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 forms the basis of the USPSTF Recommendation Statement on this topic.

The draft Research Plan was available for comment from November 14 until December 11, 2013 at 5:00 p.m., ET.

* Excludes women with pre-existing breast cancer; clinically significant BRCA gene mutations, Li-Fraumeni syndrome, Cowden syndrome, hereditary diffuse gastric cancer, or other familial breast cancer syndromes; high-risk lesions (ductal or lobular carcinoma in situ, atypical ductal or lobular hyperplasia); or previous large doses of chest radiation therapy (≥20 Gy) before age 30 years.
† Addresses Contextual Question 1.

In the target population of women age 40 years and older^a:

1. What is the effectiveness of routine mammography screening in reducing breast cancer–specific and all-cause mortality, and how does it differ by age, risk factor^b, and screening interval?
2. What is the effectiveness of routine mammography screening in reducing the incidence of advanced breast cancer and treatment-related morbidity^c, and how does it differ by age, risk factor^b, and screening interval?
3. How does the effectiveness of routine breast cancer screening in reducing breast cancer–specific and all-cause mortality differ by screening strategy^d?
4. How does the effectiveness of routine breast cancer screening in reducing the incidence of advanced breast cancer and treatment-related morbidity^c differ by screening strategy^d?
5. What are the harms^e of routine mammography screening, and how do they differ by age, risk factor^b, and screening interval?
6. How do the harms^e of routine breast cancer screening differ by screening strategy^d?
7. What are the test performance characteristics of tomosynthesis (3-D mammography) as a primary screening modality for breast cancer, performed either alone or simultaneously with 2-D digital mammography? How do these performance characteristics differ by age and risk factor^b?
8. What are the test performance characteristics of newer technologies^f for breast cancer screening when used as adjunctive screening after a negative screening mammogram in women found to have dense breasts? How do these performance characteristics differ by age and risk factor^b?
9. What is the accuracy and interrater reliability of the BI-RADS (Breast Imaging Reporting and Data System) determination of breast density?
10. What is the effectiveness of adjunctive screening for breast cancer with newer technologies^f on intermediate breast cancer outcomes^g (e.g., ductal carcinoma in situ [DCIS] detection rates, stage at diagnosis, and interval cancer rates) when performed after a negative screening mammogram in women found to have dense breasts?

^a Excludes women with pre-existing breast cancer; clinically significant BRCA gene mutations, Li-Fraumeni syndrome, Cowden syndrome, hereditary diffuse gastric cancer, or other familial breast cancer syndromes; high-risk lesions (ductal or lobular carcinoma in situ, atypical ductal or lobular hyperplasia); or previous large doses of chest radiation therapy (≥20 Gy) before age 30 years.
^b Risk factors include: age, family history, breast density, parity, race/ethnicity, age at first birth, menopausal status, current use of menopausal hormone therapy or oral contraception, prior benign breast biopsy, and, for women age >50 years, body mass index.
^c Morbidity includes: physical adverse effects of treatment, quality of life measures, and other measures of impairment.
^d Screening strategies include: mammography (digital, tomosynthesis), magnetic resonance imaging (MRI), ultrasonography, and clinical breast examination, either alone or in combination. One clinical situation in which a combined screening strategy may be employed is when a screening mammogram identifies a woman to have dense breasts, but is otherwise negative.
^e Harms include: false-positive findings, anxiety, false-positive biopsies, false-negative findings, false reassurance, overdiagnosis and resulting overtreatment, and radiation exposure.
^f Newer technologies include: MRI, hand-held ultrasonography, and whole breast ultrasonography.
^g Intermediate breast cancer outcomes include: interval breast cancer incidence, DCIS diagnosis rate, stage at breast cancer diagnosis, and invasive breast cancer recurrence rate.

Contextual questions will not be systematically reviewed, but will be evaluated using a “best evidence” approach.

1. What are the rates of specific adverse effects of current treatment regimens for invasive breast cancer and DCIS in the United States?
2. What are the absolute incidence rates of DCIS and localized and advanced invasive breast cancer in screened and nonscreened populations in the United States?
3. How do women weigh the harms and benefits of screening mammography and how do they use this information in their decisions to undergo screening?

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 specific to each of the key questions (KQs).

* Search dates vary because some KQs (KQs 1, 3, 5, 6) were included in the previous systematic review and require only an update of studies published since the previous search in 2008 (the USPSTF will continue to consider and use evidence that was included in prior systematic reviews). Other KQs were not addressed by the previous review and require a search that covers a longer time period (KQs 2 and 4 and cohort studies for KQs 1 and 3). These searches extend to 1996 because this is the last time the USPSTF evaluated similar data and represents a period when practice was shifting to digital mammography in the United States. The contextual questions have a shorter time period for searches because they require current data.
Abbreviations: BI-RADS=Breast Imaging Reporting and Data System; DCIS=ductal carcinoma in situ; MRI=magnetic resonance imaging; RCT=randomized, controlled trial; USPSTF=U.S. Preventive Services Task Force.

The draft Research Plan was posted for public comment on the USPSTF Web site from November 14 to December 11, 2013. In response, the Task Force clarified the populations of women that are included in this review, as well as definitions related to risk. The Task Force also clarified that although the current review's search dates for trials of breast cancer screening effectiveness cover the years 2008 through 2014, it will consider evidence from older trials included in prior systematic reviews. That is, the current evidence review will primarily search for new studies or updates of previous trials, but the USPSTF, in making its recommendations, will consider the totality of evidence available, not just studies published since 2008. Contextual Question 3 (examining the woman's perspective when considering breast cancer screening) was refined to provide both descriptive data as well as related information about decision outcomes. The Research Approach was expanded to include information on the test characteristics of newer screening modalities, either in a primary screening capacity (such as breast tomosynthesis) or as a screening strategy in women who have a negative mammogram but are found to have dense breasts. To further explore evidence on the issue of clinical management of women with dense breasts, the Task Force added a question about the reliability and reproducibility of BI-RADS. It will also evaluate the available evidence on the effectiveness of screening in women with negative mammograms but dense breasts on additional intermediate outcomes, such as interval breast cancer incidence rate and rate of invasive breast cancer recurrence.

The USPSTF has commissioned decision models to supplement the systematic review of the evidence on breast cancer screening, as it did for the previous topic update in 2009. Decision models are mathematical simulations that project the population-level health outcomes that result from alternative interventions for prevention, diagnosis, and treatment. For example, a decision model can describe the expected population health outcomes of a clinical preventive service over a lifetime horizon rather than the more limited range of years generally captured by clinical trials. Inputs into the decision models will include data from the systematic evidence review, which will provide the best available information on the linkages between screening and outcomes of interest. In conjunction with the systematic review of the evidence, the decision model results will help the Task Force examine how the benefits and harms of breast cancer screening strategies may vary by different starting and stopping ages and the time interval between screening tests. The model will also investigate how a woman's personal factors may affect the benefits and harms of different breast cancer screening approaches.

For more information about how the USPSTF uses decision models in formulating its recommendations, please refer to the USPSTF Procedure Manual, available at http://www.uspreventiveservicestaskforce.org/Page/Name/procedure-manual.