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Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA1/2-Related Cancer in Women: A Systematic Review for the U.S. Preventive Services Task Force [Entered Retrospectively]


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Statistics: 110 Studies, 5 Key Questions, 1 Extraction Form,
Date Published: Oct 18, 2019 08:18PM
Description: Background: Pathogenic mutations in breast cancer susceptibility genes BRCA1 and BRCA2 increase risks for breast, ovarian, fallopian tube, and peritoneal cancer in women; interventions reduce risk in mutation carriers. Purpose: To update the 2013 U.S. Preventive Services Task Force review on benefits and harms of risk assessment, genetic counseling, and genetic testing for BRCA1/2-related cancer in women. Data Sources: Cochrane libraries; MEDLINE, PsycINFO, EMBASE (January 1, 2013 to March 6, 2019 for updates; January 1, 1994 to March 6, 2019 for new key questions and populations); reference lists. Study Selection: Discriminatory accuracy studies, randomized controlled trials (RCTs), and observational studies of women without recently diagnosed BRCA1/2-related cancer. Data Extraction: Data on study methods; setting; population characteristics; eligibility criteria; interventions; numbers enrolled and lost to followup; outcome ascertainment; and results were abstracted. Two reviewers independently assessed study quality. Data Synthesis (Results): 103 studies (110 articles) were included. No studies evaluated the effectiveness of risk assessment, genetic counseling, and genetic testing in reducing incidence and mortality of BRCA1/2-related cancer. Fourteen studies of 10 risk assessment tools to guide referrals to genetic counseling demonstrated moderate to high accuracy (area under the receiver operating characteristic curve 0.68 to 0.96). No studies determined optimal ages, frequencies, or harms of risk assessment. Twenty-eight studies indicated genetic counseling is associated with reduced breast cancer worry, anxiety, and depression; increased understanding of risk; and decreased intention for testing. A RCT showed that population-based testing of Ashkenazi Jews detected more BRCA1/2 mutations than family-history based testing, while measures of anxiety, depression, distress, uncertainty, and quality of life were similar between groups; clinical outcomes were not evaluated. Twenty studies indicated breast cancer worry and anxiety were higher after testing for women with positive results and lower for others, and understanding of risk was higher. No RCTs evaluated the effectiveness of intensive screening for breast or ovarian cancer in mutation carriers. In observational studies, false-positive rates, additional imaging, and benign biopsies were higher with magnetic resonance imaging than mammography. In eight RCTs, tamoxifen (risk ratio [RR], 0.69; 95% confidence interval [CI], 0.59 to 0.84; 4 trials), raloxifene (RR, 0.44 95% CI, 0.24 to 0.80; 2 trials), and aromatase inhibitors (RR, 0.45 95% CI, 0.26 to 0.70; 2 trials) were associated with lower risks of invasive breast cancer compared with placebo; results were not specific to mutation carriers. Adverse effects included venous thromboembolic events for tamoxifen and raloxifene; endometrial cancer and cataracts for tamoxifen; and vasomotor, musculoskeletal, and other symptoms for all medications. In observational studies, mastectomy was associated with 90 to 100 percent reduction in breast cancer incidence and 81 to 100 percent reduction in breast cancer mortality; oophorectomy or salpingo-oophorectomy was associated with 69 to 100 percent reduction in ovarian cancer; complications were common with mastectomy. Limitations: Including only English-language articles and studies applicable to the United States; varying number, quality, and applicability of studies; and few studies of untested women previously treated for BRCA1/2-related cancer. Conclusions: Risk assessment, genetic counseling, and genetic testing to reduce BRCA1/2-cancer incidence and mortality as a prevention service has not been directly evaluated by current research. Risk assessment with familial risk tools accurately identifies high-risk women for genetic counseling. Genetic counseling reduces breast cancer worry, anxiety, and depression; increases understanding of risk; and decreases intention for mutation testing, while testing improves accuracy of understanding of risk. The effectiveness of intensive screening is not known, but it increases false-positive results and procedures. Risk-reducing medications and surgery are associated with reduced breast and ovarian cancer, but also have adverse effects. Evidence gaps relevant to prevention remain and additional studies are needed to better inform clinical practice.
Contributor(s): Heidi D. Nelson, MD, MPH Miranda Pappas, MA Amy Cantor, MD, MPH Elizabeth Haney, MD Rebecca Holmes, MD, MS Lucy Stillman, BS
Funding Source: This report is based on research conducted by the Pacific Northwest Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. HHSA290201500009I, Task Order No. 7)
Methodology Description: Study Selection: Discriminatory accuracy studies, randomized controlled trials (RCTs), and observational studies of women without recently diagnosed BRCA1/2-related cancer. Data Extraction: Data on study methods; setting; population characteristics; eligibility criteria; interventions; numbers enrolled and lost to followup; outcome ascertainment; and results were abstracted. Two reviewers independently assessed study quality.

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Medication Use for the Risk Reduction of Primary Breast Cancer in Women: A Systematic Review for the U.S. Preventive Services Task Force [Entered Retrospectively]


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Statistics: 82 Studies, 4 Key Questions, 1 Extraction Form,
Date Published: Oct 18, 2019 08:18PM
Description: Background: Medications to reduce breast cancer risk are an effective prevention intervention for women at increased risk, although medications also cause adverse effects. Purpose: To update the 2013 U.S. Preventive Services Task Force (USPSTF) systematic review on the use of medications to reduce the risk of primary breast cancer. Data Sources: Searches included the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, EMBASE, and MEDLINE (January 1, 2013 to February 1, 2019); and manual review of reference lists. Studies published before 2013 were identified from prior systematic reviews for the USPSTF. Study Selection: Discriminatory accuracy studies of breast cancer risk assessment methods; double-blind, placebo-controlled or head-to-head randomized controlled trials (RCT) of tamoxifen, raloxifene, and aromatase inhibitors for primary prevention of breast cancer that enrolled women without preexisting breast cancer; and RCTs and observational studies of harms of medications. Data Extraction: One investigator abstracted data on study methods; setting; population characteristics; eligibility criteria; interventions; numbers enrolled and lost to followup; method of outcome ascertainment; and results for each outcome and a second investigator checked abstractions for accuracy. Two investigators independently assessed study quality using methods developed by the USPSTF. Data Synthesis (Results): Eighteen risk models evaluated in 25 studies had generally low discriminatory accuracy in predicting the probability of breast cancer in an individual (c-statistics 0.55 to 0.65). Most models performed only slightly better than age alone as a risk predictor. No studies evaluated optimal ages or frequencies of risk assessment. In placebo-controlled trials, tamoxifen (risk ratio [RR] 0.69; 95% confidence interval [CI], 0.59 to 0.84; 7 fewer cases per 1000 women over 5 years of use [95% CI, 4 to 12]; 4 trials), raloxifene (RR 0.44; 95% CI, 0.24 to 0.80; 9 fewer cases [95% CI, 3 to 15]; 2 trials), and the aromatase inhibitors exemestane and anastrozole (RR 0.45; 95% CI, 0.26 to 0.70; 16 fewer cases [95% CI, 8 to 24]; 2 trials) reduced invasive breast cancer. Risk for invasive breast cancer was higher for raloxifene than tamoxifen in the Study of Tamoxifen And Raloxifene (STAR) head-to-head trial (RR, 1.24; 95% CI, 1.05 to 1.47) after long-term followup. Effects did not differ by age of initiation or duration of use (3 to 5 years), although these effects were not directly compared. Risk reduction persisted at least 8 years after discontinuation in tamoxifen trials with long-term followup. All medications reduced estrogen receptor positive, but not estrogen receptor negative invasive breast cancer; tamoxifen reduced noninvasive cancer in two trials; and breast-cancer specific and all-cause mortality were not reduced. In placebo-controlled trials, raloxifene (RR 0.61; 95% CI, 0.53 to 0.73; 2 trials) reduced vertebral fractures; tamoxifen reduced nonvertebral fractures in the National Surgical Adjuvant Breast and Bowel Project (NSABP P-1) trial (RR 0.66; 95% CI, 0.45 to 0.98); while the aromatase inhibitors had no effect on fractures. Tamoxifen and raloxifene had similar effects on reducing fractures at multiple vertebral and nonvertebral sites in the STAR head-to-head trial. In placebo-controlled trials, tamoxifen (RR 1.93; 95% CI, 1.33 to 2.68; 4 trials) and raloxifene (RR 1.56; 95% CI, 1.11 to 2.60; 2 trials) increased thromboembolic events, while aromatase inhibitors did not. Raloxifene caused fewer thromboembolic events (RR 0.75; 95% CI, 0.60 to 0.93) than tamoxifen in the STAR head-to-head trial. Tamoxifen, raloxifene, and aromatase inhibitors did not increase coronary heart disease events or strokes. In placebo-controlled trials, tamoxifen increased endometrial cancer (RR 2.25; 95% CI, 1.17 to 4.41; 3 trials), while raloxifene and aromatase inhibitors did not. In the STAR head-to-head trial, raloxifene caused fewer cases of endometrial cancer (RR 0.55; 95% CI, 0.36 to 0.83) and endometrial hyperplasia (RR 0.19; 95% CI, 0.12 to 0.29), and fewer hysterectomies (RR 0.45; 95% CI, 0.37 to 0.54) than tamoxifen. Tamoxifen increased cataracts (RR 1.22; 95% CI, 1.08 to 1.48; 3 trials) and cataract surgery compared with placebo, while raloxifene and aromatase inhibitors did not. Risks for thromboembolic events and endometrial cancer with tamoxifen were higher for older compared with younger women and returned to normal after discontinuation. All medications caused adverse effects, such as vasomotor or musculoskeletal symptoms, that varied by medication. Risks for invasive cancer were generally reduced in all population subgroups evaluated based on menopausal status (pre and postmenopausal); family history of breast cancer; body mass index categories; modified Gail model risk categories; and age at menarche, parity, or age at first live birth, although results varied. Tamoxifen and anastrozole had larger effects in reducing invasive breast cancer in women with previous breast lesions (lobular carcinoma in situ, atypical ductal hyperplasia, or atypical lobular hyperplasia). Limitations: Trials were limited by clinical heterogeneity related to different medications, exposure durations, eligibility criteria, adherence, and ascertainment of outcomes. No trials compared timing and duration directly. Long-term followup data were lacking from most trials, and followup was particularly short for the aromatase inhibitors. Trials were not designed for subgroup comparisons and analysis of differences may be underpowered. Conclusions: Tamoxifen, raloxifene, and the aromatase inhibitors exemestane and anastrozole reduce invasive breast cancer in women without preexisting breast cancer, but also cause adverse effects that vary by medication. Tamoxifen and raloxifene increase thromboembolic events and tamoxifen increases endometrial cancer and cataracts. Identifying candidates for therapy is complicated by risk stratification methods that demonstrate low accuracy.
Contributor(s): Heidi D. Nelson, MD, MPH Rongwei Fu, PhD Bernadette Zakher, MBBS Marian McDonagh, PharmD Miranda Pappas, MA Lucy Stillman, BS
Funding Source: This report is based on research conducted by the Pacific Northwest Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. HHSA290201500009I, Task Order No. 7)
Methodology Description: Study Selection: Discriminatory accuracy studies of breast cancer risk assessment methods; double-blind, placebo-controlled or head-to-head randomized controlled trials (RCT) of tamoxifen, raloxifene, and aromatase inhibitors for primary prevention of breast cancer that enrolled women without preexisting breast cancer; and RCTs and observational studies of harms of medications. Data Extraction: One investigator abstracted data on study methods; setting; population characteristics; eligibility criteria; interventions; numbers enrolled and lost to followup; method of outcome ascertainment; and results for each outcome and a second investigator checked abstractions for accuracy. Two investigators independently assessed study quality using methods developed by the USPSTF.

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Screening for Hepatitis B Virus Infection in Pregnant Women: An Updated Systematic Review for the U.S. Preventive Services Task Force [Entered Retrospectively]


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Statistics: 2 Studies, 4 Key Questions, 1 Extraction Form,
Date Published: Oct 18, 2019 08:18PM
Description: Objective: To update the 2009 U.S. Preventive Services Task Force (USPSTF) “A” recommendation on screening for hepatitis B virus (HBV) infection in pregnancy, we systematically reviewed evidence on the benefits (Key Question [KQ] 1) and harms (KQ 2) of universal screening programs for HBV infection in pregnant women, and the benefits (KQ 3) and harms (KQ 4) of case management programs to prevent perinatal transmission. Data Sources: We conducted a literature search of MEDLINE, PubMed Publisher-Supplied Records, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, the Cumulative Index for Nursing and Allied Health Literature, Embase, and PsycInfo from January 1, 1986 to May 3, 2018. Study Selection: We screened 5,688 titles and abstracts and 499 full-text articles to identify eligible studies based on a priori inclusion and exclusion criteria. Data Analysis: Two investigators independently appraised any article that met inclusion criteria using design-specific criteria. We abstracted and narratively synthesized included study data. Results: No studies were identified for KQs 1 or 2 that addressed either the effects of screening programs on perinatal HBV transmission or the potential harms of screening. Two fair-quality observational studies that compared perinatal transmission rates over time were included for KQ 3. One study reported outcomes of case management for infants with data reported to the national Perinatal Hepatitis B Prevention Program (PHBPP), administered by the Centers for Disease Control and Prevention (CDC). In the PHBPP, 155,081 infants born to HBV-positive women were identified for case management from 1994 to 2008; perinatal transmission outcomes were available for infants born from 1999 to 2008 who received serologic testing (N=55,362). A statistically significant decline in the perinatal transmission rate was observed; perinatal transmission was reported for 1.9 percent of case-managed infants in 1999 and 0.8 percent in 2008 (p<0.001). Over the study period, the number of infants born to HBV-positive women increased in the United States, and an increasing proportion of infants born to HBV-positive women were enrolled in the PHBPP for case management (p<0.001). Serologic testing within 24 months of birth also increased across the time period (p=0.001). The second study reported outcomes of case management for infants born to HBV-positive women in a large regional health care organization in the United States. The health system case management program reported on 4,446 infants born to HBV-positive women from 1997 to 2010. Over this period, 85 percent of infants were tested for HBV, and a decreasing trend in perinatal transmission was reported (incident rate ratio, 0.90 [95% confidence interval, 0.82 to 1.00]). Overall rates of perinatal transmission were very low (25 of 3,353 of infants tested [0.75%]). More than 97 percent of case-managed infants received HBV vaccination and hepatitis B immune globulin within 12 hours of birth. No studies were identified for KQ 4 to assess potential harms of case management. Limitations: Our review was narrowly focused on evidence of the effectiveness of screening or case management on prevention of perinatal transmission in contexts where prenatal screening and universal vaccination for HBV at birth are established practice. The included observational studies’ findings on declining perinatal transmission trends could be influenced by secular changes in other public health activities (e.g., universal HBV vaccination) or by improvements within case management program implementation and interventions (e.g., antiviral medication). Changes in data collection and reporting methods used in the studies could also introduce bias. Conclusions: Perinatal transmission would be observed in more than one third of infants born to HBV-positive mothers in the absence of prophylaxis. Very low and declining rates of perinatal transmission have been documented for infants in case management programs that track and coordinate the delivery of preventive interventions. Screening for HBV infection in pregnancy is standard prenatal care practice in the United States and identifies women and infants eligible for effective case management for effective interventions to prevent perinatal transmission.
Contributor(s): Jillian T. Henderson, PhD, MPH Elizabeth M. Webber, MS Sarah I. Bean, MPH
Funding Source: This report is based on research conducted by the Kaiser Permanente Research Affiliates Evidence-based Practice Center (EPC) under contract to the Agency for Healthcare Research and Quality (AHRQ), Rockville, MD (Contract No. HHSA-290-2015-00007-I, Task Order No. 3).
Methodology Description: Data Sources: We conducted a literature search of MEDLINE, PubMed Publisher-Supplied Records, the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, the Cumulative Index for Nursing and Allied Health Literature, Embase, and PsycInfo from January 1, 1986 to May 3, 2018. Study Selection: We screened 5,688 titles and abstracts and 499 full-text articles to identify eligible studies based on a priori inclusion and exclusion criteria. Data Analysis: Two investigators independently appraised any article that met inclusion criteria using design-specific criteria. We abstracted and narratively synthesized included study data.

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Early Diagnosis, Prevention, and Treatment of C. difficile: Update [Entered Retrospectively]


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Statistics: 92 Studies, 4 Key Questions, 1 Extraction Form,
Date Published: Oct 09, 2019 11:48AM
Description: Objective. Update a 2011 review of differences in accuracy of diagnostic tests and the effects of interventions to prevent and treat C. difficile infection (CDI) in adults. Data sources. Medline, the Cochrane Clinical Trials Registry, EMBASE, from 2010 through April 2015 plus reference lists of included studies and recent systematic reviews. Methods. Two investigators screened abstracts and full texts of identified references for eligibility. Eligible studies included studies of sensitivity and specificity for diagnostic tests in patients at risk for CDI. We included randomized controlled trials or high quality cohort studies enrolling adult patients with CDI or suspected CDI for treatment interventions. Prevention studies also included adult patients at risk for CDI and observational study designs. Two investigators extracted data, assessed individual study risk of bias, and evaluated the strength of evidence for each comparison and outcome. Pooled estimates were analyzed to assess the efficacy and comparative effectiveness of a variety of treatments. Results. We identified 37 diagnostic studies and 56 studies evaluating prevention or treatment interventions to update the review. High-strength evidence showed nucleic amplification tests were sensitive and specific for CDI when using culture as the reference standard. Low-strength evidence found some institutional prevention interventions, such as antibiotic prescribing practices and transmission interruption (terminal room cleaning with hydrogen peroxide vapor and handwashing campaigns) reduces CDI incidence. Low-strength evidence also suggests prevention programs can be sustained over several years. For CDI treatment, vancomycin is more effective than metronidazole (high-strength evidence), and the effect does not vary by severity (moderate-strength evidence). Fidaxomicin remains noninferior to vancomycin for the initial cure of CDI (moderate-strength evidence), but is superior to vancomycin for prevention of recurrent CDI (now high-strength evidence). Although both FMT and probiotics were the subject of a significant number of new studies, the overall high risk of bias of many of these studies necessitated low-strength of evidence ratings. Specifically, low-strength evidence suggests that FMT may have a significant effect on reducing recurrent CDI. Similarly, low-strength evidence suggests that lactobaccilus strains and multiorganism probiotics also can reduce recurrent CDI. However, Saccharomyces boulardii was no more effective than placebo in preventing recurrent CDI. Evidence for FMT for refractory CDI was insufficient. Few studies reported adverse events; when reported, few events were noted. Conclusions. Research on diagnostic testing for and interventions to treat CDI expanded considerably in 4 years. Nucleic acid amplification tests have high sensitivity and specificity for CDI. Vancomycin is more effective than metronidazole for initial CDI, while fidaxomicin is more effective than vancomycin for the prevention of recurrent CDI. FMT and lactobacillus probiotics to restore colonic biodiversity and improve patient resistance to CDI or recurrence have low strength but relatively consistent positive evidence for efficacy.
Contributor(s): Mary Butler, Ph.D., M.B.A. Andrew Olson, M.D. Dimitri Drekonja, M.D., M.S. Aasma Shaukat, M.B.B.S., M.P.H. Natalie Schwehr, M.Ac., B.A. Nathen Shippee, Ph.D. Timothy J. Wilt, Ph.D., M.P.H.
Funding Source: AHRQ
Methodology Description: None Provided

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Physiologic Predictors of Severe Injury: Systematic Review [Entered Retrospectively]


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Statistics: 138 Studies, 3 Key Questions, 1 Extraction Form,
Date Published: Sep 20, 2019 09:42AM
Description: Objectives. To systematically identify and summarize evaluations of measures of circulatory and respiratory compromise, focusing on measures that can be used in field assessment by emergency medical services to inform decisions about the level of trauma care needed. We identified research on the ability of different measures to predict whether a patient was seriously injured and thus required transport to the highest level of trauma care available. Data sources. We searched Ovid MEDLINE®, CINAHL®, and the Cochrane databases from 1996 through August 2017. Reference lists of included articles were reviewed for additional relevant citations. Review methods. We included studies of individual measures and measures that combined circulatory, respiratory, and level of consciousness assessment. Evaluations included diagnostic accuracy (sensitivity and specificity) and area under the receiver operating characteristic curve (AUROC). We used data provided to calculate values that were not reported and pooled estimates across studies when feasible. Results. We identified and included 138 articles reporting results of 134 studies. Circulatory compromise measures evaluated in these studies included systolic blood pressure, heart rate, shock index, lactate, base deficit, and heart rate variability or complexity. The respiratory measures evaluated included respiration rate, oxygen saturation, partial pressure of carbon dioxide, and need for airway support. Many different combination measures were identified, but most were evaluated in only one or two studies. Pooled AUROCs from out-of-hospital data were 0.67 for systolic blood pressure (moderate strength of evidence); 0.67 for heart rate, 0.72 for shock index, 0.77 for lactate, 0.70 for respiratory rate, and 0.89 for Revised Trauma Score combination measure (all low strength of evidence); and were considered poor to fair. The only AUROC that reached a level considered excellent was for the Glasgow Coma Scale, age, and arterial pressure (GAP) combination measure (AUROC, 0.96; estimate based on emergency department data). All of the measures had low sensitivities and comparatively high specificities (e.g., sensitivities ranging from 13% to 74% and specificities ranging from 62% to 96% for out-of-hospital pooled estimates). Conclusions. Physiologic measures usable in triaging trauma patients have been evaluated in multiple studies; however, their predictive utilities are moderate and far from ideal. Overall, the measures have low sensitivities, high specificities, and AUROCs in the poor-to-fair range. Combination measures that include assessments of consciousness seem to perform better, but whether they are feasible and valuable for out-of-hospital use needs to be determined. Modification of triage measures for children or older adults is needed, given that the measures perform worse in these age groups; however, research has not yet conclusively identified modifications that result in better performance.
Contributor(s): Annette M. Totten, Ph.D. Tamara P. Cheney, M.D. Maya E. O'Neil, Ph.D. Craig D. Newgard, M.D., M.P.H. Mohamud Daya, M.D., M.S. Rongwei Fu, Ph.D. Ngoc Wasson, M.P.H. Erica L. Hart, M.S.T. Roger Chou, M.D.
Funding Source: Agency for Healthcare Research and Quality (AHRQ)
Methodology Description: Review methods. We included studies of individual measures and measures that combined circulatory, respiratory, and level of consciousness assessment. Evaluations included diagnostic accuracy (sensitivity and specificity) and area under the receiver operating characteristic curve (AUROC). We used data provided to calculate values that were not reported and pooled estimates across studies when feasible.

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