February 11, 2019.
We are pleased to have the opportunity to express our strong concerns about the draft recommendations for the use of prophylactic hormonal treatments for women at increased risk for breast cancer. The Cancer Prevention and Treatment Fund is a nonprofit program that conducts, analyzes, and reviews research, with a particular focus on which prevention strategies and treatments are most effective for which patients and consumers. We do not accept funding from pharmaceutical companies and have no financial ties to this issue.
We have several concerns about the draft proposal and strongly urge USPSTF to reconsider the recommendation guidelines proposed for the following reasons:
- Most importantly, the evidence does not include information on absolute risk, which is much more meaningful to patients than relative risk. The overall lifetime risk of breast cancer attributed to Tamoxifen would be reduced from 12% to 8%[i],[ii] if tamoxifen is taken over 5 years. At the same time however, it would increase the lifetime risk of endometrial cancer from 3% to 6.5%[iii],[ii] and the lifetime risk of thromboembolism from 20% to 39%.[iv] Similarly, raloxifene reduces the lifetime risk of breast cancer from 12% to 5%[i],[iii] but increases the risk of thromboembolism from 20% to 31%.[iv] Aromatase inhibitors lower the absolute risk of breast cancer from 12% to 5%,[i],[ii] while the lifetime risk of venous thromboembolism increased from 20% to 25%4 and the average lifetime risk of stroke from 20% to 23% as well.[v] The risk of fractures increases with AI and decreases with tamoxifen and raloxifene, but those comparisons are primarily based on x-rays and bone mineral density, rather than health outcomes of importance to patients, such as pain, other quality of life issues, or abilities regarding activities of daily living.[ii] In summary, the increases in absolute risk for several serious outcomes are considerably higher than the decrease in absolute risk of breast cancer.
- The importance of shared decision-makingthat was included in 2013 is missing in 2019. The 2013 USPSTF recommendations included “shared informed decision-making” but the 2019 draft recommends that doctors “offer to prescribe.” Research shows that informative discussions have a significant impact on patients’ decisions; those who are better informed of their associated risks are less likely to take these hormonal drugs.[vi],[vii] As noted above, this discussion should focus on absolute risks, not relative risks. The 2019 draft guidelines recommend physicians “offer to prescribe” these drugs to women who are at high risk of breast cancer but at low risk for adverse events; the ambivalence over risk-benefit ratio that was included in the evidence review draft is not reflected in this wording.[ii]
- Another major concern is the definition of women at high risk of breast cancer. Since the risk of breast cancer increases with age, most women over 65 with one or two other risk factors would be categorized by the NCI risk model as “high risk” because their risk would be above 1.7% in the following 5 years.[viii] In addition, the NCI risk model is based on certain characteristics, but not mitigating variables. The USPSTF definition of high risk would expose many women who have a moderate to low increased risk of breast cancer to the many unpleasant and serious side effects of these drugs. In 2013, the USPSTF referred to high risk of breast cancer as at least 3% over the next 5 years, and that is a much more appropriate definition.[ix]
- Impact of side effects on quality of life is not adequately considered. Studies have shown that women on tamoxifen have significanly increased rates of hot flashes, arthralgia, vaginal dryness, and sexual dysfunction. For these reasons, high-risk women on tamoxifen were more likely to discontinue these drugs within 5 years due to adverse events when compared to women in the placebo group.[x]
In addition to the specific issues above, we strongly urge the USPSTF to consider its recommendations regarding hormonal treatments in the context of other factors that can decrease the risk of breast cancer. Healthy habits such as a healthy weight, a diet low in red meat and alcohol, as well as regular exercise have been known to reduce the overall risk of breast cancer. For example, a major prospective study looking at health outcomes in postmenopausal women found that women with the healthiest diets and the most exercise will decrease their lifetime risk of breast cancer from 12% to 9%.[xi]
As noted above, the risks of these drugs are likely to outweigh the benefits for most women. The USPSTF key questions focus too heavily on benefits of these drugs and do not give sufficient consideration to risks. They should be revised to better assess cancer risk, potential benefit, and potential harm. Only the women at very high risk of breast cancer and low risk of endometrial cancer and vascular disease should consider them. We strongly urge USPSTF to substantially change the recommendations in light of the absolute risks involved, and that doctors engage in shared decision-making discussions, considering these drugs only for their highest-risk patients, focused on those absolute risks, in order to ensure informed decisions.
For questions or more information, please contact Dr. Diana Zuckerman at email@example.com.
- NCHR calculated the absolute risk based on the statistics provided by the National Cancer Institute; National Cancer Institute. (2012). Breast Cancer Risk in American Women. https://www.cancer.gov/types/breast/risk-fact-sheet
- NCHR calculated the absolute risk based on the statistics provided by the United States Preventative Services Task Force Draft Recommendation Statement. (2019). Breast Cancer: Medication Use to Reduce Risk.
- NCHR calculated the absolute risk based on the statistics provided by the National Cancer Institute. (2013). Uterine Cancer – Cancer Stat Facts. https://seer.cancer.gov/statfacts/html/corp.html
- NCHR calculated the absolute risk based on the statistics provided by Bell EJ, Lutsey PL, et al. (2015). Lifetime Risk of Venous Thromboembolism in Two Cohort Studies. American Journal of Medicine.
- NCHR calculated the absolute risk based on the statistics provided by Seshadri S., & Wolf, P.A. (2007). Lifetime risk of stroke and dementia: current concepts, and estimates from the Framingham Study. The Lancet Neurology.
- Fagerlin A, Zikmund-Fisher BJ, et al. (2010). Women’s decisions regarding tamoxifen for breast cancer prevention: responses to a tailored decision aid. Breast Cancer Res. Treatment.
- Melnikow J, Paterniti D, et al. (2005). Preferences of Women Evaluating Risks of Tamoxifen (POWER) study of preferences for tamoxifen for breast cancer risk reduction. Cancer.
- National Cancer Institute. The Breast Cancer Risk Assessment tool. https://bcrisktool.cancer.gov/
- United States Preventative Services Task Force. (2013). Breast Cancer: Medications for Risk Reduction. https://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/breast-cancer-medications-for-risk-reduction
- Day, R. (2001). Quality of Life and Tamoxifen in a Breast Cancer Prevention Trial. Annals of the New York Academy of Sciences.
- Thomson, CA et al. (2014). Nutrition and Physical Activity Cancer Prevention Guidelines, Cancer Risk, and Mortality in the Women’s Health Initiative. Cancer Prevention Research.