself—not simply a ‘surrogate’ or intermediate endpoint for mortality. Even if the proven decrease in incidence never translates into lower mortality, tamoxifen and raloxifene have proven their worth in women at high risk of breast cancer.”
The guideline reviews long-term follow-up on trials covered in the 2002 update of this guideline. Follow-up data on tamoxifen are available for up to a median of 11 years and 5.6 years for raloxifene. Data from the International Breast Intervention Study-I are included in the guideline. The median follow-up in this study, which compared tamoxifen to placebo, was eight years. Data are presented from the period during active treatment, during post-treatment, and during the entire follow-up period. In addition, the guideline now includes findings from the STAR trial, which examines the efficacy of tamoxifen compared to raloxifene of reducing the risk of breast cancer.
Several models exist to estimate woman’s risk of developing breast cancer. These risk models are generally based on various combinations of family history, a woman’s age, reproductive history, race/ethnicity, hormonal factors, and any benign breast disease. The guideline recommendations refer to the Breast Cancer Risk Assessment Model of the National Cancer Institute (NCI), based on the Gail model, when defining women who may consider taking tamoxifen or raloxifene. The Women’s Contraceptive and Reproductive Experiences (CARE) model provides better estimates for black women. Both models are available at
http://dceg.cancer.gov/tools/riskassessment.
According to the guideline, a woman who was premenopausal and at high risk or with LCIS would be eligible to take tamoxifen, but not raloxifene. A woman who was postmenopausal and at high risk or had LCIS may consider being treated with either tamoxifen or raloxifene. With tamoxifen, a greater benefit in risk reduction has been seen in premenopausal women.
There is a risk of adverse events or side effects with both of these agents; many were greater among tamoxifen users in the STAR trial, including venous thromboembolism and cataracts. That and other studies showed that both agents can lead to other side effects, including gynecological and vasomotor symptoms.
Some serious side effects, such as venous thromboembolism, seen at statistical significance with tamoxifen, were not seen with raloxifene. In another example, the risk of stroke is increased in women age 50 or older with tamoxifen, as was the risk of endometrial cancer. However, those elevated risks were not seen with raloxifene. The guideline details the rates of adverse events seen with these agents in trials.
The guideline also reviews results of trials on aromatase inhibitors and fenretinide but does not find enough evidence at this time to recommend them for breast cancer risk reduction. There are ongoing trials that may further inform this question.
Discussions about breast cancer risk reduction may occur between a woman and her primary care physician, or at breast cancer screening clinics. The guideline provides suggestions to facilitate these conversations.
An executive summary, slide set, and the full text of the guideline are available at
www.asco.org/guidelines/bcrr.
