Key QuestionsIncludeExcludeDuration and size of studyOutcomes
1. Benefits*
3. Benefits among population subgroups†
  • Randomized, double-blind, placebo controlled trials of tamoxifen, raloxifene, or tibolone for breast cancer prevention.
  • Head-to-head trials that include direct comparisons between tamoxifen, raloxifene, or tibolone.
  • Trials report breast cancer results as primary or secondary outcomes.‡
  • Trials enroll women without pre-existing breast cancer and can include women of all ages, pre or postmenopausal status, hysterectomy or nonhysterectomy status, US and non US.
  • English language publications.
  • Non RCT study designs.
  • Non breast cancer prevention studies.
  • Women with pre-existing breast cancer, known precursor conditions, or known carriers of breast cancer susceptibility mutations (BRCA1, BRCA2, or others).
  • Drugs other than tamoxifen, raloxifene, or tibolone.
  • No breast cancer results as primary or secondary outcomes.
  • Laboratory or animal studies.
  • Non-English language publications.
≥3 months

≥100 participants		Primary or secondary breast cancer outcomes; other benefits defined by key question 1.
2. Harms§
3. Harms among population subgroups†
  • Randomized, double-blind, placebo controlled trials of tamoxifen, raloxifene, or tibolone.
  • Head-to-head trials that include direct comparisons between tamoxifen, raloxifene, or tibolone.
  • Observational studies that report results for women using tamoxifen, raloxifene, or tibolone and compares results to a nonuser group or compares results between these drug use groups.
  • Studies enroll women without pre-existing breast cancer and can include women of all ages, pre or postmenopausal status, hysterectomy or nonhysterectomy status, US and non US.
  • Health outcomes.‡
  • English language publications.
  • Women with pre-existing breast cancer, known precursor conditions, or known carriers of breast cancer susceptibility mutations (BRCA1 BRCA2, or others).
  • Drugs other than tamoxifen, raloxifene, or tibolone.
  • No harms results.
  • Intermediate outcomes rather than health outcomes.‡
  • Laboratory or animal studies.
  • Non-English language publications.
≥3 months

≥100 participants		Any health outcome defined by key question 2.
4. Treatment adherence, persistence, concordance, or treatment choice†
  • Randomized, double-blind, placebo controlled trials of tamoxifen, raloxifene, or tibolone for breast cancer prevention.
  • Head-to-head trials that include direct comparisons between tamoxifen, raloxifene, or tibolone.
  • Observational and descriptive studies that report results for women using tamoxifen, raloxifene, or tibolone and compares results to a nonuser group or compares results between these drug use groups.
  • Trials enroll women without pre-existing breast cancer and can include women of all ages, pre or postmenopausal status, hysterectomy or nonhysterectomy status, US and non US.
  • Observational and descriptive studies of treatment choice.
  • Studies include data for treatment adherence, persistence, concordance, or treatment choice.
  • English language publications.
  • Women with pre-existing breast cancer, known precursor conditions, or known carriers of breast cancer susceptibility mutations (BRCA1, BRCA2, or others).
  • Drugs other than tamoxifen, raloxifene, or tibolone.
  • No adherence, persistence, concordance, or treatment choice data.
  • Laboratory or animal studies.
  • Non-English language publications.
RCTS: >3 months and >100 participantsAny measure of treatment adherence, persistence, or concordance; data on treatment choice.
5. Clinical risk assessment models
  • Studies of risk stratification models for women of any age.
  • Models used to identify women at higher than average risk for breast cancer.
  • Derivation or validation studies.
  • Study must include discriminatory accuracy of the model.
  • Models must be applicable to the primary care setting.
  • English language publications.
  • Family history/genetics models designed to determine risk for BRCA mutations.
  • Studies of individual risk factors.
  • Laboratory tests.
  • Non-English language publications.
Not specified.Evaluation of risk models for breast cancer that include more than 1 risk factor.
*

Benefit outcomes are defined by key question 1 and include:

  • Invasive breast cancer
  • Noninvasive breast cancer including ductal carcinoma in situ (DCIS)
  • Breast cancer mortality
  • All-cause mortality
  • Osteoporotic fractures

†

Population subgroups are defined by key question 3 and include but are not limited to those based on:

Age, menopausal status (pre-, peri-, postmenopausal), hysterectomy status, use of exogenous estrogen, level of risk of breast cancer (based on family history, body mass index, parity [number of pregnancies], age at first live birth, age at menarche, personal history of breast abnormalities, prior breast biopsy, estradiol levels, breast density), ethnicity and race, metabolism status (CYP 2D6 mutation), and risk for thromboembolic events (obesity, and other risk factors).

‡

Definitions of types of outcomes:

  • A primary outcome is the main outcome of a study that the study was designed and powered to demonstrate.
  • A secondary outcome is a major outcome of a study that the study was designed and powered to demonstrate, but is not the primary outcome of the study.
  • Health outcomes are signs, symptoms, conditions, or events that individuals experience, such as myocardial infarction, death, or hot flahes.
  • Intermediate outcomes are health measures that individuals do not personally experience, such as a laboratory test results or bone mineral density.

§

Harms outcomes are defined by key question 2 and may include but are not limited to:

  • Thromboembolic events (deep vein thrombosis, pulmonary embolism)
  • Cardiovascular events (coronary heart disease, stroke and transient ischemic attack, arrhythmias)
  • Metabolic disorders (diabetes)
  • Musculoskeletal symptoms (myalgia, leg cramps)
  • Mental health (depression, mood changes)
  • Genitourinary outcomes (vaginal dryness, uterine bleeding, hysterectomy, endometrial cancer, urinary symptoms)
  • Adverse breast outcomes (biopsies)
  • Other malignancies (incidence, death)
  • Ophthalmologic disorders (cataracts)
  • Gastrointestinal/hepatobiliary disorders (abdominal pain, nausea)
  • Other adverse events impacting quality of life (vasomotor symptoms, sexual function, sleep disturbances, headaches, cognitive changes, peripheral edema)

From: Appendix A, Searches

Cover of Comparative Effectiveness of Medications To Reduce Risk of Primary Breast Cancer in Women
Comparative Effectiveness of Medications To Reduce Risk of Primary Breast Cancer in Women [Internet].
AHRQ Comparative Effectiveness Reviews, No. 17.
Nelson HD, Fu R, Humphrey L, et al.
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