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Guise JM, Nakamoto EK, LaBrant L, et al. Future Research Needs To Reduce the Risk of Primary Breast Cancer in Women: Identification of Future Research Needs from Comparative Effectiveness Review No. 17 [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2010 Sep. (Future Research Needs Papers, No. 5.)

Cover of Future Research Needs To Reduce the Risk of Primary Breast Cancer in Women

Future Research Needs To Reduce the Risk of Primary Breast Cancer in Women: Identification of Future Research Needs from Comparative Effectiveness Review No. 17 [Internet].

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Appendix ACER Section on Future Research Needs

Excerpted from:

Nelson H, Fu R, Humphrey L, Smith M, Griffin J, Nygren P. Comparative effectiveness of medications to reduce risk of primary breast cancer in women. Comparative Effectiveness Review No. 17. Rockville, MD: Agency for Healthcare Research and Quality; 2009.

Although several essential questions have been addressed by current studies, many more remain. More research is needed on tibolone’s role in reducing risk for breast cancer and its harms. Although tibolone is not currently approved for use in the United States, it is widely used elsewhere and may be approved in the future. To avoid increasing risk for stroke, future trials of tibolone will need to focus on younger women. Future trials could confirm results of the LIFT trial and compare tibolone’s efficacy in head-to-head trials with other medications. More research is needed to further evaluate findings from other studies of tibolone and determine their relevance to women using it for breast cancer risk reduction. For example, a recent multi-center trial of 3,148 breast cancer patients with vasomotor symptoms was stopped early because women using tibolone had higher breast cancer recurrence rates compared with placebo (HR 1.40;1.14,1.70). The Tibolone Histology of the Endometrium and Breast Endpoints Study (THEBES) comparing tibolone and continuous combined conjugated equine estrogen plus medroxyprogesterone acetate indicated that tibolone did not cause endometrial hyperplasia or carcinoma in postmenopausal women and had a more favorable vaginal bleeding profile.

Trials of other emerging medications to reduce breast cancer risk, such as aromatase inhibitors and retinoids, will be needed as these are developed. Well designed and powered head-to-head trials could contribute much needed information on outcomes, duration and timing of treatment, and identification of optimal candidates. Controlled trials of lifestyle modification interventions to reduce risk for breast cancer, such as weight loss and exercise, should also be explored. These interventions could be incorporated into comparative trials that also include medications.

While the efficacy of tamoxifen, raloxifene, and tibolone has been demonstrated for women in randomized controlled trials, it is not clear which women in clinical practice would optimally benefit from risk reducing medications. Inclusion criteria for three of the placebo-controlled tamoxifen trials (NSABP P-1, IBIS, Royal Marsden) and STAR included an assessment of risk for breast cancer, and only women reaching a specified threshold were enrolled. However, for the other raloxifene and tibolone trials, no breast cancer risk assessment was performed and women of all risk groups were included. Despite these differences, trials of all the medications demonstrated efficacy in reducing invasive breast cancer. Our further analysis by various population subgroups, such as by age, menopausal status, and others, also indicated no major differences, suggesting that everyone would benefit. Future research to determine the optimal candidates for these medications would help focus risk reducing efforts. Applying these findings to clinical selection criteria would improve identification of candidates in practice settings.

In addition to improving our understanding of which women are optimal candidates, research is needed to further evaluate clinical risk instruments to identify high-risk women who are most likely to benefit from risk reducing interventions. Current research indicates that prediction models that include breast density offer marginal improvement in diagnostic accuracy. Addition of other factors such as diet, alcohol use, physical activity, smoking status, and height offer little improvement in diagnostic accuracy. The use of previously acknowledged risk factors, such as prior postmenopausal hormone therapy, needs to be reconsidered as new research indicating no associations with breast cancer are reported. New models need to build on research findings from older models, and research needs to expand beyond diagnostic accuracy studies. Models need to be evaluated in relevant clinical settings and populations to 48 determine their effectiveness in identifying high-risk women for clinical decisionmaking. Effective models should also be validated in various racial and ethnic populations, among non- English speakers, and across multiple age groups. This work should include research regarding optimal methods for communicating risks and benefits to women.

The results of trials indicate that adverse effects differ between medications and may drive decisions for risk reducing medications as much or more than benefits. Further research to more clearly identify characteristics of individuals experiencing specific adverse effects would guide physicians and patients to regimens that cause the least harm. Strategies could be tested that optimize benefits and minimize harms. For example, the effects of adding aspirin in conjunction with tamoxifen or raloxifene could improve the benefit/harm balance for women by reducing risks of thromboembolic adverse events, stroke, and possibly breast cancer itself. Further analysis of data from the MORE and RUTH trials could address this question because a large proportion of subjects were using aspirin in these trials. Future trials could evaluate the benefits and harms of using tamoxifen or raloxifene with an anticoagulant such as warfarin, heparin, or low molecular weight heparin.

Primary prevention trials need to be continually evaluated for long-term and unanticipated outcomes. For example, tamoxifen users in the NSABP P-1 trial who developed estrogen receptor negative breast cancer had shorter times to diagnosis and were more likely to be detected by routine mammograms than placebo users who developed estrogen receptor negative breast cancer. Additional research to assess the use of raloxifene since its recent FDA approval for reducing risk for breast cancer will also be useful.

Evaluating the timing of medication use may also lead to effective clinical strategies. Results of current trials suggest that breast cancer risk reduction persists after treatment while some harms diminish. It is important to understand these changes over time. Use of medication for risk reduction at younger ages (45 to 55 years) could provide better long-term benefit and short-term harm for individuals at lower risk of thromboembolism or stroke than use at older ages (>60 years). Further analysis of data from currently available trials could compare risk/benefit profiles for women of various ages and risk groups. Additional analysis could also indicate optimal treatment durations. Shortening treatment duration would reduce harms, but also could compromise efficacy.

Despite prior recommendations to identify women at high-risk for breast cancer and offer medications to reduce their risks, and the availability of two SERMs for this purpose, use is believed to be low in the United States. This contrasts sharply with the use of statin medications to reduce cholesterol levels and cardiovascular disease. Understanding the differences and similarities in these approaches to risk reduction would be useful for clinicians. This requires research regarding the attitudes of physicians toward recommending 5 years of medication therapy to reduce risk as well as attitudes of patients regarding receptivity to this recommendation and adherence over time. Research on the physician and patient decision making process could identify factors important for selecting use of medications to reduce breast cancer risk beyond empirical risk.


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