Victor G. Vogel, MD, MHS, FACP
Despite strong evidence that it is efficacious, chemoprevention has been underused in eligible women. Several agents have been studied prospectively in randomized, controlled trials that have examined benefits, life-threatening side effects, and quality-of-life outcomes. We have estimates of the population benefit of using selective estrogen receptor modulators (SERMs) for breast cancer risk reduction,1 and we have estimates of the cost per year of life saved.2,3
Yet, despite the fact that the number of women needed to treat to prevent a case of breast cancer is acceptable with both of the SERMs tamoxifen and raloxifene, neither drug has broad usage within the high-risk population for breast cancer risk reduction.4
|Dr. Victor G. Vogel|
Patients—and perhaps their physicians—are confused by the concept of probabilistic risk, they fear endometrial cancer out of proportion to its true tamoxifen-related risk, and they do not understand that there is no increased risk of uterine malignancy associated with raloxifene.
Additional reasons not to initiate strategies to reduce the risk of breast cancer include the fear of adverse effects and high medication costs, as well as both a lack of reasonably accurate and feasible methods for assessing individual risk and a lack of established risk thresholds that maximize benefit and minimize harms.5-7
Multiple studies have shown that tamoxifen reduces the risk in women at increased risk of breast cancer.8,9 In addition, there are several strategies to identify women at increased risk including quantitative risk models, increased mammographic density, circulating estrogen levels, and the presence of high-risk benign breast disease such as atypical hyperplasia and lobular carcinoma in situ.10 On the basis of a woman’s risk factors (i.e., age, ethnicity, breast cancer risk, and whether she has a uterus), one can calculate her probability of having a health event in 5 years in the absence or presence of chemoprevention (Table).
To summarize risks and benefits of preventative therapy in a single index, weights are assigned for life-threatening events (i.e., invasive breast cancer, hip fracture, endometrial cancer, stroke, and pulmonary embolism) and for severe events (i.e., in situ breast cancer and deep vein thrombosis). The net benefit index is the expected number of life-threatening equivalent events in 5 years without chemoprevention in 10,000 such women minus the expected number of lifethreatening equivalent events if chemoprevention is used. For example, in the table, among 10,000 non-Hispanic white women aged 50 to 59 who have a uterus and a 5-year risk of breast cancer equal to 3.5%, one expects that 108 lifethreatening events would be prevented in 5 years if raloxifene is administered instead of placebo.
There is strong evidence (p > 0.9; blue) that the benefits of receiving raloxifene outweigh the risks. If tamoxifen were used instead, chemoprevention would result in 25 excess lifethreatening events (p < 0.6; gray).
The Study of Tamoxifen and Raloxifene (STAR) Trial compared the first-generation SERM, tamoxifen, to the second-generation drug, raloxifene, in high-risk, postmenopausal women. Raloxifene caused half as many uterine malignancies, 20% fewer pulmonary emboli, and 28% fewer deep vein thrombi. There were few strokes, and raloxifene was nearly as effective in preventing invasive breast cancer. However, use of raloxifene did not increase after the trial results were released.11-13
Available data show that tamoxifen will prevent 20 invasive and 20 noninvasive breast cancers in 1,000 women at the elevated 5-year risk of 4% while causing 2.2 endometrial cancers and 3.3 thromboembolic events in the same group of women over 7 years.14
In the 2009 update to the ASCO Clinical Practice Guideline on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction, it is stated that, "Five years of tamoxifen (20 mg/d) may be offered to women at increased risk of breast cancer to reduce their risk of estrogen receptor (ER)–positive invasive breast cancers for up to 10 years. Eligible women include those with a 5-year projected breast cancer risk > 1.66%, or women with LCIS. The greatest clinical benefit and the fewest side effects were derived from the use of tamoxifen in younger (premenopausal) women 35 to 50 years of age who are unlikely to experience thromboembolic sequelae or uterine cancer, women without a uterus, and women at high risk of breast cancer."15
ASCO also says that for postmenopausal women at increased risk for breast cancer, raloxifene (60 mg/d) for 5 years may be offered as another option to reduce the risk of ER-positive invasive breast cancer. They also note that "To ensure that women at risk of breast cancer are given the option of taking preventive agents in an informed manner, breast cancer risk assessment and risk communication must become an integral part of clinical practice. A broader educational effort is needed to alert women from all racial/ethnic and socioeconomic groups, as well as primary care providers, that treatment is available to reduce breast cancer risk."
We all should heed this advice to reduce the burden of breast cancer throughout the population of women who are at increased risk.
About the Author: Dr. Vogel is Director of the Cancer Institute at Geisinger Medical Center. He is the immediate past chair of ASCO’s Cancer Prevention Committee, a former member of the Board of Directors of the NSABP, and was the protocol chairman for the Study of Tamoxifen and Raloxifene (STAR Trial). Dr. Vogel will be presenting information about the medical management and prevention of premalignant lesions in DCIS, LCIS, and ADH in today’s General Session II: Risk Assessment, Prevention, Detection, and Screening.
- Freedman AN, Costantino JP, Gail MH, et al. A benefi t/risk assessment tool for breast cancer chemoprevention treatment. J Clin Oncol. 2011;29(17):2327-2333.
- Smith TJ, Hillner BE. Tamoxifen should be cost-effective in reducing breast cancer risk in high-risk women. J Clin Oncol. 2000;18(2):284-286.
- Hershman D, Sundararajan V, Jacobson JS, et al. Outcomes of tamoxifen chemoprevention for breast cancer in very high-risk women: a costeffectiveness analysis. J Clin Oncol. 2002;20(1):9-16.
- Waters, EA, Cronin KA, Graubard BI, et al. Prevalence of tamoxifen use for breast cancer chemoprevention among U.S. women. Cancer Epidemiol Biomarkers Prev. 2010;19(2):443-446.
- Melnikow J, Kuenneth C, Helms LJ, et al. Chemoprevention: drug pricing and mortality: the case of tamoxifen. Cancer. 2006;107(5):950-958.
- Melnikow J, Birch S, Slee C, et al. Tamoxifen for breast cancer risk reduction: impact of alternative approaches to quality-of-life adjustment on cost-effectiveness analysis. Med Care. 2008;46(9):946-953.
- Rockhill B, Spiegelman D, Byrne C, et al. Validation of the Gail et al. model of breast cancer risk prediction and implications for chemoprevention. J Natl Cancer Inst. 2001;93(5):358-366.
- Cuzick J, Powles T, Veronesi U, et al. Overview of the main outcomes in breast cancer prevention trials. Lancet. 2003;361(9354):296-300.
- Nelson HD, Fu R, Griffi n JC, et al. Systematic review: comparative effectiveness of medications to reduce risk for primary breast cancer. Ann Intern Med. 2009;151(10):703-715.
- Vogel VG. Tipping the valance for the primary prevention of breast cancer. J Natl Cancer Inst. 2010;102(22):1683- 1685.
- Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs. raloxifene on the risk of developing invasive breast cancer and other disease outcomes: The NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 Trial. JAMA. 2006;295(23):2727-2741.
- Vogel VG, Costantino JP, Wickerham DL, et al. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing Breast Cancer. Cancer Prev Res (Phila). 2010;3(6):696-706. Epub 2010 Apr 19.
- Ravdin PM. The lack, need, and opportunities for decision-making and informational tools to educate primary-care physicians and women about breast cancer chemoprevention. Cancer Prev Res (Phila). 2010;3(6):686-688.
- Hortobagyi GN, Brown PH. Two good choices to prevent breast cancer: great taste, less filling. Cancer Prev Res (Phila). 2010;3(6):681-685.
- Visvanathan K, Chlebowski RT, Hurley P, et al. American Society of Clinical Oncology Practice Guideline Update on the use of pharmacologic intervention including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction. J Clin Oncol. 2009;27(19):3235-3258. Epub 2009 May 26.