Final Research Plan
Breast Cancer: Medication Use to Reduce Risk
July 20, 2017
Recommendations made by the USPSTF are independent of the U.S. government. They should not be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.
The final Research Plan is used to guide a systematic review of the evidence by researchers at an Evidence-based Practice Center. The resulting Evidence Review will form the basis of the USPSTF Recommendation Statement on this topic.
The draft Research Plan was available for comment from March 23 to April 19, 2017.
Figure 1 is a flow diagram of selection of candidates for medications to reduce the risk for primary breast cancer. Women without preexisting breast cancer are screened and sorted into either appropriate or inappropriate candidates for therapy. Women who are appropriate candidates for therapy receive medications to reduce the risk for primary breast cancer. Women may experience adverse effects due to these medications. Women who are treated with these medications may have reduced incidence of invasive or noninvasive breast cancer or other beneficial health outcomes, which may lead to improved breast cancer–related mortality and all-cause mortality.
- In adult women without preexisting breast cancer, what is the accuracy of risk assessment methods to identify women who could benefit from medications to reduce risk for primary breast cancer (e.g., clinical risk assessment models)?
- What is the optimal age at which to begin risk assessment to identify women who could benefit from medications to reduce risk for primary breast cancer?
- What is the optimal frequency of risk assessment to identify women who could benefit from medications to reduce risk for primary breast cancer?
- In adult women without preexisting breast cancer, what is the effectiveness and comparative effectiveness of medications to reduce risk for primary breast cancer on improvement in short- and long-term health outcomes, including invasive breast cancer, noninvasive breast cancer (including ductal carcinoma in situ), breast cancer mortality, all-cause mortality, and other beneficial outcomes (such as reduced fractures caused by certain medications and improved quality of life)?
- Does the effectiveness of risk-reducing medications vary by timing of initiation or duration of use?
- Does the effectiveness of risk-reducing medications persist beyond discontinuation of use?
- What are the harms of using medications to reduce risk for primary breast cancer?
- Do the harms of risk-reducing medications vary by timing of initiation or duration of use?
- Do the harms of risk-reducing medications persist beyond discontinuation of use?
- Do the outcomes of using medications to reduce risk for primary breast cancer vary by population subgroups?
Contextual questions will not be systematically reviewed and are not shown in the Analytic Framework.
- What are current clinician and patient attitudes and practices regarding use of medications to reduce risk for primary breast cancer? Do they vary by population subgroups, including nonwhite women; premenopausal women; women with comorbid conditions; and women with lower educational levels, socioeconomic status, and access to care?
- How well do statistical models inform the practice of identifying and treating women with medications to reduce risk for breast cancer?
The Research Approach identifies the study characteristics and criteria that the Evidence-based Practice Center will use to search for publications and to determine whether identified studies should be included or excluded from the Evidence Review. Criteria are overarching as well as specific to each of the key questions (KQs).
Since current clinical practice in the United States includes the use of aromatase inhibitors to reduce risk for breast cancer, these medications will be included in the evidence review, along with tamoxifen and raloxifene. KQs 1, 2, 3, and 4 are similar to those in the previous review. Two additional questions about the use of risk assessment to identify women who could benefit from medications to reduce risk for primary breast cancer focus on optimal ages (KQ 1a) and intervals (KQ 1b). Questions relating to the timing, duration, and persistence of benefits (KQs 2a, 2b) parallel similar questions for harms (KQs 3a, 3b). In the previous evidence review, the question "How do benefits and harms affect decisions to use medications to reduce risk for primary breast cancer, concordance, adherence, and persistence?" did not yield findings useful or applicable to clinical practice. This KQ was replaced with a contextual question about current clinician and patient attitudes and practices regarding use of risk-reducing medications.
|Populations||Women without preexisting breast cancer, including women who are known carriers of BRCA genetic mutations and women with previous nonmalignant breast biopsies (e.g., atypical hyperplasia)||Women with preexisting breast cancer (invasive or ductal carcinoma in situ); men; populations dissimilar to those in the United States|
|Interventions||KQ 1: Risk assessment
KQs 2–4: Tamoxifen, raloxifene, and aromatase inhibitors
|KQs 2–4: Medications not used or available in the United States; other medications not listed as included|
|Comparisons||KQ 1: Risk assessment methods vs. usual care or an alternative risk assessment method
KQs 2–4: Medication vs. placebo; tamoxifen vs. raloxifene, tamoxifen vs. aromatase inhibitors, and raloxifene vs. aromatase inhibitors
|Comparisons with other types of medications|
|Outcomes||KQ 1: Measures of risk assessment test performance (sensitivity, specificity; positive and negative likelihood ratio; c-statistic)
KQs 2, 4: Invasive and noninvasive breast cancer incidence; breast cancer and all-cause mortality; other beneficial outcomes (e.g., reduced fractures caused by certain medications)
KQs 3, 4: Adverse effects (including but not limited to: thromboembolic events, cardiovascular events, metabolic disorders, musculoskeletal symptoms, mental health, genitourinary outcomes, adverse breast outcomes, other malignancies, ophthalmologic disorders, gastrointestinal/hepatobiliary disorders, other adverse events affecting quality of life)
|Setting||Primary care settings; settings comparable to U.S. practice||Practice settings dissimilar to those in the United States|
|Study Design||KQ 1: Discriminatory accuracy studies
KQs 1a, 1b, 2–4: Randomized, controlled trials; observational studies, with or without comparison groups, except for efficacy (KQ 2)
|Other study designs|
|Study Quality||Good- and fair-quality studies for meta-analyses||Poor-quality studies|
The draft Research Plan was posted for public comment on the USPSTF Web site from March 23 to April 20, 2017. Some comments suggested that other beneficial outcomes should be included in KQ 2, such as reduced fractures caused by certain medications and improved quality of life. In response, the USPSTF included these as secondary outcomes in the revised Research Plan. Two additional comments did not require revisions because they were already addressed. These include understanding how to best communicate the risk-to-benefit tradeoff to women to help them make informed decisions about risk-reducing medications, and how these tradeoffs vary by population subgroup. Finally, comments related to risk assessment suggested that risk stratification for patients without ovarian function should be included. The review will include studies of all types of risk stratification approaches that are available in the literature.