Karla Kerlikowske

Previous meta-analysis of outcome trials in hypertension have not specifically focused on isolated systolic hypertension or they have explained treatment benefit mainly in function of the achieved diastolic blood pressure reduction. We therefore undertook a quantitative overview of the trials to further evaluate the risks associated with systolic blood pressure in treated and untreated older patients with isolated systolic hypertensionPatients were 60 years old or more. Systolic blood pressure was 160 mm Hg or greater and diastolic blood pressure was less than 95 mm Hg. We used non-parametric methods and Cox regression to model the risks associated with blood pressure and to correct for regression dilution bias. We calculated pooled effects of treatment from stratified 2 x 2 contingency tables after application of Zelen's test of heterogeneity.In eight trials 15 693 patients with isolated systolic hypertension were followed up for 3.8 years (median). After correction for regression dilution bias, sex, age, and diastolic blood pressure, the relative hazard rates associated with a 10 mm Hg higher initial systolic blood pressure were 1.26 (p=0.0001) for total mortality, 1.22 (p=0.02) for stroke, but only 1.07 (p=0.37) for coronary events. Independent of systolic blood pressure, diastolic blood pressure was inversely correlated with total mortality, highlighting the role of pulse pressure as risk factor. Active treatment reduced total mortality by 13% (95% CI 2-22, p=0.02), cardiovascular mortality by 18%, all cardiovascular complications by 26%, stroke by 30%, and coronary events by 23%. The number of patients to treat for 5 years to prevent one major cardiovascular event was lower in men (18 vs 38), at or above age 70 (19 vs 39), and in patients with previous cardiovascular complications (16 vs 37).Drug treatment is justified in older patients with isolated systolic hypertension whose systolic blood pressure is 160 mm Hg or higher. Absolute benefit is larger in men, in patients aged 70 or more and in those with previous cardiovascular complications or wider pulse pressure. Treatment prevented stroke more effectively than coronary events. However, the absence of a relation between coronary events and systolic blood pressure in untreated patients suggests that the coronary protection may have been underestimated.

The relationships among breast density, age, and use of hormone replacement therapy (HRT) in breast cancer detection have not been fully evaluated.To determine how breast density, age, and use of HRT individually and in combination affect the accuracy of screening mammography.Prospective cohort study.7 population-based mammography registries in North Carolina; New Mexico; New Hampshire; Vermont; Colorado; Seattle, Washington; and San Francisco, California.329 495 women 40 to 89 years of age who had 463 372 screening mammograms from 1996 to 1998; 2223 women received a diagnosis of breast cancer.Breast density, age, HRT use, rate of breast cancer occurrence, and sensitivity and specificity of screening mammography.Adjusted sensitivity ranged from 62.9% in women with extremely dense breasts to 87.0% in women with almost entirely fatty breasts; adjusted sensitivity increased with age from 68.6% in women 40 to 44 years of age to 83.3% in women 80 to 89 years of age. Adjusted specificity increased from 89.1% in women with extremely dense breasts to 96.9% in women with almost entirely fatty breasts. In women who did not use HRT, adjusted specificity increased from 91.4% in women 40 to 44 years of age to 94.4% in women 80 to 89 years of age. In women who used HRT, adjusted specificity was about 91.7% for all ages.Mammographic breast density and age are important predictors of the accuracy of screening mammography. Although HRT use is not an independent predictor of accuracy, it probably affects accuracy by increasing breast density.

To determine the efficacy of screening mammography by age, number of mammographic views per screen, screening interval, and duration of follow-up.Literature review and meta-analysis. DATA IDENTIFICATION AND ANALYSIS: Literature search of English-language studies reported from January 1966 to October 31, 1993, using MEDLINE, manual literature review, and consultation with experts. A total of 13 studies were selected, and their results were combined using meta-analytic techniques based on the assumption of fixed effects.The overall summary relative risk (RR) estimate for breast cancer mortality for women aged 50 to 74 years undergoing screening mammography compared with those who did not was 0.74 (95% confidence interval [CI], 0.66 to 0.83). The magnitude of the benefit in this age group was similar regardless of number of mammographic views per screen, screening interval, or duration of follow-up. In contrast, none of the summary RR estimates for women aged 40 to 49 years was significantly less than 1.0, irrespective of screening intervention or duration of follow-up. The overall summary RR estimate in women aged 40 to 49 years was 0.93 (95% CI, 0.76 to 1.13); the summary RR estimate for those studies that used two-view mammography was 0.87 (95% CI, 0.68 to 1.12) compared with 1.02 (95% CI, 0.73 to 1.44) for those studies that used one-view mammography, and for those studies with 7 to 9 years of follow-up, the summary RR estimate was 1.02 (95% CI, 0.82 to 1.27) compared with 0.83 (95% CI, 0.65 to 1.06) for those studies with 10 to 12 years of follow-up.Screening mammography significantly reduces breast cancer mortality in women aged 50 to 74 years after 7 to 9 years of follow-up, regardless of screening interval or number of mammographic views per screen. There is no reduction in breast cancer mortality in women aged 40 to 49 years after 7 to 9 years of follow-up. Screening mammography may be effective in reducing breast cancer mortality in women aged 40 to 49 years after 10 to 12 years of follow-up, but the same benefit could probably be achieved by beginning screening at menopause or 50 years of age.

To assess the association of unopposed estrogen or estrogen plus progestin and the risk of developing endometrial cancer or dying of that disease. A literature search of English-language studies was performed using MEDLINE, a review of bibliographies, and consultations with experts. We identified 30 studies with adequate controls and risk estimates. Risk estimates were extracted by two authors and summarized using meta-analytic methods. The summary relative risk (RR) was 2.3 for estrogen users compared to nonusers (95% confidence interval [CI] 2.1–2.5), with a much higher RR associated with prolonged duration of use (RR 9.5 for 10 or more years). The summary RR of endometrial cancer remained elevated 5 or more years after discontinuation of unopposed estrogen therapy (RR 2.3). Interrupting estrogen for 5–7 days per month was not associated with lower risk than daily use. Users of unopposed conjugated estrogen had a greater increase in RR of developing endometrial cancer than users of synthetic estrogens. The risk for endometrial cancer death was elevated among unopposed estrogen users (RR 2.7, 95% CI 0.9–8.0). Among estrogen plus progestin users, cohort studies showed a decreased risk of endometrial cancer (RR 0.4), whereas case-control studies showed a small increase (RR 1.8). Endometrial cancer risk increases substantially with long duration of unopposed estrogen use, and this increased risk persists for several years after discontinuation of estrogen. Although not statistically significant, the risk of death from endometrial cancer among unopposed estrogen users is increased, similar to the increased risk of developing the disease. Data regarding risk for endometrial cancer among estrogen plus progestin users are limited and conflicting.

Postmenopausal vaginal bleeding is a common clinical problem. Endovaginal ultrasound (EVUS) is a noninvasive diagnostic test that may help determine which women should undergo endometrial biopsy.To determine the accuracy of EVUS in detecting endometrial disease in postmenopausal women with vaginal bleeding according to hormone replacement use.Literature search of English-language and non-English-language articles published from 1966 through November 1996 using MEDLINE and by a manual search of bibliographies of published articles.Studies were included if they prospectively collected EVUS measurements of endometrial thickness prior to obtaining endometrial tissue for histologic evaluation in postmenopausal women with vaginal bleeding. Of 85 studies that included data on EVUS and endometrial histology, 35 were included in the meta-analysis and included 5892 women.Articles were reviewed and independently selected and abstracted by 2 reviewers. Disagreement was resolved by consensus.The overall summary mean weighted estimates of sensitivity and specificity were calculated for thresholds of endometrial thickness from 3 to 10 mm. Using a 5-mm threshold to define abnormal endometrial thickening, 96% (95% confidence interval [CI], 94%-98%) of women with cancer had an abnormal EVUS result, whereas 92% (95% CI, 90%-93%) of women with endometrial disease (cancer, polyp, or atypical hyperplasia) had an abnormal result. This did not vary by hormone replacement use. However, the number of women with normal histology who had an abnormal EVUS result did vary by hormone replacement use. In women who were not using hormone replacement therapy, 593 (8%) with normal histological findings had an abnormal EVUS result (specificity, 92%; 95% CI, 90%-94%), whereas 1544 (23%) using hormone replacement therapy had an abnormal EVUS result (specificity, 77%; 95% CI, 75%-79%). For a postmenopausal woman with vaginal bleeding with a 10% pretest probability of endometrial cancer, her probability of cancer is 1% following a normal EVUS result.Endovaginal ultrasound has a high sensitivity for detecting endometrial cancer and other endometrial disease and can reliably identify postmenopausal women with vaginal bleeding who are highly unlikely to have significant endometrial disease so that endometrial sampling may be unnecessary.

Beneficial clinical effects of treatment with antihypertensive drugs have been shown in middle-aged patients and in those hypertensive patients over 60 years old, but whether treatment is beneficial in patients over 80 years old is not known.We collected data from all participants aged 80 years and over in randomised controlled trials of antihypertensive drugs through direct contact with study investigators. Our primary outcome was fatal and non-fatal stroke. Secondary outcomes were death from all causes, cardiovascular death, fatal and non-fatal major coronary and cardiovascular events, and heart failure.There were 57 strokes and 34 deaths among 874 actively treated patients, compared with 77 strokes and 28 stroke deaths among 796 controls, representing 1 non-fatal stroke prevented for about 100 patients treated each year. The meta-analysis of data from 1670 participants aged 80 years or older suggested that treatment prevented 34% (95% CI 8-52) of strokes. Rates of major cardiovascular events and heart failure were significantly decreased, by 22% and 39%, respectively. However, there was no treatment benefit for cardiovascular death, and a non-significant 6% (-5 to 18) relative excess of death from all causes.The inconclusive findings for mortality contrast with the benefit of treatment for non-fatal events. Results of a large-scale specific trial are needed for definite conclusion that antihypertensive treatment is beneficial in very elderly hypertensive patients. Meanwhile, an age threshold beyond which hypertension should not be treated cannot be justified.

With the large number of women having mammography-an estimated 28.4 million U.S. women aged 40 years and older in 1998-the percentage of cancers detected as ductal carcinoma in situ (DCIS), which has an uncertain prognosis, has increased. We pooled data from seven regional mammography registries to determine the percentage of mammographically detected cancers that are DCIS and the rate of DCIS per 1000 mammograms.We analyzed data on 653 833 mammograms from 540 738 women between 40 and 84 years of age who underwent screening mammography at facilities participating in the National Cancer Institute's Breast Cancer Surveillance Consortium (BCSC) throughout 1996 and 1997. Mammography results were linked to population-based cancer and pathology registries. We calculated the percentage of screen-detected breast cancers that were DCIS, the rate of screen-detected DCIS per 1000 mammograms by age and by previous mammography status, and the sensitivity of screening mammography. Statistical tests were two-sided.A total of 3266 cases of breast cancer were identified, 591 DCIS and 2675 invasive breast cancer. The percentage of screen-detected breast cancers that were DCIS decreased with age (from 28.2% [95% confidence interval (CI) = 23.9% to 32.5%] for women aged 40-49 years to 16.0% [95% CI = 13.3% to 18.7%] for women aged 70-84 years). However, the rate of screen-detected DCIS cases per 1000 mammograms increased with age (from 0.56 [95% CI = 0.41 to 0.70] for women aged 40-49 years to 1.07 [95% CI = 0.87 to 1.27] for women aged 70-84 years). Sensitivity of screening mammography in all age groups combined was higher for detecting DCIS (86.0% [95% CI = 83.2% to 88.8%]) than it was for detecting invasive breast cancer (75.1% [95% CI = 73.5% to 76.8%]).Overall, approximately 1 in every 1300 screening mammography examinations leads to a diagnosis of DCIS. Given uncertainty about the natural history of DCIS, the clinical significance of screen-detected DCIS needs further investigation.

To describe trends in incidence and treatment for ductal carcinoma in situ (DCIS) of the breast in the United States between 1973 and 1992 and to estimate total numbers of in situ cases diagnosed and numbers treated by mastectomy since 1983, when screening mammography for breast cancer began to become widespread.Analysis of population-based breast cancer incidence data collected by the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program since 1973 and treatment data collected by the SEER program since 1983.All women in the geographic areas af the United States included in the SEER program.Annual age-adjusted and age-specific incidence rates for DCIS; time trends in distribution of cases by type of treatment; percentage of cases treated by mastectomy by geographic area; and estimated numbers for the entire United States of DCIS cases, mastectomies for DCIS, and cases attributable to mammography.There was a marked increase in DCIS incidence beginning in the early 1980s. Average annual increases in rates between 1973 and 1983 and between 1983 and 1992 changed from 0.3% to 12.0% among women aged 30 to 39 years, from 0.4% to 17.4% among women aged 40 to 49, and from 5.2% to 18.1% among women aged 50 years or older. The total estimated number of DCIS cases in the United States in 1992 (23,368) was 200% higher than expected based on 1983 rates and trends between 1973 and 1983. Between 1983 and 1992, there was a marked decline in the proportion of DCIS cases treated by mastectomy (from 71% to 43.8%) and an increase in those treated by lumpectomy (from 25.6% to 53.3%). In 1992, 23.3% of cases were treated by lumpectomy and radiation, 30.2% by lumpectomy alone, and 2.6% with no surgery. Treatment patterns varied substantially by geographic area, with 57.7% of cases in New Mexico treated by mastectomy in 1992 compared with 28.8% in Connecticut. Despite the decline in the proportion of cases treated by mastectomy, the increased DCIS incidence rates resulted in an increase in the absolute number of cases treated by mastectomy until 1990 (n=10,657); in 1992, there were an estimated 10,242 DCIS cases treated by mastectomy.Incidence rates of DCIS of the breast have increased dramatically since 1983. This increase correlates with the widespread adoption of modern mammographic screening. While early detection of invasive breast cancer is beneficial, the value of DCIS detection is currently unknown. There is cause for concern about the large number of DCIS cases that are being diagnosed as a consequence of screening mammography, most of which are treated by some form of surgery. In addition, the proportion of cases treated by mastectomy may be inappropriately high, particularly in some areas of the United States.

Background & Aims: Esophageal carcinomas have high fatality rates, making chemoprevention agents desirable. We performed a systematic review with meta-analysis of observational studies evaluating the association of aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and esophageal cancer. Methods: We evaluated the MEDLINE, BIOSIS, and Web of Science electronic databases (1980–2001); manually reviewed the literature; and consulted with experts. Studies were included if they: (1) evaluated exposure to NSAIDs, aspirin, or both; (2) evaluated esophageal cancer; and (3) reported relative risks or odds ratios or provided data for their calculation. Data were independently abstracted by 2 investigators. The primary and sensitivity analyses used both fixed and random-effects models. Results: Nine studies (2 cohort, 7 case control) containing 1813 cancer cases were identified. All primary summary estimates were homogeneous. Statistical pooling showed a protective association between any use of aspirin/NSAID and esophageal cancer (odds ratio [OR] = 0.57; 95% confidence interval [CI], 0.47–0.71). Both intermittent (OR = 0.82; CI, 0.67–0.99) and frequent medication use were protective (OR = 0.54; CI, 0.43–0.67), with greater protection with more frequent use. Stratified by medication type, aspirin use was protective (OR = 0.5; CI, 0.38–0.66), and NSAIDs had a borderline protective association (OR = 0.75; CI, 0.54–1.0). Any use was protective against both esophageal adenocarcinoma (OR = 0.67; CI, 0.51–0.87) and squamous cell carcinoma (OR = 0.58; CI, 0.43–0.78). Conclusions: Pooled results support a protective association between aspirin and NSAIDs and esophageal cancer (of both histological types) and provide evidence for a dose effect. These findings support evaluating these agents in clinical trials of high-risk patients.GASTROENTEROLOGY 2003;124:47-56

After the US Food and Drug Administration (FDA) approved computer-aided detection (CAD) for mammography in 1998, and the Centers for Medicare and Medicaid Services (CMS) provided increased payment in 2002, CAD technology disseminated rapidly. Despite sparse evidence that CAD improves accuracy of mammographic interpretations and costs over $400 million a year, CAD is currently used for most screening mammograms in the United States.To measure performance of digital screening mammography with and without CAD in US community practice.We compared the accuracy of digital screening mammography interpreted with (n = 495 818) vs without (n = 129 807) CAD from 2003 through 2009 in 323 973 women. Mammograms were interpreted by 271 radiologists from 66 facilities in the Breast Cancer Surveillance Consortium. Linkage with tumor registries identified 3159 breast cancers in 323 973 women within 1 year of the screening.Mammography performance (sensitivity, specificity, and screen-detected and interval cancers per 1000 women) was modeled using logistic regression with radiologist-specific random effects to account for correlation among examinations interpreted by the same radiologist, adjusting for patient age, race/ethnicity, time since prior mammogram, examination year, and registry. Conditional logistic regression was used to compare performance among 107 radiologists who interpreted mammograms both with and without CAD.Screening performance was not improved with CAD on any metric assessed. Mammography sensitivity was 85.3% (95% CI, 83.6%-86.9%) with and 87.3% (95% CI, 84.5%-89.7%) without CAD. Specificity was 91.6% (95% CI, 91.0%-92.2%) with and 91.4% (95% CI, 90.6%-92.0%) without CAD. There was no difference in cancer detection rate (4.1 in 1000 women screened with and without CAD). Computer-aided detection did not improve intraradiologist performance. Sensitivity was significantly decreased for mammograms interpreted with vs without CAD in the subset of radiologists who interpreted both with and without CAD (odds ratio, 0.53; 95% CI, 0.29-0.97).Computer-aided detection does not improve diagnostic accuracy of mammography. These results suggest that insurers pay more for CAD with no established benefit to women.

Background: Current models for assessing breast cancer risk are complex and do not include breast density, a strong risk factor for breast cancer that is routinely reported with mammography. Objective: To develop and validate an easy-to-use breast cancer risk prediction model that includes breast density. Design: Empirical model based on Surveillance, Epidemiology, and End Results incidence, and relative hazards from a prospective cohort. Setting: Screening mammography sites participating in the Breast Cancer Surveillance Consortium. Patients: 1 095 484 women undergoing mammography who had no previous diagnosis of breast cancer. Measurements: Self-reported age, race or ethnicity, family history of breast cancer, and history of breast biopsy. Community radiologists rated breast density by using 4 Breast Imaging Reporting and Data System categories. Results: During 5.3 years of follow-up, invasive breast cancer was diagnosed in 14 766 women. The breast density model was well calibrated overall (expected–observed ratio, 1.03 [95% CI, 0.99 to 1.06]) and in racial and ethnic subgroups. It had modest discriminatory accuracy (concordance index, 0.66 [CI, 0.65 to 0.67]). Women with low-density mammograms had 5-year risks less than 1.67% unless they had a family history of breast cancer and were older than age 65 years. Limitation: The model has only modest ability to discriminate between women who will develop breast cancer and those who will not. Conclusion: A breast cancer prediction model that incorporates routinely reported measures of breast density can estimate 5-year risk for invasive breast cancer. Its accuracy needs to be further evaluated in independent populations before it can be recommended for clinical use.

Purpose To establish performance benchmarks for modern screening digital mammography and assess performance trends over time in U.S. community practice. Materials and Methods This HIPAA-compliant, institutional review board-approved study measured the performance of digital screening mammography interpreted by 359 radiologists across 95 facilities in six Breast Cancer Surveillance Consortium (BCSC) registries. The study included 1 682 504 digital screening mammograms performed between 2007 and 2013 in 792 808 women. Performance measures were calculated according to the American College of Radiology Breast Imaging Reporting and Data System, 5th edition, and were compared with published benchmarks by the BCSC, the National Mammography Database, and performance recommendations by expert opinion. Benchmarks were derived from the distribution of performance metrics across radiologists and were presented as 50th (median), 10th, 25th, 75th, and 90th percentiles, with graphic presentations using smoothed curves. Results Mean screening performance measures were as follows: abnormal interpretation rate (AIR), 11.6 (95% confidence interval [CI]: 11.5, 11.6); cancers detected per 1000 screens, or cancer detection rate (CDR), 5.1 (95% CI: 5.0, 5.2); sensitivity, 86.9% (95% CI: 86.3%, 87.6%); specificity, 88.9% (95% CI: 88.8%, 88.9%); false-negative rate per 1000 screens, 0.8 (95% CI: 0.7, 0.8); positive predictive value (PPV) 1, 4.4% (95% CI: 4.3%, 4.5%); PPV2, 25.6% (95% CI: 25.1%, 26.1%); PPV3, 28.6% (95% CI: 28.0%, 29.3%); cancers stage 0 or 1, 76.9%; minimal cancers, 57.7%; and node-negative invasive cancers, 79.4%. Recommended CDRs were achieved by 92.1% of radiologists in community practice, and 97.1% achieved recommended ranges for sensitivity. Only 59.0% of radiologists achieved recommended AIRs, and only 63.0% achieved recommended levels of specificity. Conclusion The majority of radiologists in the BCSC surpass cancer detection recommendations for screening mammography; however, AIRs continue to be higher than the recommended rate for almost half of radiologists interpreting screening mammograms. © RSNA, 2016 Online supplemental material is available for this article.

Risk prediction models for breast cancer can be improved by the addition of recently identified risk factors, including breast density and use of hormone therapy. We used prospective risk information to predict a diagnosis of breast cancer in a cohort of 1 million women undergoing screening mammography.There were 2,392,998 eligible screening mammograms from women without previously diagnosed breast cancer who had had a prior mammogram in the preceding 5 years. Within 1 year of the screening mammogram, 11,638 women were diagnosed with breast cancer. Separate logistic regression risk models were constructed for premenopausal and postmenopausal examinations by use of a stringent (P<.0001) criterion for the inclusion of risk factors. Risk models were constructed with 75% of the data and validated with the remaining 25%. Concordance of the predicted with the observed outcomes was assessed by a concordance (c) statistic after logistic regression model fit. All statistical tests were two-sided.Statistically significant risk factors for breast cancer diagnosis among premenopausal women included age, breast density, family history of breast cancer, and a prior breast procedure. For postmenopausal women, the statistically significant factors included age, breast density, race, ethnicity, family history of breast cancer, a prior breast procedure, body mass index, natural menopause, hormone therapy, and a prior false-positive mammogram. The model may identify high-risk women better than the Gail model, although predictive accuracy was only moderate. The c statistics were 0.631 (95% confidence interval [CI] = 0.618 to 0.644) for premenopausal women and 0.624 (95% CI = 0.619 to 0.630) for postmenopausal women.Breast density is a strong additional risk factor for breast cancer, although it is unknown whether reduction in breast density would reduce risk. Our risk model may be able to identify women at high risk for breast cancer for preventive interventions or more intensive surveillance.

False-positive mammography results are common. Biennial screening may decrease the cumulative probability of false-positive results across many years of repeated screening but could also delay cancer diagnosis.To compare the cumulative probability of false-positive results and the stage distribution of incident breast cancer after 10 years of annual or biennial screening mammography.Prospective cohort study.7 mammography registries in the National Cancer Institute-funded Breast Cancer Surveillance Consortium.169,456 women who underwent first screening mammography at age 40 to 59 years between 1994 and 2006 and 4492 women with incident invasive breast cancer diagnosed between 1996 and 2006.False-positive recalls and biopsy recommendations stage distribution of incident breast cancer.False-positive recall probability was 16.3% at first and 9.6% at subsequent mammography. Probability of false-positive biopsy recommendation was 2.5% at first and 1.0% at subsequent examinations. Availability of comparison mammograms halved the odds of a false-positive recall (adjusted odds ratio, 0.50 [95% CI, 0.45 to 0.56]). When screening began at age 40 years, the cumulative probability of a woman receiving at least 1 false-positive recall after 10 years was 61.3% (CI, 59.4% to 63.1%) with annual and 41.6% (CI, 40.6% to 42.5%) with biennial screening. Cumulative probability of false-positive biopsy recommendation was 7.0% (CI, 6.1% to 7.8%) with annual and 4.8% (CI, 4.4% to 5.2%) with biennial screening. Estimates were similar when screening began at age 50 years. A non-statistically significant increase in the proportion of late-stage cancers was observed with biennial compared with annual screening (absolute increases, 3.3 percentage points [CI, -1.1 to 7.8 percentage points] for women age 40 to 49 years and 2.3 percentage points [CI, -1.0 to 5.7 percentage points] for women age 50 to 59 years) among women with incident breast cancer.Few women underwent screening over the entire 10-year period. Radiologist characteristics influence recall rates and were unavailable. Most mammograms were film rather than digital. Incident cancer was analyzed in a small sample of women who developed cancer.After 10 years of annual screening, more than half of women will receive at least 1 false-positive recall, and 7% to 9% will receive a false-positive biopsy recommendation. Biennial screening appears to reduce the cumulative probability of false-positive results after 10 years but may be associated with a small absolute increase in the probability of late-stage cancer diagnosis.National Cancer Institute.

October 1997Breast Cancer Surveillance Consortium: a national mammography screening and outcomes database.Authors: R Ballard-Barbash, S H Taplin, B C Yankaskas, V L Ernster, R D Rosenberg, P A Carney, W E Barlow, … Show All … , B M Geller, K Kerlikowske, B K Edwards, C F Lynch, N Urban, C A Chrvala, C R Key, S P Poplack, J K Worden, and L G Kessler Show FewerAuthor Info & AffiliationsVolume 169, Issue 4https://doi.org/10.2214/ajr.169.4.9308451 METRICS PDF

Background: Identifying risk factors for breast cancer specific to women in their 40s could inform screening decisions. Purpose: To determine what factors increase risk for breast cancer in women aged 40 to 49 years and the magnitude of risk for each factor. Data Sources: MEDLINE (January 1996 to the second week of November 2011), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (fourth quarter of 2011), Scopus, reference lists of published studies, and the Breast Cancer Surveillance Consortium. Study Selection: English-language studies and systematic reviews of risk factors for breast cancer in women aged 40 to 49 years. Additional inclusion criteria were applied for each risk factor. Data Extraction: Data on participants, study design, analysis, follow-up, and outcomes were abstracted. Study quality was rated by using established criteria, and only studies rated as good or fair were included. Results were summarized by using meta-analysis when sufficient studies were available or from the best evidence based on study quality, size, and applicability when meta-analysis was not possible. Data from the Breast Cancer Surveillance Consortium were analyzed with proportional hazards models by using partly conditional Cox regression. Reference groups for comparisons were set at U.S. population means. Data Synthesis: Sixty-six studies provided data for estimates. Extremely dense breasts on mammography or first-degree relatives with breast cancer were associated with at least a 2-fold increase in risk for breast cancer. Prior breast biopsy, second-degree relatives with breast cancer, or heterogeneously dense breasts were associated with a 1.5- to 2.0-fold increased risk; current use of oral contraceptives, nulliparity, and age 30 years or older at first birth were associated with a 1.0- to 1.5-fold increased risk. Limitations: Studies varied by measures, reference groups, and adjustment for confounders, which could bias combined estimates. Effects of multiple risk factors were not considered. Conclusion: Extremely dense breasts and first-degree relatives with breast cancer were each associated with at least a 2-fold increase in risk for breast cancer in women aged 40 to 49 years. Identification of these risk factors may be useful for personalized mammography screening. Primary Funding Source: National Cancer Institute.

To retrospectively evaluate the range of performance outcomes of the radiologist in an audit of screening mammography by using a representative sample of U.S. radiologists to allow development of performance benchmarks for screening mammography.Institutional review board approval was obtained, and study was HIPAA compliant. Informed consent was or was not obtained according to institutional review board guidelines. Data from 188 mammographic facilities and 807 radiologists obtained between 1996 and 2002 were analyzed from six registries from the Breast Cancer Surveillance Consortium (BCSC). Contributed data included demographic information, clinical findings, mammographic interpretation, and biopsy results. Measurements calculated were positive predictive values (PPVs) from screening mammography (PPV(1)), biopsy recommendation (PPV(2)), biopsy performed (PPV(3)), recall rate, cancer detection rate, mean cancer size, and cancer stage. Radiologist performance data are presented as 50th (median), 10th, 25th, 75th, and 90th percentiles and as graphic presentations by using smoothed curves.There were 2 580 151 screening mammographic studies from 1 117 390 women (age range, <30 to >/=80 years). The respective means and ranges of performance outcomes for the middle 50% of radiologists were as follows: recall rate, 9.8% and 6.4%-13.3%; PPV(1), 4.8% and 3.4%-6.2%; and PPV(2), 24.6% and 18.8%-32.0%. Mean cancer detection rate was 4.7 per 1000, and the median [corrected] mean size of invasive cancers was 13 mm. The range of performance outcomes for the middle 80% of radiologists also was presented.Community screening mammographic performance measurements of cancer outcomes for the majority of radiologists in the BCSC surpass performance recommendations. Recall rate for almost half of radiologists, however, is higher than the recommended rate.

Studies have failed to identify characteristics of women who have been diagnosed with ductal carcinoma in situ (DCIS) and have a high or low risk of subsequent invasive cancer.We conducted a nested case-control study in a population-based cohort of 1162 women who were diagnosed with DCIS and treated by lumpectomy alone from 1983 to 1994. We collected clinical characteristics and information on subsequent tumors, defined as invasive breast cancer or DCIS diagnosed in the ipsilateral breast containing the initial DCIS lesion or at a regional or distant site greater than 6 months after initial treatment of DCIS (N = 324). We also conducted standardized pathology reviews and immunohistochemical staining for the estrogen receptor (ER), progesterone receptor, Ki67 antigen, p53, p16, epidermal growth factor receptor-2 (ERBB2, HER2/neu oncoprotein), and cyclooxygenase-2 (COX-2) on the initial paraffin-embedded DCIS tissue. Competing risk models were used to determine factors associated with risk of subsequent invasive cancer vs DCIS, and cumulative incidence survival functions were used to estimate 8-year risk.Factors associated with subsequent invasive cancer differed from those associated with subsequent DCIS. Eight-year risk of subsequent invasive cancer was statistically significantly (P = .018) higher for women with initial DCIS lesions that were detected by palpation or that were p16, COX-2, and Ki67 triple positive (p16(+)COX-2(+)Ki67(+)) (19.6%, 95% confidence interval [CI] = 18.0% to 21.3%) than for women with initial lesions that were detected by mammography and were p16, COX-2, and Ki67 triple negative (p16(-)COX-2(-)Ki67(-)) (4.1%, 95% CI = 3.4% to 5.0%). In a multivariable model, DCIS lesions that were p16(+)COX-2(+)Ki67(+) or those detected by palpation were statistically significantly associated with subsequent invasive cancer, but nuclear grade was not. Eight-year risk of subsequent DCIS was highest for women with DCIS lesions that had disease-free margins of 1 mm or greater combined with either ER(-)ERBB2(+)Ki67(+) or p16(+)COX-2(-)Ki67(+) status (23.6%, 95% CI = 18.1% to 34.0%).Biomarkers can identify which women who were initially diagnosed with DCIS are at high or low risk of subsequent invasive cancer, whereas histopathology information cannot.

Background: Reasons for persistent differences in breast cancer mortality rates among various racial and ethnic groups have been difficult to ascertain. Objective: To determine reasons for disparities in breast cancer outcomes across racial and ethnic groups. Design: Prospective cohort. Setting: The authors pooled data from 7 mammography registries that participate in the National Cancer Institute–funded Breast Cancer Surveillance Consortium. Cancer diagnoses were ascertained through linkage with pathology databases; Surveillance, Epidemiology, and End Results programs; and state tumor registries. Participants: 1 010 515 women 40 years of age and older who had at least 1 mammogram between 1996 and 2002; 17 558 of these women had diagnosed breast cancer. Measurements: Patterns of mammography and the probability of inadequate mammography screening were examined. The authors evaluated whether overall and advanced cancer rates were similar across racial and ethnic groups and whether these rates were affected by the use of mammography. Results: African-American, Hispanic, Asian, and Native American women were more likely than white women to have received inadequate mammographic screening (relative risk, 1.2 [95% CI, 1.2 to 1.2], 1.3 [CI, 1.2 to 1.3], 1.4 [CI, 1.3 to 1.4], and 1.2 [CI, 1.1 to 1.2] respectively). African-American women were more likely than white, Asian, and Native American women to have large, advanced-stage, high-grade, and lymph node–positive tumors of the breast. The observed differences in advanced cancer rates between African American and white women were attenuated or eliminated after the cohort was stratified by screening history. Among women who were previously screened at intervals of 4 to 41 months, African-American women were no more likely to have large, advanced-stage tumors or lymph node involvement than white women with the same screening history. African-American women had higher rates of high-grade tumors than white women regardless of screening history. The lower rates of advanced cancer among Asian and Native American women persisted when the cohort was stratified by mammography history. Limitations: Results are based on a cohort of women who had received mammographic evaluations. Conclusions: African-American women are less likely to receive adequate mammographic screening than white women, which may explain the higher prevalence of advanced breast tumors among African-American women. Tumor characteristics may also contribute to differences in cancer outcomes because African-American women have higher-grade tumors than white women regardless of screening. These results suggest that adherence to recommended mammography screening intervals may reduce breast cancer mortality rates.

National legislation is under consideration that would require women with mammographically dense breasts to be informed of their breast density and encouraged to discuss supplemental breast cancer screening with their health care providers. The number of US women potentially affected by this legislation is unknown.We determined the mammographic breast density distribution by age and body mass index (BMI) using data from 1518 599 mammograms conducted from 2007 through 2010 at mammography facilities in the Breast Cancer Surveillance Consortium (BCSC). We applied these breast density distributions to age- and BMI-specific counts of the US female population derived from the 2010 US Census and the National Health and Nutrition Examination Survey (NHANES) to estimate the number of US women with dense breasts.Overall, 43.3% (95% confidence interval [CI] = 43.1% to 43.4%) of women 40 to 74 years of age had heterogeneously or extremely dense breasts, and this proportion was inversely associated with age and BMI. Based on the age and BMI distribution of US women, we estimated that 27.6 million women (95% CI = 27.5 to 27.7 million) aged 40 to 74 years in the United States have heterogeneously or extremely dense breasts. Women aged 40 to 49 years (N = 12.3 million) accounted for 44.3% of this group.The prevalence of dense breasts among US women of common breast cancer screening ages exceeds 25 million. Policymakers and healthcare providers should consider this large prevalence when debating breast density notification legislation and designing strategies to ensure that women who are notified have opportunities to evaluate breast cancer risk and discuss and pursue supplemental screening options if deemed appropriate.

Current guidelines recommend mammography every 1 or 2 years starting at age 40 or 50 years, regardless of individual risk for breast cancer.To estimate the cost-effectiveness of mammography by age, breast density, history of breast biopsy, family history of breast cancer, and screening interval.Markov microsimulation model.Surveillance, Epidemiology, and End Results program, Breast Cancer Surveillance Consortium, and the medical literature.U.S. women aged 40 to 49, 50 to 59, 60 to 69, and 70 to 79 years with initial mammography at age 40 years and breast density of Breast Imaging Reporting and Data System (BI-RADS) categories 1 to 4.Lifetime.National health payer.Mammography annually, biennially, or every 3 to 4 years or no mammography.Costs per quality-adjusted life-year (QALY) gained and number of women screened over 10 years to prevent 1 death from breast cancer.Biennial mammography cost less than $100,000 per QALY gained for women aged 40 to 79 years with BI-RADS category 3 or 4 breast density or aged 50 to 69 years with category 2 density; women aged 60 to 79 years with category 1 density and either a family history of breast cancer or a previous breast biopsy; and all women aged 40 to 79 years with both a family history of breast cancer and a previous breast biopsy, regardless of breast density. Biennial mammography cost less than $50,000 per QALY gained for women aged 40 to 49 years with category 3 or 4 breast density and either a previous breast biopsy or a family history of breast cancer. Annual mammography was not cost-effective for any group, regardless of age or breast density.Mammography is expensive if the disutility of false-positive mammography results and the costs of detecting nonprogressive and nonlethal invasive cancer are considered.Results are not applicable to carriers of BRCA1 or BRCA2 mutations.Mammography screening should be personalized on the basis of a woman's age, breast density, history of breast biopsy, family history of breast cancer, and beliefs about the potential benefit and harms of screening.Eli Lilly, Da Costa Family Foundation for Research in Breast Cancer Prevention of the California Pacific Medical Center, and Breast Cancer Surveillance Consortium.

Background: Few studies have examined the comparative effectiveness of digital versus film-screen mammography in U.S. community practice. Objective: To determine whether the interpretive performance of digital and film-screen mammography differs. Design: Prospective cohort study. Setting: Mammography facilities in the Breast Cancer Surveillance Consortium. Participants: 329 261 women aged 40 to 79 years underwent 869 286 mammograms (231 034 digital; 638 252 film-screen). Measurements: Invasive cancer or ductal carcinoma in situ diagnosed within 12 months of a digital or film-screen examination and calculation of mammography sensitivity, specificity, cancer detection rates, and tumor outcomes. Results: Overall, cancer detection rates and tumor characteristics were similar for digital and film-screen mammography, but the sensitivity and specificity of each modality varied by age, tumor characteristics, breast density, and menopausal status. Compared with film-screen mammography, the sensitivity of digital mammography was significantly higher for women aged 60 to 69 years (89.9% vs. 83.0%; P = 0.014) and those with estrogen receptor–negative cancer (78.5% vs. 65.8%; P = 0.016); borderline significantly higher for women aged 40 to 49 years (82.4% vs. 75.6%; P = 0.071), those with extremely dense breasts (83.6% vs. 68.1%; P = 0.051), and pre- or perimenopausal women (87.1% vs. 81.7%; P = 0.057); and borderline significantly lower for women aged 50 to 59 years (80.5% vs. 85.1%; P = 0.097). The specificity of digital and film-screen mammography was similar by decade of age, except for women aged 40 to 49 years (88.0% vs. 89.7%; P < 0.001). Limitation: Statistical power for subgroup analyses was limited. Conclusion: Overall, cancer detection with digital or film-screen mammography is similar in U.S. women aged 50 to 79 years undergoing screening mammography. Women aged 40 to 49 years are more likely to have extremely dense breasts and estrogen receptor–negative tumors; if they are offered mammography screening, they may choose to undergo digital mammography to optimize cancer detection. Primary Funding Source: National Cancer Institute.

BackgroundIt is uncertain whether evidence supports routinely estimating a postmenopausal woman's risk of breast cancer and intervening to reduce risk.

Twenty-one states have laws requiring that women be notified if they have dense breasts and that they be advised to discuss supplemental imaging with their provider.To better direct discussions of supplemental imaging by determining which combinations of breast cancer risk and Breast Imaging Reporting and Data System (BI-RADS) breast density categories are associated with high interval cancer rates.Prospective cohort.Breast Cancer Surveillance Consortium (BCSC) breast imaging facilities.365,426 women aged 40 to 74 years who had 831,455 digital screening mammography examinations.BI-RADS breast density, BCSC 5-year breast cancer risk, and interval cancer rate (invasive cancer ≤12 months after a normal mammography result) per 1000 mammography examinations. High interval cancer rate was defined as more than 1 case per 1000 examinations.High interval cancer rates were observed for women with 5-year risk of 1.67% or greater and extremely dense breasts or 5-year risk of 2.50% or greater and heterogeneously dense breasts (24% of all women with dense breasts). The interval rate of advanced-stage disease was highest (>0.4 case per 1000 examinations) among women with 5-year risk of 2.50% or greater and heterogeneously or extremely dense breasts (21% of all women with dense breasts). Five-year risk was low to average (0% to 1.66%) for 51.0% of women with heterogeneously dense breasts and 52.5% with extremely dense breasts, with interval cancer rates of 0.58 to 0.63 and 0.72 to 0.89 case per 1000 examinations, respectively.The benefit of supplemental imaging was not assessed.Breast density should not be the sole criterion for deciding whether supplemental imaging is justified because not all women with dense breasts have high interval cancer rates. BCSC 5-year risk combined with BI-RADS breast density can identify women at high risk for interval cancer to inform patient-provider discussions about alternative screening strategies.National Cancer Institute.

Background: Controversy persists about optimal mammography screening strategies. Objective: To evaluate screening outcomes, taking into account advances in mammography and treatment of breast cancer. Design: Collaboration of 6 simulation models using national data on incidence, digital mammography performance, treatment effects, and other-cause mortality. Setting: United States. Patients: Average-risk U.S. female population and subgroups with varying risk, breast density, or comorbidity. Intervention: Eight strategies differing by age at which screening starts (40, 45, or 50 years) and screening interval (annual, biennial, and hybrid [annual for women in their 40s and biennial thereafter]). All strategies assumed 100% adherence and stopped at age 74 years. Measurements: Benefits (breast cancer–specific mortality reduction, breast cancer deaths averted, life-years, and quality-adjusted life-years); number of mammograms used; harms (false-positive results, benign biopsies, and overdiagnosis); and ratios of harms (or use) and benefits (efficiency) per 1000 screens. Results: Biennial strategies were consistently the most efficient for average-risk women. Biennial screening from age 50 to 74 years avoided a median of 7 breast cancer deaths versus no screening; annual screening from age 40 to 74 years avoided an additional 3 deaths, but yielded 1988 more false-positive results and 11 more overdiagnoses per 1000 women screened. Annual screening from age 50 to 74 years was inefficient (similar benefits, but more harms than other strategies). For groups with a 2- to 4-fold increased risk, annual screening from age 40 years had similar harms and benefits as screening average-risk women biennially from 50 to 74 years. For groups with moderate or severe comorbidity, screening could stop at age 66 to 68 years. Limitation: Other imaging technologies, polygenic risk, and nonadherence were not considered. Conclusion: Biennial screening for breast cancer is efficient for average-risk populations. Decisions about starting ages and intervals will depend on population characteristics and the decision makers' weight given to the harms and benefits of screening. Primary Funding Source: National Institutes of Health.

Women with proliferative breast lesions are candidates for primary prevention, but few risk models incorporate benign findings to assess breast cancer risk. We incorporated benign breast disease (BBD) diagnoses into the Breast Cancer Surveillance Consortium (BCSC) risk model, the only breast cancer risk assessment tool that uses breast density.We developed and validated a competing-risk model using 2000 to 2010 SEER data for breast cancer incidence and 2010 vital statistics to adjust for the competing risk of death. We used Cox proportional hazards regression to estimate the relative hazards for age, race/ethnicity, family history of breast cancer, history of breast biopsy, BBD diagnoses, and breast density in the BCSC.We included 1,135,977 women age 35 to 74 years undergoing mammography with no history of breast cancer; 17% of the women had a prior breast biopsy. During a mean follow-up of 6.9 years, 17,908 women were diagnosed with invasive breast cancer. The BCSC BBD model slightly overpredicted risk (expected-to-observed ratio, 1.04; 95% CI, 1.03 to 1.06) and had modest discriminatory accuracy (area under the receiver operator characteristic curve, 0.665). Among women with proliferative findings, adding BBD to the model increased the proportion of women with an estimated 5-year risk of 3% or higher from 9.3% to 27.8% (P<.001).The BCSC BBD model accurately estimates women's risk for breast cancer using breast density and BBD diagnoses. Greater numbers of high-risk women eligible for primary prevention after BBD diagnosis are identified using the BCSC BBD model.

Many states have laws requiring mammography facilities to tell women with dense breasts and negative results on screening mammography to discuss supplemental screening tests with their providers. The most readily available supplemental screening method is ultrasonography, but little is known about its effectiveness.To evaluate the benefits, harms, and cost-effectiveness of supplemental ultrasonography screening for women with dense breasts.Comparative modeling with 3 validated simulation models.Surveillance, Epidemiology, and End Results Program; Breast Cancer Surveillance Consortium; and medical literature.Contemporary cohort of women eligible for routine screening.Lifetime.Payer.Supplemental ultrasonography screening for women with dense breasts after a negative screening mammography result.Breast cancer deaths averted, quality-adjusted life-years (QALYs) gained, biopsies recommended after a false-positive ultrasonography result, and costs.Supplemental ultrasonography screening after a negative mammography result for women aged 50 to 74 years with heterogeneously or extremely dense breasts averted 0.36 additional breast cancer deaths (range across models, 0.14 to 0.75), gained 1.7 QALYs (range, 0.9 to 4.7), and resulted in 354 biopsy recommendations after a false-positive ultrasonography result (range, 345 to 421) per 1000 women with dense breasts compared with biennial screening by mammography alone. The cost-effectiveness ratio was $325,000 per QALY gained (range, $112,000 to $766,000). Supplemental ultrasonography screening for only women with extremely dense breasts cost $246,000 per QALY gained (range, $74,000 to $535,000).The conclusions were not sensitive to ultrasonography performance characteristics, screening frequency, or starting age.Provider costs for coordinating supplemental ultrasonography were not considered.Supplemental ultrasonography screening for women with dense breasts would substantially increase costs while producing relatively small benefits.National Cancer Institute.

We evaluated whether a 76-locus polygenic risk score (PRS) and Breast Imaging Reporting and Data System (BI-RADS) breast density were independent risk factors within three studies (1643 case patients, 2397 control patients) using logistic regression models. We incorporated the PRS odds ratio (OR) into the Breast Cancer Surveillance Consortium (BCSC) risk-prediction model while accounting for its attributable risk and compared five-year absolute risk predictions between models using area under the curve (AUC) statistics. All statistical tests were two-sided. BI-RADS density and PRS were independent risk factors across all three studies (P interaction = .23). Relative to those with scattered fibroglandular densities and average PRS (2(nd) quartile), women with extreme density and highest quartile PRS had 2.7-fold (95% confidence interval [CI] = 1.74 to 4.12) increased risk, while those with low density and PRS had reduced risk (OR = 0.30, 95% CI = 0.18 to 0.51). PRS added independent information (P < .001) to the BCSC model and improved discriminatory accuracy from AUC = 0.66 to AUC = 0.69. Although the BCSC-PRS model was well calibrated in case-control data, independent cohort data are needed to test calibration in the general population.

Controversy exists about the frequency women should undergo screening mammography and whether screening interval should vary according to risk factors beyond age.To compare the benefits and harms of screening mammography frequencies according to age, breast density, and postmenopausal hormone therapy (HT) use.Prospective cohort.Data collected January 1994 to December 2008 from mammography facilities in community practice that participate in the Breast Cancer Surveillance Consortium (BCSC) mammography registries.Data were collected prospectively on 11,474 women with breast cancer and 922,624 without breast cancer who underwent mammography at facilities that participate in the BCSC.We used logistic regression to calculate the odds of advanced stage (IIb, III, or IV) and large tumors (>20 mm in diameter) and 10-year cumulative probability of a false-positive mammography result by screening frequency, age, breast density, and HT use. The main predictor was screening mammography interval.Mammography biennially vs annually for women aged 50 to 74 years does not increase risk of tumors with advanced stage or large size regardless of women's breast density or HT use. Among women aged 40 to 49 years with extremely dense breasts, biennial mammography vs annual is associated with increased risk of advanced-stage cancer (odds ratio [OR], 1.89; 95% CI, 1.06-3.39) and large tumors (OR, 2.39; 95% CI, 1.37-4.18). Cumulative probability of a false-positive mammography result was high among women undergoing annual mammography with extremely dense breasts who were either aged 40 to 49 years (65.5%) or used estrogen plus progestogen (65.8%) and was lower among women aged 50 to 74 years who underwent biennial or triennial mammography with scattered fibroglandular densities (30.7% and 21.9%, respectively) or fatty breasts (17.4% and 12.1%, respectively).Women aged 50 to 74 years, even those with high breast density or HT use, who undergo biennial screening mammography have similar risk of advanced-stage disease and lower cumulative risk of false-positive results than those who undergo annual mammography. When deciding whether to undergo mammography, women aged 40 to 49 years who have extremely dense breasts should be informed that annual mammography may minimize their risk of advanced-stage disease but the cumulative risk of false-positive results is high.

<h3>Importance</h3> Many established breast cancer risk factors are used in clinical risk prediction models, although the proportion of breast cancers explained by these factors is unknown. <h3>Objective</h3> To determine the population-attributable risk proportion (PARP) for breast cancer associated with clinical breast cancer risk factors among premenopausal and postmenopausal women. <h3>Design, Setting, and Participants</h3> Case-control study with 1:10 matching on age, year of risk factor assessment, and Breast Cancer Surveillance Consortium (BCSC) registry. Risk factor data were collected prospectively from January 1, 1996, through October 31, 2012, from BCSC community-based breast imaging facilities. A total of 18 437 women with invasive breast cancer or ductal carcinoma in situ were enrolled as cases and matched to 184 309 women without breast cancer, with a total of 58 146 premenopausal and 144 600 postmenopausal women enrolled in the study. <h3>Exposures</h3> Breast Imaging Reporting and Data System (BI-RADS) breast density (heterogeneously or extremely dense vs scattered fibroglandular densities), first-degree family history of breast cancer, body mass index (&gt;25 vs 18.5-25), history of benign breast biopsy, and nulliparity or age at first birth (≥30 years vs &lt;30 years). <h3>Main Outcomes and Measures</h3> Population-attributable risk proportion of breast cancer. <h3>Results</h3> Of the 18 437 women with breast cancer, the mean (SD) age was 46.3 (3.7) years among premenopausal women and 61.7 (7.2) years among the postmenopausal women. Overall, 4747 (89.8%) premenopausal and 12 502 (95.1%) postmenopausal women with breast cancer had at least 1 breast cancer risk factor. The combined PARP of all risk factors was 44.3% (95% CI, 40.8%-47.8%) among premenopausal women and 43.2% (95% CI, 41.0%-45.5%) among postmenopausal women. High breast density was one of the most prevalent risk factors for both premenopausal and postmenopausal women and had the largest effect on the PARP; 28.9% (95% CI, 25.3%-32.5%) of premenopausal and 14.4% (95% CI, 12.6%-16.0%) of postmenopausal breast cancers could potentially be averted if all women with heterogeneously or extremely dense breasts shifted to scattered fibroglandular breast density. Among postmenopausal women, 16.4% (95% CI, 14.4%-18.4%) of breast cancers could potentially be averted if all overweight and obese women attained a body mass index of less than 25. <h3>Conclusions and Relevance</h3> Most women with breast cancer have at least 1 breast cancer risk factor routinely documented at the time of mammography, and more than 40% of premenopausal and postmenopausal breast cancers are explained by these factors. These easily assessed risk factors should be incorporated into risk prediction models to stratify breast cancer risk and promote risk-based screening and targeted prevention efforts.

Purpose To compare the classification of breast density with two automated methods, Volpara (version 1.5.0; Matakina Technology, Wellington, New Zealand) and Quantra (version 2.0; Hologic, Bedford, Mass), with clinical Breast Imaging Reporting and Data System (BI-RADS) density classifications and to examine associations of these measures with breast cancer risk. Materials and Methods In this study, 1911 patients with breast cancer and 4170 control subjects matched for age, race, examination date, and mammography machine were evaluated. Participants underwent mammography at Mayo Clinic or one of four sites within the San Francisco Mammography Registry between 2006 and 2012 and provided informed consent or a waiver for research, in compliance with HIPAA regulations and institutional review board approval. Digital mammograms were retrieved a mean of 2.1 years (range, 6 months to 6 years) before cancer diagnosis, with the corresponding clinical BI-RADS density classifications, and Volpara and Quantra density estimates were generated. Agreement was assessed with weighted κ statistics among control subjects. Breast cancer associations were evaluated with conditional logistic regression, adjusted for age and body mass index. Odds ratios, C statistics, and 95% confidence intervals (CIs) were estimated. Results Agreement between clinical BI-RADS density classifications and Volpara and Quantra BI-RADS estimates was moderate, with κ values of 0.57 (95% CI: 0.55, 0.59) and 0.46 (95% CI: 0.44, 0.47), respectively. Differences of up to 14% in dense tissue classification were found, with Volpara classifying 51% of women as having dense breasts, Quantra classifying 37%, and clinical BI-RADS assessment used to classify 43%. Clinical and automated measures showed similar breast cancer associations; odds ratios for extremely dense breasts versus scattered fibroglandular densities were 1.8 (95% CI: 1.5, 2.2), 1.9 (95% CI: 1.5, 2.5), and 2.3 (95% CI: 1.9, 2.8) for Volpara, Quantra, and BI-RADS classifications, respectively. Clinical BI-RADS assessment showed better discrimination of case status (C = 0.60; 95% CI: 0.58, 0.61) than did Volpara (C = 0.58; 95% CI: 0.56, 0.59) and Quantra (C = 0.56; 95% CI: 0.54, 0.58) BI-RADS classifications. Conclusion Automated and clinical assessments of breast density are similarly associated with breast cancer risk but differ up to 14% in the classification of women with dense breasts. This could have substantial effects on clinical practice patterns. (©) RSNA, 2015 Online supplemental material is available for this article.

Women screened with digital mammography may receive false-positive and false-negative results and subsequent imaging and biopsies. How these outcomes vary by age, time since the last screening, and individual risk factors is unclear.To determine factors associated with false-positive and false-negative digital mammography results, additional imaging, and biopsies among a general population of women screened for breast cancer.Analysis of registry data.Participating facilities at 5 U.S. Breast Cancer Surveillance Consortium breast imaging registries with linkages to pathology databases and tumor registries.405,191 women aged 40 to 89 years screened with digital mammography between 2003 and 2011. A total of 2963 were diagnosed with invasive cancer or ductal carcinoma in situ within 12 months of screening.Rates of false-positive and false-negative results and recommendations for additional imaging and biopsies from a single screening round; comparisons by age, time since the last screening, and risk factors.Rates of false-positive results (121.2 per 1000 women [95% CI, 105.6 to 138.7]) and recommendations for additional imaging (124.9 per 1000 women [CI, 109.3 to 142.3]) were highest among women aged 40 to 49 years and decreased with increasing age. Rates of false-negative results (1.0 to 1.5 per 1000 women) and recommendations for biopsy (15.6 to 17.5 per 1000 women) did not differ greatly by age. Results did not differ by time since the last screening. False-positive rates were higher for women with risk factors, particularly family history of breast cancer; previous benign breast biopsy result; high breast density; and, for younger women, low body mass index.Confounding by variation in patient-level characteristics and outcomes across registries and regions may have been present. Some factors, such as numbers of first- and second-degree relatives with breast cancer and diagnoses associated with previous benign biopsy results, were not examined.False-positive mammography results and additional imaging are common, particularly for younger women and those with risk factors, whereas biopsies occur less often. Rates of false-negative results are low.Agency for Healthcare Research and Quality and National Cancer Institute.

Abstract Background The coronavirus disease 2019 (COVID-19) pandemic has disrupted breast cancer control through short-term declines in screening and delays in diagnosis and treatments. We projected the impact of COVID-19 on future breast cancer mortality between 2020 and 2030. Methods Three established Cancer Intervention and Surveillance Modeling Network breast cancer models modeled reductions in mammography screening use, delays in symptomatic cancer diagnosis, and reduced use of chemotherapy for women with early-stage disease for the first 6 months of the pandemic with return to prepandemic patterns after that time. Sensitivity analyses were performed to determine the effect of key model parameters, including the duration of the pandemic impact. Results By 2030, the models project 950 (model range = 860-1297) cumulative excess breast cancer deaths related to reduced screening, 1314 (model range = 266-1325) associated with delayed diagnosis of symptomatic cases, and 151 (model range = 146-207) associated with reduced chemotherapy use in women with hormone positive, early-stage cancer. Jointly, 2487 (model range = 1713-2575) excess breast cancer deaths were estimated, representing a 0.52% (model range = 0.36%-0.56%) cumulative increase over breast cancer deaths expected by 2030 in the absence of the pandemic’s disruptions. Sensitivity analyses indicated that the breast cancer mortality impact would be approximately double if the modeled pandemic effects on screening, symptomatic diagnosis, and chemotherapy extended for 12 months. Conclusions Initial pandemic-related disruptions in breast cancer care will have a small long-term cumulative impact on breast cancer mortality. Continued efforts to ensure prompt return to screening and minimize delays in evaluation of symptomatic women can largely mitigate the effects of the initial pandemic-associated disruptions.

Abstract Background The coronavirus disease 2019 (COVID-19) pandemic led to a near-total cessation of mammography services in the United States in mid-March 2020. It is unclear if screening and diagnostic mammography volumes have recovered to prepandemic levels and whether use has varied by women’s characteristics. Methods We collected data on 461 083 screening mammograms and 112 207 diagnostic mammograms conducted during January 2019 through July 2020 at 62 radiology facilities in the Breast Cancer Surveillance Consortium. We compared monthly screening and diagnostic mammography volumes before and during the pandemic stratified by age, race and ethnicity, breast density, and family history of breast cancer. Results Screening and diagnostic mammography volumes in April 2020 were 1.1% (95% confidence interval [CI] = 0.5% to 2.4%) and 21.4% (95% CI = 18.7% to 24.4%) of the April 2019 prepandemic volumes, respectively, but by July 2020 had rebounded to 89.7% (95% CI = 79.6% to 101.1%) and 101.6% (95% CI = 93.8% to 110.1%) of the July 2019 prepandemic volumes, respectively. The year-to-date cumulative volume of screening and diagnostic mammograms performed through July 2020 was 66.2% (95% CI = 60.3% to 72.6%) and 79.9% (95% CI = 75.4% to 84.6%), respectively, of year-to-date volume through July 2019. Screening mammography rebound was similar across age groups and by family history of breast cancer. Monthly screening mammography volume in July 2020 for Black, White, Hispanic, and Asian women reached 96.7% (95% CI = 88.1% to 106.1%), 92.9% (95% CI = 82.9% to 104.0%), 72.7% (95% CI = 56.5% to 93.6%), and 51.3% (95% CI = 39.7% to 66.2%) of the July 2019 prepandemic volume, respectively. Conclusions Despite a strong overall rebound in mammography volume by July 2020, the rebound lagged among Asian and Hispanic women, and a substantial cumulative deficit in missed mammograms accumulated, which may have important health consequences.

To determine the positive predictive value (PPV) of low-cost screening mammography according to age and family history of breast cancer.Cross-sectional.Six counties in northern California.A total of 31,814 women aged 30 years and older referred for mammography to the University of California, San Francisco, Mobile Mammography Screening Program from April 18, 1985, through November 20, 1992.Breast cancer risk profile, two standard mammographic views per breast, and follow-up of abnormal screening examinations.Although women aged 50 years or older constituted only 38.3% of all women who received first-screening mammography, 74% of breast cancers were detected in this group. Ten cancers were diagnosed per 1000 first-screening examinations in women aged 50 years or older, with 14.8 diagnostic procedures per cancer diagnosed compared with two cancers per 1000 screening examinations and 48.3 diagnostic tests per cancer diagnosed in women younger than 50 years. The PPV of first-screening mammography (number of breast cancers detected per abnormal examination) increased with age: .03 for those aged 30 to 39 years; .04 for those aged 40 to 49; .09 for those aged 50 to 59; .17 for those aged 60 to 69; and .19 for those aged 70 years or older (chi 2 for trend, P < .001). Women aged 50 to 59 years had a higher PPV for first-screening mammography than women aged 40 to 49 years (.09 vs. .04; P = .004), and women with a family history of breast cancer had higher PPVs compared with women without history (40 to 49 years of age, .13 vs .04, P = .01; and 50 to 59 years of age, .22 vs .09, P = .01).Five times as many cancers per 1000 first-screening mammographic examinations were diagnosed in women aged 50 years or older compared with women aged less than 50 years. The highest PPVs for mammography were in women aged 50 years or older and in women aged 40 years or older with a family history of breast cancer. Efforts to promote screening mammography should focus on women in these groups, in whom the majority of breast cancers occur and for whom mammography has the highest PPVs.

Background: The recent publication of clinical trial results has led to a dramatic shift in the evidence about postmenopausal hormone therapy. Objective: To examine whether the publication of clinical trial results, specifically the Heart and Estrogen/progestin Replacement Study (HERS) in 1998 and the Women's Health Initiative (WHI) in 2002, has influenced the use of hormone therapy among postmenopausal women. Design: Observational cohort (1997 to 2003). Setting: San Francisco Mammography Registry, San Francisco, California. Participants: Postmenopausal women between the ages of 50 and 74 years without a personal history of breast cancer who underwent mammography (151862 mammograms). Measurements: Self-reported current use of hormone therapy. Results: Among menopausal women who had mammography, it was estimated that 41% were currently using hormone therapy in 1997. Before the publication of HERS, the use of hormone therapy was increasing at a rate of 1% (95% CI, 0% to 2%) per quarter. After the publication of HERS, use decreased by 1% (CI, −3% to 0%) per quarter. In contrast, the publication of the WHI in 2002 was associated with a more substantial decline in the use of hormone therapy of 18% (CI, −21% to −16%) per quarter. Similar associations were observed for most subgroups of women, including women older than 65 years of age; women with a previous hysterectomy; and women who described their race or ethnicity as white, African American, Latina, Chinese, or Filipina. Conclusions: The release of the HERS data was temporally associated with a modest decline in the use of hormone therapy. In contrast, the release of the principal findings from the WHI was associated with a more substantial decline in use by postmenopausal women. The reason for the differences in decline may relate to the fact that the WHI results were widely publicized or were more applicable to most postmenopausal women because the WHI study was performed in healthy women.

Screening mammography differs between the United States and the United Kingdom; a direct comparison may suggest methods to improve the practice.To compare screening mammography performance between the United States and the United Kingdom among similar-aged women.Women aged 50 years or older were identified who underwent 5.5 million mammograms from January 1, 1996, to December 31, 1999, within 3 large-scale mammography registries or screening programs: the Breast Cancer Surveillance Consortium (BCSC, n = 978 591) and National Breast and Cervical Cancer Early Detection Program (NBCCEDP, n = 613 388) in the United States; and the National Health Service Breast Screening Program (NHSBSP, n = 3.94 million) in the United Kingdom. A total of 27 612 women were diagnosed with breast cancer (invasive or ductal carcinoma in situ) within 12 months of screening among the 3 groups.Recall rates (recommendation for further evaluation including diagnostic imaging, ultrasound, clinical examination, or biopsy) and cancer detection rates were calculated for first and subsequent mammograms, and within 5-year age groups.Recall rates were approximately twice as high in the United States than in the United Kingdom for all age groups; however, cancer rates were similar. Among women aged 50 to 54 years who underwent a first screening mammogram, 14.4% in the BCSC and 12.5% in the NBCCEDP were recalled for further evaluation vs only 7.6% in the NHSBSP. Cancer detection rates per 1000 mammogram screens were 5.8, 5.9, and 6.3, in the BCSC, NBCCEDP, and NHSBSP, respectively. Recall rates were lower for subsequent examinations in all 3 settings but remained twice as high in the United States. A similar percentage of women underwent biopsy in each setting, but rates of percutaneous biopsy were lower and open surgical biopsy higher in the United States. Open surgical biopsies not resulting in a diagnosis of cancer (negative biopsies) were twice as high in the United States than in the United Kingdom. Based on a 10-year period of screening 1000 women aged 50 to 59 years, 477, 433, and 175 women in the BCSC, NBCCEDP, and NHSBSP, respectively, would be recalled; and for women aged 60 to 69 years, 396, 334, and 133 women, respectively. The estimated cancer detection rates per 1000 women aged 50 to 59 years were 24.5, 23.8, and 19.4, respectively, and for women aged 60 to 69 years, 31.5, 26.6, and 27.9, respectively.Recall and negative open surgical biopsy rates are twice as high in US settings than in the United Kingdom but cancer detection rates are similar. Efforts to improve US mammographic screening should target lowering the recall rate without reducing the cancer detection rate.

Several studies, which were limited by their small sample size and selection of difficult cases for review, have reported substantial variability among radiologists in interpretation of mammographic examinations. We have determined, in the largest study to date, intraobserver and interobserver agreement in interpreting screening mammography and accuracy of mammography by use of the American College of Radiology Breast Imaging Reporting and Data System (BI-RADS).The mammographic examinations were randomly selected on the basis of original mammographic interpretation and cancer outcome from 71,713 screening examinations performed by the Mobile Mammography Screening Program of the University of California, San Francisco, during the period from April 1985 through February 1995. The final sample included 786 abnormal examinations with no cancer detected, 267 abnormal examinations with cancer detected, and 1563 normal examinations. Films were read separately by two radiologists according to BI-RADS. Cancer status was determined by contacting women's physicians and by linkage to the regional Surveillance, Epidemiology, and End Results Program.There was moderate agreement between radiologists in reporting the presence of a finding when cancer was present (kappa = 0.54) and substantial agreement when cancer was not present (kappa = 0.62). Agreement was moderate in assigning one of the five assessment categories but was statistically significantly lower when cancer was present relative to when cancer was not present (kappa = 0.46 versus 0.56; two-sided P = .02). Agreement for reporting the presence of a finding and mammographic assessment was two-fold more likely for examinations with less dense breasts. Agreement was higher on repeat readings by the same radiologists than between radiologists. The sensitivity of mammography was lower with BI-RADS than with the original system for mammographic interpretation, but the positive predictive value of mammography was higher.Considerable variability in interpretation of mammographic examinations exists; this variability and the accuracy of mammography are neither improved nor diminished with use of BI-RADS.

Over 14% of breast cancers diagnosed in the United States annually are ductal carcinomas in situ (DCIS). There are no published population-based reports of the likelihood of breast cancer death among US women with DCIS.We used data from the Surveillance, Epidemiology and End Results program to determine the likelihood of breast cancer death at 5 and 10 years among US women aged 40 and older diagnosed with DCIS from 1978 to 1983 (before screening mammography was common; n = 1525) and from 1984 to 1989 (when screening mammography became common; n = 5547). We also calculated standardized mortality ratios (SMRs) to compare observed deaths from breast cancer, cardiovascular disease, and all causes combined among women with DCIS with deaths expected based on general population mortality rates.Among women diagnosed with DCIS from 1978 to 1983, 1.5% died of breast cancer within 5 years and 3.4% within 10 years. Among women diagnosed from 1984 to 1989, 0.7% died of breast cancer within 5 years and 1.9% within 10 years. Relative to the general population, risk of breast cancer death was greater for women diagnosed from 1978 to 1983 (SMR, 3.4; 95% confidence interval [CI], 2.5-4.5) than for women diagnosed from 1984 to 1989 (10-year SMR, 1.9; 95% CI, 1.5-2.3). Women diagnosed from 1984 to 1989 were significantly less likely than women in the general population to have died of cardiovascular diseases (10-year SMR, 0.6; 95% CI, 0.5-0.7) or of all causes combined (SMR, 0.8; 95% CI, 0.7-0.8).Among women diagnosed with DCIS, risk of death from breast cancer was low, at least within the 10 years following diagnosis. This may reflect the effectiveness of treatment for DCIS, the "benign" nature of DCIS, or both. At 10 years, women diagnosed from 1984 to 1989 were less likely than women diagnosed from 1978 to 1983 to have died of breast cancer, and their risk of dying of all causes combined was lower than that in the general population.

Screening mammography is recommended for women 50 to 69 years of age because of its proven efficacy and reasonable cost-effectiveness. Extending screening recommendations to include women 40 to 49 years of age remains controversial.To compare the cost-effectiveness of screening mammography in women of different age groups.Cost-effectiveness analysis done using Markov and Monte Carlo models.General population of women 40 years of age and older.Biennial screening from 50 to 69 years of age was compared with no screening. Screening done every 18 months from ages 40 to 49 years, followed by biennial screening from ages 50 to 69 years, was compared with biennial screening from ages 50 to 69 years.Life-expectancy, costs, and incremental cost-effectiveness.Screening women from 50 to 69 years of age improved life expectancy by 12 days at a cost of $704 per woman, resulting in a cost-effectiveness ratio of $21,400 per year of life saved. Extending screening to include women 40 to 49 years of age improved life expectancy by 2.5 days at a cost of $676 per woman. The incremental cost-effectiveness of screening women 40 to 49 years of age was $105,000 per year of life saved. On the basis of a multiway sensitivity analysis, there is a 75% chance that screening mammography in women 50 to 69 years of age costs less than $50,000 per year of life saved, compared with a 7% chance in women 40 to 49 years of age.The cost-effectiveness of screening mammography in women 40 to 49 years of age is almost five times that in older women. When breast cancer screening policies are being set, the incremental cost-effectiveness of extending mammographic screening to younger women should be considered.

To identify radiologists' characteristics associated with interpretive performance in screening mammography.The study was approved by institutional review boards of University of Washington (Seattle, Wash) and institutions at seven Breast Cancer Surveillance Consortium sites, informed consent was obtained, and procedures were HIPAA compliant. Radiologists who interpreted mammograms in seven U.S. regions completed a self-administered mailed survey; information on demographics, practice type, and experience in and perceptions of general radiology and breast imaging was collected. Survey data were linked to data on screening mammograms the radiologists interpreted between January 1, 1998, and December 31, 2005, and included patient risk factors, Breast Imaging Reporting and Data System assessment, and follow-up breast cancer data. The survey was returned by 71% (257 of 364) of radiologists; in 56% (205 of 364) of the eligible radiologists, complete data on screening mammograms during the study period were provided; these data were used in the final analysis. An evaluation of whether the radiologists' characteristics were associated with recall rate, false-positive rate, sensitivity, or positive predictive value of recall (PPV(1)) of the screening examinations was performed with logistic regression models that were adjusted for patients' characteristics and radiologist-specific random effects.Study radiologists interpreted 1 036 155 screening mammograms; 4961 breast cancers were detected. Median percentages and interquartile ranges, respectively, were as follows: recall rate, 9.3% and 6.3%-13.2%; false-positive rate, 8.9% and 5.9%-12.8%; sensitivity, 83.8% and 74.5%-92.3%; and PPV(1), 4.0% and 2.6%-5.9%. Wide variability in sensitivity was noted, even among radiologists with similar false-positive rates. In adjusted regression models, female radiologists or fellowship-trained radiologists had significantly higher recall and false-positive rates (P < .05, all). Fellowship training in breast imaging was the only characteristic significantly associated with improved sensitivity (odds ratio, 2.32; 95% confidence interval: 1.42, 3.80; P < .001) and the overall accuracy parameter (odds ratio, 1.61; 95% confidence interval: 1.05, 2.45; P = .028).Fellowship training in breast imaging may lead to improved cancer detection, but it is associated with higher false-positive rates.

Although it is recommended that women with a family history of breast cancer begin screening mammography at a younger age than average-risk women, few studies have evaluated the performance of mammography in this group.To compare the performance of screening mammography in women with a first-degree family history of breast cancer and women of similar age without such history.Cross-sectional.Mammography registries in California (n = 1), New Hampshire (n = 1), New Mexico (n = 1), Vermont (n = 1), Washington State n = 2), and Colorado (n = 1).389 533 women 30 to 69 years of age who were referred for screening mammography from April 1985 to November 1997.Risk factors for breast cancer; results of first screening examination captured for a woman by a registry; and any invasive cancer or ductal carcinoma in situ identified by linkage to a pathology database, the Surveillance, Epidemiology, and End Results program, or a state tumor registry.The number of cancer cases per 1000 examinations increased with age and was higher in women with a family history of breast cancer than in those without (3.2 vs. 1.6 for ages 30 to 39 years, 4.7 vs. 2.7 for ages 40 to 49 years, 6.6 vs. 4.6 for ages 50 to 59 years, and 9.3 vs. 6.9 for ages 60 to 69 years). The sensitivity of mammography increased significantly with age (P = 0.001 [chi-square test for trend]) in women with a family history and in those without (63.2% [95% CI, 41. 5% to 84.8%] vs. 69.5% [CI, 57.7% to 81.2%] for ages 30 to 39 years, 70.2% [CI, 61.0% to 79.5%] vs. 77.5% [CI, 73.3% to 81.8%] for ages 40 to 49 years, 81.3% [CI, 73.3% to 89.3%] vs. 80.2% [CI, 76.5% to 83.9%] for ages 50 to 59 years, and 83.8% [CI, 76.8% to 90.9%] vs. 87.7% [CI, 84.8% to 90.7%] for ages 60 to 69 years). Sensitivity was similar for each decade of age regardless of family history. The positive predictive value of mammography was higher in women with a family history than in those without (3.7% vs. 2.9%; P = 0.001).Cancer detection rates in women who had a first-degree relative with a history of breast cancer were similar to those in women a decade older without such a history. The sensitivity of screening mammography was influenced primarily by age.

Drug treatment of high blood pressure has been shown to reduce the associated cardiovascular risk. Stroke represents the type of event more strongly linked with high blood pressure, responsible for a high rate of death or invalidity, and with the highest proportion of events that can be avoided by treatment. Hypertensive patients with a history of cerebrovascular accident are at particularly high risk of recurrence. Specific trials of blood pressure lowering drugs in stroke survivors showed inconclusive results in the past.We performed a meta-analysis using all available randomized controlled clinical trials assessing the effect of blood pressure lowering drugs on clinical outcomes (recurrence of stroke, coronary events, cause-specific, and overall mortality) in patients with prior stroke or transient ischemic attack.We identified 9 trials, including a total of 6752 patients: 2 trials included 551 hypertensive stroke survivors; 6 trials of hypertensive patients included a small proportion of stroke survivors (536 patients); 1 trial included stroke survivors, whether hypertensive or not (5665 patients). The recurrence of stroke, fatal and nonfatal, was significantly reduced in active groups compared with control groups consistently across the different sources of data (relative risk of 0.72, 95% confidence interval: 0.61 to 0.85). There was no evidence that this intervention induced serious adverse effect.Blood pressure lowering drug interventions reduced the risk of stroke recurrence in stroke survivors. Available data did not allow to verify whether such benefit depends on initial blood pressure level. More data are needed before considering antihypertensive therapy in normotensive patients at high cerebrovascular risk.

Studies of octreotide have not demonstrated a consistent benefit in efficacy or safety compared with conventional therapies. This study statistically pooled existing trials to evaluate the safety and efficacy of octreotide for esophageal variceal hemorrhage.We identified randomized trials of octreotide for variceal hemorrhage from computerized databases, scientific meeting abstracts, and the manufacturer of octreotide. Blinded reviewers abstracted the data, and a meta-analysis was performed.Octreotide improved control of esophageal variceal hemorrhage compared with all alternative therapies combined (relative risk [RR], 0.63; 95% confidence interval [CI], 0.51-0.77); vasopressin/terlipressin (RR, 0.58; 95% CI, 0.42-0.81); or no additional intervention/placebo (among patients that received initial sclerotherapy/banding before randomization) (RR, 0.46; 95% CI, 0.32-0.67). Octreotide had comparable efficacy to immediate sclerotherapy for control of bleeding (RR, 0.94; 95% CI, 0.55-1.62), fewer major complications than vasopressin/terlipessin (RR, 0.31; 95% CI, 0.11-0.87), and a complication profile comparable to no intervention/placebo (RR, 1.06; 95% CI, 0.72-1.55). No specific alternative therapy demonstrated a mortality benefit.These results favor octreotide over vasopressin/terlipressin in the control of esophageal variceal bleeding and suggest it is a safe and effective adjunctive therapy after variceal obliteration techniques. Trials are needed to determine the optimal dose, route, and duration of octreotide treatment.

Approximately 15%-30% of women diagnosed with ductal carcinoma in situ (DCIS) develop a subsequent tumor event within 10 years after surgical lumpectomy. To date, little is known about the molecular pathways that confer this differential risk for developing subsequent disease. In this study, we demonstrate that expression of biomarkers indicative of an abrogated response to cellular stress predicts DCIS with worse outcome and is a defining characteristic of basal-like invasive tumors. Mechanistic studies identify the Rb pathway as a key regulator of this response. Conversely, biomarkers indicative of an intact response to cellular stress are strongly associated with a disease-free prognosis. Assessment of these biomarkers in DCIS begins to allow prediction of tumor formation years before it actually occurs.

Ductal carcinoma in situ (DCIS) is a relatively common diagnosis among women undergoing screening mammography. The greatest increases in DCIS incidence have been in non-comedo subtypes of DCIS that are not associated with subsequent invasive cancer. After a 500% increase in DCIS from 1983 to 2003, the incidence of DCIS declined in women aged 50 years and older, whereas the incidence in women younger than age 50 continues to increase. Having undergone mammography is one of the strongest and most prevalent risk factors associated with a diagnosis of DCIS. Other risk factors for DCIS are similar to that for invasive cancer including increasing age, family history of breast cancer, high mammographic breast density, and postmenopausal hormone therapy use. Treatment for DCIS is relatively aggressive with the use of both surgery and radiation therapy and most recently adjuvant hormonal therapy. Breast cancer mortality is low and similar with all types of treatment. New information regarding incidence of DCIS and subtypes of DCIS according to frequency of mammography and risk factors could lead to insights into the biology of DCIS.

Purpose We determined whether the association between breast density and breast cancer risk and cancer severity differs according to menopausal status and postmenopausal hormone therapy (HT) use. Methods We collected data on 587,369 women who underwent 1,349,027 screening mammography examinations; 14,090 women were diagnosed with breast cancer. We calculated 5-year breast cancer risk from a survival model for subgroups of women classified by their Breast Imaging Reporting and Data System (BIRADS) breast density, age, menopausal status, and current HT use, assuming a body mass index of 25 kg/m 2 . Odds of advanced (ie, IIb, III, IV) versus early (ie, I, IIa) stage invasive cancer was calculated according to BIRADS density. Results Breast cancer risk was low among women with low density (BIRADS-1): women age 55 to 59 years, 5-year risk was 0.8% (95% CI, 0.6 to 0.9%) for non-HT users and 0.9% (95% CI, 0.7% to 1.1%) for estrogen and estrogen plus progestin users. Breast cancer risk was high among women with very high density (BIRADS-4), particularly estrogen plus progestin users: women age 55 to 59 years, 5-year risk was 2.4% (95% CI, 2.0% to 2.8%) for non-HT users, 3.0% (95% CI, 2.6% to 3.5%) for estrogen users, and 4.2% (95% CI, 3.7% to 4.6%) for estrogen plus progestin users. Advanced-stage breast cancer risk was increased 1.7-fold for postmenopausal HT users who had very high density (BIRADS-4) compared to those with average density (BIRADS-2). Conclusion Postmenopausal women with high breast density are at increased risk of breast cancer and should be aware of the added risk of taking HT, especially estrogen plus progestin.

OBJECTIVES. This study examined the association of smoking status and pack-years of smoking with facial wrinkling in men and women. METHODS. We conducted a cross-sectional study of 299 never smokers, 551 former smokers and 286 current smokers, aged 30 through 69 years, drawn from a health maintenance organization. Smoking status, pack-years of smoking, and potential confounding variables were assessed by questionnaire. Facial wrinkle category, a dichotomous variable, and facial wrinkle score, a computed continuous variable, were assessed by blinded standardized visual assessment. Wrinkling was so uncommon among 30- through 39-year-old subjects that analyses were restricted to subjects aged 40 and over (227 never smokers, 456 former smokers, and 228 current smokers). RESULTS. With age, average sun exposure, and body mass index controlled, the estimated relative risk of moderate/severe wrinkling for current smokers compared to never smokers was 2.3 (95% confidence interval [CI] = 1.2, 4.2) among men and 3.1 (95% CI = 1.6, 5.9) among women. Pack-years was positively associated with facial wrinkle score in women aged 40 through 69 years and in men aged 40 through 59 years. In both groups, the increased risk of wrinkling was equivalent to about 1.4 years of aging. CONCLUSIONS. Our results support earlier findings that risk of facial wrinkling is greater in cigarette smokers than in never smokers.

Mammography is recommended and is cost-effective for women aged 50 to 69 years, but the value of continuing screening mammography after age 69 years is not known. In particular, older women with low bone mineral density (BMD) have a lower risk of breast cancer and may benefit less from continued screening.To compare life expectancy and cost-effectiveness of screening mammography in elderly women based on 3 screening strategies.Decision analysis and cost-effectiveness analysis using a Markov model.General population of women aged 65 years or older.The analysis compared 3 strategies: (1) Undergoing biennial mammography from age 65 to 69 years; (2) undergoing biennial mammography from age 65 to 69 years, measurement of distal radial BMD at age 65 years, discontinuing screening at age 69 years in women in the lowest BMD quartile for age, and continuing biennial mammography to age 79 years in those in the top 3 quartiles of distal radius BMD; and (3) undergoing biennial mammography from age 65 to 79 years.Deaths due to breast cancer averted, life expectancy, and incremental cost-effectiveness ratios.Compared with discontinuing mammography screening at age 69 years, measuring BMD at age 65 years in 10000 women and continuing mammography to age 79 years only in women with BMD in the top 3 quartiles would prevent 9.4 deaths and add, on average, 2.1 days to life expectancy at an incremental cost of $66773 per year of life saved. Continuing mammography to age 79 years in all 10000 elderly women would prevent 1.4 additional breast cancer deaths and add only 7.2 hours to life expectancy at an incremental cost of $117689 per year of life saved compared with only continuing mammography to age 79 years in women with BMD in the top 3 quartiles.This analysis suggests that continuing mammography screening after age 69 years results in a small gain in life expectancy and is moderately cost-effective in those with high BMD and more costly in those with low BMD. Women's preferences for a small gain in life expectancy and the potential harms of screening mammography should play an important role when elderly women are deciding about screening.

Although high mammographic density is considered one of the strongest risk factors for invasive breast cancer, the genes involved in modulating this clinical feature are unknown. Tissues of high mammographic density share key histologic features with stromal components within malignant lesions of tumor tissues, specifically low adipocyte and high extracellular matrix (ECM) content. We show that CD36, a transmembrane receptor that coordinately modulates multiple protumorigenic phenotypes, including adipocyte differentiation, angiogenesis, cell-ECM interactions, and immune signaling, is greatly repressed in multiple cell types of disease-free stroma associated with high mammographic density and tumor stroma. Using both in vitro and in vivo assays, we show that CD36 repression is necessary and sufficient to recapitulate the above-mentioned phenotypes observed in high mammographic density and tumor tissues. Consistent with a functional role for this coordinated program in tumorigenesis, we observe that clinical outcomes are strongly associated with CD36 expression.CD36 simultaneously controls adipocyte content and matrix accumulation and is coordinately repressed in multiple cell types within tumor and high mammographic density stroma, suggesting that activation of this stromal program is an early event in tumorigenesis. Levels of CD36 and extent of mammographic density are both modifiable factors that provide potential for intervention.

Understanding whether mammographic density (MD) is associated with all breast tumor subtypes and whether the strength of association varies by age is important for utilizing MD in risk models.Data were pooled from six studies including 3414 women with breast cancer and 7199 without who underwent screening mammography. Percent MD was assessed from digitized film-screen mammograms using a computer-assisted threshold technique. We used polytomous logistic regression to calculate breast cancer odds according to tumor type, histopathological characteristics, and receptor (estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor (HER2)) status by age (<55, 55-64, and ≥ 65 years).MD was positively associated with risk of invasive tumors across all ages, with a two-fold increased risk for high (>51%) versus average density (11-25%). Women ages <55 years with high MD had stronger increased risk of ductal carcinoma in situ (DCIS) compared to women ages 55-64 and ≥ 65 years (P(age-interaction) = 0.02). Among all ages, MD had a stronger association with large (>2.1 cm) versus small tumors and positive versus negative lymph node status (P's < 0.01). For women ages <55 years, there was a stronger association of MD with ER-negative breast cancer than ER-positive tumors compared to women ages 55-64 and ≥ 65 years (P(age-interaction) = 0.04). MD was positively associated with both HER2-negative and HER2-positive tumors within each age group.MD is strongly associated with all breast cancer subtypes, but particularly tumors of large size and positive lymph nodes across all ages, and ER-negative status among women ages <55 years, suggesting high MD may play an important role in tumor aggressiveness, especially in younger women.

Abstract Background: Assessing the volume of mammographic density might more accurately reflect the amount of breast volume at risk of malignant transformation and provide a stronger indication of risk of breast cancer than methods based on qualitative scores or dense breast area. Methods: We prospectively collected mammograms for women undergoing screening mammography. We determined the diagnosis of subsequent invasive or ductal carcinoma in situ for 275 cases, selected 825 controls matched for age, ethnicity, and mammography system, and assessed three measures of breast density: percent dense area, fibroglandular volume, and percent fibroglandular volume. Results: After adjustment for familial breast cancer history, body mass index, history of breast biopsy, and age at first live birth, the ORs for breast cancer risk in the highest versus lowest measurement quintiles were 2.5 (95% CI: 1.5–4.3) for percent dense area, 2.9 (95% CI: 1.7–4.9) for fibroglandular volume, and 4.1 (95% CI: 2.3–7.2) for percent fibroglandular volume. Net reclassification indexes for density measures plus risk factors versus risk factors alone were 9.6% (P = 0.07) for percent dense area, 21.1% (P = 0.0001) for fibroglandular volume, and 14.8% (P = 0.004) for percent fibroglandular volume. Fibroglandular volume improved the categorical risk classification of 1 in 5 women for both women with and without breast cancer. Conclusion: Volumetric measures of breast density are more accurate predictors of breast cancer risk than risk factors alone and than percent dense area. Impact: Risk models including dense fibroglandular volume may more accurately predict breast cancer risk than current risk models. Cancer Epidemiol Biomarkers Prev; 20(7); 1473–82. ©2011 AACR.

Women with elevated mammographic density have an increased risk of developing breast cancer. However, among women diagnosed with breast cancer, it is unclear whether higher density portends reduced survival, independent of other factors.We evaluated relationships between mammographic density and risk of death from breast cancer and all causes within the US Breast Cancer Surveillance Consortium. We studied 9232 women diagnosed with primary invasive breast carcinoma during 1996-2005, with a mean follow-up of 6.6 years. Mammographic density was assessed using the Breast Imaging Reporting and Data System (BI-RADS) density classification. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated by Cox proportional hazards regression; women with scattered fibroglandular densities (BI-RADS 2) were the referent group. All statistical tests were two-sided.A total of 1795 women died, of whom 889 died of breast cancer. In multivariable analyses (adjusted for site, age at and year of diagnosis, American Joint Committee on Cancer stage, body mass index, mode of detection, treatment, and income), high density (BI-RADS 4) was not related to risk of death from breast cancer (HR = 0.92, 95% CI = 0.71 to 1.19) or death from all causes (HR = 0.83, 95% CI = 0.68 to 1.02). Analyses stratified by stage and other prognostic factors yielded similar results, except for an increased risk of breast cancer death among women with low density (BI-RADS 1) who were either obese (HR = 2.02, 95% CI = 1.37 to 2.97) or had tumors of at least 2.0 cm (HR = 1.55, 95% CI = 1.14 to 2.09).High mammographic breast density was not associated with risk of death from breast cancer or death from any cause after accounting for other patient and tumor characteristics. Thus, risk factors for the development of breast cancer may not necessarily be the same as factors influencing the risk of death after breast cancer has developed.

Breast magnetic resonance imaging (MRI) is increasingly used for breast cancer screening, diagnostic evaluation, and surveillance. However, we lack data on national patterns of breast MRI use in community practice.To describe patterns of breast MRI use in US community practice during the period 2005 through 2009.Observational cohort study using data collected from 2005 through 2009 on breast MRI and mammography from 5 national Breast Cancer Surveillance Consortium registries. Data included 8931 breast MRI examinations and 1,288,924 screening mammograms from women aged 18 to 79 years.We calculated the rate of breast MRI examinations per 1000 women with breast imaging within the same year and described the clinical indications for the breast MRI examinations by year and age. We compared women screened with breast MRI to women screened with mammography alone for patient characteristics and lifetime breast cancer risk.The overall rate of breast MRI from 2005 through 2009 nearly tripled from 4.2 to 11.5 examinations per 1000 women, with the most rapid increase from 2005 to 2007 (P = .02). The most common clinical indication was diagnostic evaluation (40.3%), followed by screening (31.7%). Compared with women who received screening mammography alone, women who underwent screening breast MRI were more likely to be younger than 50 years, white non-Hispanic, and nulliparous and to have a personal history of breast cancer, a family history of breast cancer, and extremely dense breast tissue (all P < .001). The proportion of women screened using breast MRI at high lifetime risk for breast cancer (>20%) increased during the study period from 9% in 2005 to 29% in 2009.Use of breast MRI for screening in high-risk women is increasing. However, our findings suggest that there is a need to improve appropriate use, including among women who may benefit from screening breast MRI.

Breast cancer risk assessment can inform the use of screening and prevention modalities. We investigated the performance of the Breast Cancer Surveillance Consortium (BCSC) risk model in combination with a polygenic risk score (PRS) comprised of 83 single nucleotide polymorphisms identified from genome-wide association studies. We conducted a nested case–control study of 486 cases and 495 matched controls within a screening cohort. The PRS was calculated using a Bayesian approach. The contributions of the PRS and variables in the BCSC model to breast cancer risk were tested using conditional logistic regression. Discriminatory accuracy of the models was compared using the area under the receiver operating characteristic curve (AUROC). Increasing quartiles of the PRS were positively associated with breast cancer risk, with OR 2.54 (95 % CI 1.69–3.82) for breast cancer in the highest versus lowest quartile. In a multivariable model, the PRS, family history, and breast density remained strong risk factors. The AUROC of the PRS was 0.60 (95 % CI 0.57–0.64), and an Asian-specific PRS had AUROC 0.64 (95 % CI 0.53–0.74). A combined model including the BCSC risk factors and PRS had better discrimination than the BCSC model (AUROC 0.65 versus 0.62, p = 0.01). The BCSC-PRS model classified 18 % of cases as high-risk (5-year risk ≥3 %), compared with 7 % using the BCSC model. The PRS improved discrimination of the BCSC risk model and classified more cases as high-risk. Further consideration of the PRS’s role in decision-making around screening and prevention strategies is merited.

To evaluate the risk of cancer (positive predictive value [PPV]) associated with specific findings (mass, calcifications, architectural distortion, asymmetry) in mammographic examinations with abnormal results, to determine the distribution of these findings in examinations in which the patients received a diagnosis of cancer and examinations in which the patients did not, and to analyze PPV variation according to radiologist and patient factors.HIPAA-compliant institutional review board approval was obtained. PPV of mammographic findings was evaluated in a prospective cohort of 10,262 women who underwent 10,641 screening or diagnostic mammographic examinations with abnormal results between January 1998 and December 2002 in the San Francisco Mammography Registry. The cohort was linked with the Surveillance Epidemiology and End Results program to determine cancer status among these women. PPVs were calculated for each finding and were stratified according to patient characteristics, cancer type, and radiologist reader.Cases of breast cancer (n = 1552) were identified (invasive, n = 1287; ductal carcinoma in situ, n = 270); in five, both kinds of breast cancer were recorded. Overall, of the number of interpretations, masses were most frequently noted in 56%, followed by calcifications in 29%, asymmetry in 12%, and architectural distortion in 4%. Masses, calcifications, architectural distortion, and developing asymmetry demonstrated similar PPVs in screening examinations (9.7%, 12.7%, 10.2%, and 7.4%, respectively), whereas one-view-only and focal asymmetry demonstrated lower PPVs (3.6% and 3.7%, respectively) and were a frequent reason for an abnormal result (42%). Overall, one (5%) in 20 invasive cancers was identified with asymmetry, one (6%) in 16 invasive cancers was identified with architectural distortion, one (21%) in five invasive cancers was identified with calcifications, and two (68%) in three invasive cancers were identified with a mass.Five percent of invasive cancers were identified with asymmetry, and asymmetry is more weakly associated with cancer in screening examinations than are mass, calcifications, and architectural distortion.

Estimates of risk for radiation-induced breast cancer from mammography screening have not considered variation in dose exposure or diagnostic work-up after abnormal screening results.To estimate distributions of radiation-induced breast cancer incidence and mortality from digital mammography screening while considering exposure from screening and diagnostic mammography and dose variation among women.2 simulation-modeling approaches.U.S. population.Women aged 40 to 74 years.Annual or biennial digital mammography screening from age 40, 45, or 50 years until age 74 years.Lifetime breast cancer deaths averted (benefits) and radiation-induced breast cancer incidence and mortality (harms) per 100,000 women screened.Annual screening of 100,000 women aged 40 to 74 years was projected to induce 125 breast cancer cases (95% CI, 88 to 178) leading to 16 deaths (CI, 11 to 23), relative to 968 breast cancer deaths averted by early detection from screening. Women exposed at the 95th percentile were projected to develop 246 cases of radiation-induced breast cancer leading to 32 deaths per 100,000 women. Women with large breasts requiring extra views for complete examination (8% of population) were projected to have greater radiation-induced breast cancer risk (266 cancer cases and 35 deaths per 100,000 women) than other women (113 cancer cases and 15 deaths per 100,000 women). Biennial screening starting at age 50 years reduced risk for radiation-induced cancer 5-fold.Life-years lost from radiation-induced breast cancer could not be estimated.Radiation-induced breast cancer incidence and mortality from digital mammography screening are affected by dose variability from screening, resultant diagnostic work-up, initiation age, and screening frequency. Women with large breasts may have a greater risk for radiation-induced breast cancer.Agency for Healthcare Research and Quality, U.S. Preventive Services Task Force, National Cancer Institute.

Compared with film, digital mammography has superior sensitivity but lower specificity for women aged 40 to 49 years and women with dense breasts. Digital has replaced film in virtually all US facilities, but overall population health and cost from use of this technology are unclear.Using five independent models, we compared digital screening strategies starting at age 40 or 50 years applied annually, biennially, or based on density with biennial film screening from ages 50 to 74 years and with no screening. Common data elements included cancer incidence and test performance, both modified by breast density. Lifetime outcomes included mortality, quality-adjusted life-years, and screening and treatment costs.For every 1000 women screened biennially from age 50 to 74 years, switching to digital from film yielded a median within-model improvement of 2 life-years, 0.27 additional deaths averted, 220 additional false-positive results, and $0.35 million more in costs. For an individual woman, this translates to a health gain of 0.73 days. Extending biennial digital screening to women ages 40 to 49 years was cost-effective, although results were sensitive to quality-of-life decrements related to screening and false positives. Targeting annual screening by density yielded similar outcomes to targeting by age. Annual screening approaches could increase costs to $5.26 million per 1000 women, in part because of higher numbers of screens and false positives, and were not efficient or cost-effective.The transition to digital breast cancer screening in the United States increased total costs for small added health benefits. The value of digital mammography screening among women aged 40 to 49 years depends on women's preferences regarding false positives.

The long-term prognostic role of functional limitations among women with breast cancer is poorly understood.We studied a cohort of 2202 women with breast cancer at two sites in the United States, who provided complete information on body functions involving endurance, strength, muscular range of motion, and small muscle dexterity following initial adjuvant treatment. Associations of baseline functional limitations with survival were evaluated in delayed entry Cox proportional hazards models, with adjustment for baseline sociodemographic factors, body mass index, smoking, physical activity, comorbidity, tumor characteristics, and treatment. Difference in covariates between women with and without limitations was assessed with Pearson χ(2) and Student t tests. All statistical tests were two-sided.During the median follow-up of 9 years, 112 deaths were attributable to competing causes (5% of the cohort) and 157 were attributable to breast cancer causes (7% of the cohort). At least one functional limitation was present in 39% of study participants. Proportionately, more breast cancer patients with functional limitations after initial adjuvant treatment were older, less educated, and obese (P < .001). In multivariable models, functional limitations were associated with a statistically significantly increased risk of death from all causes (hazard ratio [HR] = 1.40, 95% confidence interval [CI] = 1.03 to 1.92) and from competing causes (HR = 2.60, 95% CI = 1.69 to 3.98) but not from breast cancer (HR = 0.90, 95% CI = 0.64 to 1.26). The relationship between functional limitations and overall survival differed by tumor stage (among women with stage I and stage III breast cancer, HR = 2.02, 95% CI = 1.23 to 3.32 and HR = 0.74, 95% CI = 0.42 to 1.30, respectively).In this prospective cohort study, functional limitations following initial breast cancer treatment were associated with an important reduction in all-cause and competing-cause survival, irrespective of clinical, lifestyle, and sociodemographic factors.

Clinical scores of mammographic breast density are highly subjective. Automated technologies for mammography exist to quantify breast density objectively, but the technique that most accurately measures the quantity of breast fibroglandular tissue is not known.To compare the agreement of three automated mammographic techniques for measuring volumetric breast density with a quantitative volumetric MRI-based technique in a screening population.Women were selected from the UCSF Medical Center screening population that had received both a screening MRI and digital mammogram within one year of each other, had Breast Imaging Reporting and Data System (BI-RADS) assessments of normal or benign finding, and no history of breast cancer or surgery. Agreement was assessed of three mammographic techniques (Single-energy X-ray Absorptiometry [SXA], Quantra, and Volpara) with MRI for percent fibroglandular tissue volume, absolute fibroglandular tissue volume, and total breast volume.Among 99 women, the automated mammographic density techniques were correlated with MRI measures with R(2) values ranging from 0.40 (log fibroglandular volume) to 0.91 (total breast volume). Substantial agreement measured by kappa statistic was found between all percent fibroglandular tissue measures (0.72 to 0.63), but only moderate agreement for log fibroglandular volumes. The kappa statistics for all percent density measures were highest in the comparisons of the SXA and MRI results. The largest error source between MRI and the mammography techniques was found to be differences in measures of total breast volume.Automated volumetric fibroglandular tissue measures from screening digital mammograms were in substantial agreement with MRI and if associated with breast cancer could be used in clinical practice to enhance risk assessment and prevention.

Objectives Menopausal status is a common covariate in epidemiologic studies. Still, there are no standard definitions for menopausal status using observational data. This study assesses distinctions between menopausal status definitions using commonly collected epidemiologic data, and explores their impact on study outcomes using breast cancer rates as an example. Study design Using survey data from 227,700 women aged 40–64 who received screening mammograms from the Breast Cancer Surveillance Consortium, we classified menopausal status under five different definitions: one complex definition combining multiple variables, two definitions using age as a proxy for menopausal status, one based only on menstrual period status, and one based on age and menstrual period status. Main outcome measures We compared the distribution of menopausal status and menopausal status-specific breast cancer incidence and detection rates across definitions for menopausal status. Results Overall, 36% and 29% of women were consistently classified as postmenopausal and premenopausal, respectively, across all definitions. Menopausal status-specific breast cancer incidence and detection rates were similar across definitions. Rates were unchanged when information regarding natural menopause, bilateral oophorectomy, hormone therapy, and timing of last menstrual period were sequentially added to definitions of postmenopausal status. Conclusions Distinctions in menopausal status definitions contribute to notable differences in how women are classified, but translate to only slight differences in menopausal status-specific breast cancer rates.

Tamoxifen decreases breast cancer recurrence, mortality, and breast cancer risk in high-risk women. Despite these proven benefits, tamoxifen use is often limited due to side effects. We identified predictors of tamoxifen-induced side effects based on clinical variables and serum tamoxifen metabolite biomarkers in a cross-sectional study of patients taking tamoxifen. We enrolled 241 women and collected data on demographics, tamoxifen use and side effects, as well as potential clinical and serum predictors. We used logistic regression models and adjusted for age, body mass index, ethnicity, education, prior post-menopausal hormone therapy (HT), tamoxifen duration, and endoxifen levels to identify factors associated with side effects. Common tamoxifen attributed side effects were hot flashes (64%), vaginal dryness (35%), sleep problems (36%), weight gain (6%), and depression, irritability or mood swings (6%). In multi-variate models, tamoxifen duration, age, prior post-menopausal HT, and endoxifen levels all predicted side effects. Women who had been on tamoxifen for >12 months were less likely to report side effects (OR 0.15, 95% CI 0.04-0.58) or severe side effects (OR 0.05, 95% CI 0.005-0.58) compared to women on tamoxifen for <12 months. Compared to women younger than 50, women who were age 60-70 and older than 70 were less likely to report side effects (OR 0.22, 95% CI 0.03-1.35; OR 0.13, 95% CI 0.01-0.99; respectively). Women who previously took post-menopausal HT were more likely to report severe side effects. Women with higher endoxifen levels were more likely to report side effects (OR 1.67, 95% CI 1.01-2.77 per standard deviation increase in endoxifen). Clinicians should consider closely monitoring adherence in women taking tamoxifen, especially in younger women, and women who previously took HT. The association between endoxifen levels and side effects is consistent with the data that suggest that endoxifen is the most highly active metabolite of tamoxifen.

Benign breast disease and high breast density are prevalent, strong risk factors for breast cancer. Women with both risk factors may be at very high risk.We included 42818 women participating in the Breast Cancer Surveillance Consortium who had no prior diagnosis of breast cancer and had undergone at least one benign breast biopsy and mammogram; 1359 women developed incident breast cancer in 6.1 years of follow-up (78.1% invasive, 21.9% ductal carcinoma in situ). We calculated hazard ratios (HRs) using Cox regression analysis. The referent group was women with nonproliferative changes and average density. All P values are two-sided.Benign breast disease and breast density were independently associated with breast cancer. The combination of atypical hyperplasia and very high density was uncommon (0.6% of biopsies) but was associated with the highest risk for breast cancer (HR = 5.34; 95% confidence interval [CI] = 3.52 to 8.09, P < .001). Proliferative disease without atypia (25.6% of biopsies) was associated with elevated risk that varied little across levels of density: average (HR = 1.37; 95% CI = 1.11 to 1.69, P = .003), high (HR = 2.02; 95% CI = 1.68 to 2.44, P < .001), or very high (HR = 2.05; 95% CI = 1.54 to 2.72, P < .001). Low breast density (4.5% of biopsies) was associated with low risk (HRs <1) for all benign pathology diagnoses.Women with high breast density and proliferative benign breast disease are at very high risk for future breast cancer. Women with low breast density are at low risk, regardless of their benign pathologic diagnosis.

To evaluate the effectiveness of combined biennial digital mammography and tomosynthesis screening, compared with biennial digital mammography screening alone, among women with dense breasts.An established, discrete-event breast cancer simulation model was used to estimate the comparative clinical effectiveness and cost-effectiveness of biennial screening with both digital mammography and tomosynthesis versus digital mammography alone among U.S. women aged 50-74 years with dense breasts from a federal payer perspective and a lifetime horizon. Input values were estimated for test performance, costs, and health state utilities from the National Cancer Institute Breast Cancer Surveillance Consortium, Medicare reimbursement rates, and medical literature. Sensitivity analyses were performed to determine the implications of varying key model parameters, including combined screening sensitivity and specificity, transient utility decrement of diagnostic work-up, and additional cost of tomosynthesis.For the base-case analysis, the incremental cost per quality-adjusted life year gained by adding tomosynthesis to digital mammography screening was $53 893. An additional 0.5 deaths were averted and 405 false-positive findings avoided per 1000 women after 12 rounds of screening. Combined screening remained cost-effective (less than $100 000 per quality-adjusted life year gained) over a wide range of incremental improvements in test performance. Overall, cost-effectiveness was most sensitive to the additional cost of tomosynthesis.Biennial combined digital mammography and tomosynthesis screening for U.S. women aged 50-74 years with dense breasts is likely to be cost-effective if priced appropriately (up to $226 for combined examinations vs $139 for digital mammography alone) and if reported interpretive performance metrics of improved specificity with tomosynthesis are met in routine practice.

Purpose To establish contemporary performance benchmarks for diagnostic digital mammography with use of recent data from the Breast Cancer Surveillance Consortium (BCSC). Materials and Methods Institutional review board approval was obtained for active or passive consenting processes or to obtain a waiver of consent to enroll participants, link data, and perform analyses. Data were obtained from six BCSC registries (418 radiologists, 92 radiology facilities). Mammogram indication and assessments were prospectively collected for women undergoing diagnostic digital mammography and linked with cancer diagnoses from state cancer registries. The study included 401 548 examinations conducted from 2007 to 2013 in 265 360 women. Results Overall diagnostic performance measures were as follows: cancer detection rate, 34.7 per 1000 (95% confidence interval [CI]: 34.1, 35.2); abnormal interpretation rate, 12.6% (95% CI: 12.5%, 12.7%); positive predictive value (PPV) of a biopsy recommendation (PPV2), 27.5% (95% CI: 27.1%, 27.9%); PPV of biopsies performed (PPV3), 30.4% (95% CI: 29.9%, 30.9%); false-negative rate, 4.8 per 1000 (95% CI: 4.6, 5.0); sensitivity, 87.8% (95% CI: 87.3%, 88.4%); and specificity, 90.5% (95% CI: 90.4%, 90.6%). Among cancers detected, 63.4% were stage 0 or 1 cancers, 45.6% were minimal cancers, the mean size of invasive cancers was 21.2 mm, and 69.6% of invasive cancers were node negative. Performance metrics varied widely across diagnostic indications, with cancer detection rate (64.5 per 1000) and abnormal interpretation rate (18.7%) highest for diagnostic mammograms obtained to evaluate a breast problem with a lump. Compared with performance during the screen-film mammography era, diagnostic digital performance showed increased abnormal interpretation and cancer detection rates and decreasing PPVs, with less than 70% of radiologists within acceptable ranges for PPV2 and PPV3. Conclusion These performance measures can serve as national benchmarks that may help transform the marked variation in radiologists’ diagnostic performance into targeted quality improvement efforts. © RSNA, 2017 Online supplemental material is available for this article.

Background: Biennial screening is generally recommended for average-risk women aged 50 to 74 years, but tailored screening may provide greater benefits. Objective: To estimate outcomes for various screening intervals after age 50 years based on breast density and risk for breast cancer. Design: Collaborative simulation modeling using national incidence, breast density, and screening performance data. Setting: United States. Patients: Women aged 50 years or older with various combinations of breast density and relative risk (RR) of 1.0, 1.3, 2.0, or 4.0. Intervention: Annual, biennial, or triennial digital mammography screening from ages 50 to 74 years (vs. no screening) and ages 65 to 74 years (vs. biennial digital mammography from ages 50 to 64 years). Measurements: Lifetime breast cancer deaths, life expectancy and quality-adjusted life-years (QALYs), false-positive mammograms, benign biopsy results, overdiagnosis, cost-effectiveness, and ratio of false-positive results to breast cancer deaths averted. Results: Screening benefits and overdiagnosis increase with breast density and RR. False-positive mammograms and benign results on biopsy decrease with increasing risk. Among women with fatty breasts or scattered fibroglandular density and an RR of 1.0 or 1.3, breast cancer deaths averted were similar for triennial versus biennial screening for both age groups (50 to 74 years, median of 3.4 to 5.1 vs. 4.1 to 6.5 deaths averted; 65 to 74 years, median of 1.5 to 2.1 vs. 1.8 to 2.6 deaths averted). Breast cancer deaths averted increased with annual versus biennial screening for women aged 50 to 74 years at all levels of breast density and an RR of 4.0, and those aged 65 to 74 years with heterogeneously or extremely dense breasts and an RR of 4.0. However, harms were almost 2-fold higher. Triennial screening for the average-risk subgroup and annual screening for the highest-risk subgroup cost less than $100 000 per QALY gained. Limitation: Models did not consider women younger than 50 years, those with an RR less than 1, or other imaging methods. Conclusion: Average-risk women with low breast density undergoing triennial screening and higher-risk women with high breast density receiving annual screening will maintain a similar or better balance of benefits and harms than average-risk women receiving biennial screening. Primary Funding Source: National Cancer Institute.

Screening mammography intervals remain under debate in the United States.To compare the proportion of breast cancers with less vs more favorable prognostic characteristics in women screening annually vs biennially by age, menopausal status, and postmenopausal hormone therapy (HT) use.This was a study of a prospective cohort from 1996 to 2012 at Breast Cancer Surveillance Consortium facilities. A total of 15,440 women ages 40 to 85 years with breast cancer diagnosed within 1 year of an annual or within 2 years of a biennial screening mammogram.We updated previous analyses by using narrower intervals for defining annual (11-14 months) and biennial (23-26 months) screening.We defined less favorable prognostic characteristics as tumors that were stage IIB or higher, size greater than 15 mm, positive nodes, and any 1 or more of these characteristics. We used log-binomial regression to model the proportion of breast cancers with less favorable characteristics following a biennial vs annual screen by 10-year age groups and by menopausal status and current postmenopausal HT use.Among 15,440 women with breast cancer, most were 50 years or older (13,182 [85.4%]), white (12,063 [78.1%]), and postmenopausal (9823 [63.6%]). Among 2027 premenopausal women (13.1%), biennial screeners had higher proportions of tumors that were stage IIB or higher (relative risk [RR], 1.28 [95% CI, 1.01-1.63]; P=.04), size greater than 15 mm (RR, 1.21 [95% CI, 1.07-1.37]; P=.002), and with any less favorable prognostic characteristic (RR, 1.11 [95% CI, 1.00-1.22]; P=.047) compared with annual screeners. Among women currently taking postmenopausal HT, biennial screeners tended to have tumors with less favorable prognostic characteristics compared with annual screeners; however, 95% CIs were wide, and differences were not statistically significant (for stage 2B+, RR, 1.14 [95% CI, 0.89-1.47], P=.29; size>15 mm, RR, 1.13 [95% CI, 0.98-1.31], P=.09; node positive, RR, 1.18 [95% CI, 0.98-1.42], P=.09; any less favorable characteristic, RR, 1.12 [95% CI, 1.00-1.25], P=.053). The proportions of tumors with less favorable prognostic characteristics were not significantly larger for biennial vs annual screeners among postmenopausal women not taking HT (eg, any characteristic: RR, 1.03 [95% CI, 0.95-1.12]; P=.45), postmenopausal HT users after subdividing by type of hormone use (eg, any characteristic: estrogen+progestogen users, RR, 1.16 [95% CI, 0.91-1.47]; P=.22; estrogen-only users, RR, 1.14 [95% CI, 0.94-1.37]; P=.18), or any 10-year age group (eg, any characteristic: ages 40-49 years, RR, .1.04 [95% CI, 0.94-1.14]; P=.48; ages 50-59 years, RR, 1.03 [95% CI, 0.94-1.12]; P=.58; ages 60-69 years, RR, 1.07 [95% CI, 0.97-1.19]; P=.18; ages 70-85 years, RR, 1.05 [95% CI, 0.94-1.18]; P=.35).Premenopausal women diagnosed as having breast cancer following biennial vs annual screening mammography are more likely to have tumors with less favorable prognostic characteristics. Postmenopausal women not using HT who are diagnosed as having breast cancer following a biennial or annual screen have similar proportions of tumors with less favorable prognostic characteristics.

<h3>Importance</h3> Whole-breast ultrasonography has been advocated to supplement screening mammography to improve outcomes in women with dense breasts. <h3>Objective</h3> To determine the performance of screening mammography plus screening ultrasonography compared with screening mammography alone in community practice. <h3>Design, Setting, and Participants</h3> Observational cohort study. Two Breast Cancer Surveillance Consortium registries provided prospectively collected data on screening mammography with vs without same-day breast ultrasonography from January 1, 2000, to December 31, 2013. The dates of analysis were March 2014 to December 2018. A total of 6081 screening mammography plus same-day screening ultrasonography examinations in 3386 women were propensity score matched 1:5 to 30 062 screening mammograms without screening ultrasonography in 15 176 women from a sample of 113 293 mammograms. Exclusion criteria included a personal history of breast cancer and self-reported breast symptoms. <h3>Exposures</h3> Screening mammography with vs without screening ultrasonography. <h3>Main Outcomes and Measures</h3> Cancer detection rate and rates of interval cancer, false-positive biopsy recommendation, short-interval follow-up, and positive predictive value of biopsy recommendation were estimated and compared using log binomial regression. <h3>Results</h3> Screening mammography with vs without ultrasonography examinations was performed more often in women with dense breasts (74.3% [n = 4317 of 5810] vs 35.9% [n = 39 928 of 111 306] in the overall sample), in women who were younger than 50 years (49.7% [n = 3022 of 6081] vs 31.7% [n = 16 897 of 112 462]), and in women with a family history of breast cancer (42.9% [n = 2595 of 6055] vs 15.0% [n = 16 897 of 112 462]). While 21.4% (n = 1154 of 5392) of screening ultrasonography examinations were performed in women with high or very high (≥2.50%) Breast Cancer Surveillance Consortium 5-year risk scores, 53.6% (n = 2889 of 5392) had low or average (&lt;1.67%) risk. Comparing mammography plus ultrasonography with mammography alone, the cancer detection rate was similar at 5.4 vs 5.5 per 1000 screens (adjusted relative risk [RR], 1.14; 95% CI, 0.76-1.68), as were interval cancer rates at 1.5 vs 1.9 per 1000 screens (RR, 0.67; 95% CI, 0.33-1.37). The false-positive biopsy rates were significantly higher at 52.0 vs 22.2 per 1000 screens (RR, 2.23; 95% CI, 1.93-2.58), as was short-interval follow-up at 3.9% vs 1.1% (RR, 3.10; 95% CI, 2.60-3.70). The positive predictive value of biopsy recommendation was significantly lower at 9.5% vs 21.4% (RR, 0.50; 95% CI, 0.35-0.71). <h3>Conclusions and Relevance</h3> In a relatively young population of women at low, intermediate, and high breast cancer risk, these results suggest that the benefits of supplemental ultrasonography screening may not outweigh associated harms.

Digital mammography (DM) and digital breast tomosynthesis (DBT) are used for routine breast cancer screening. There is minimal evidence on performance outcomes by age, screening round, and breast density in community practice.To compare DM vs DBT performance by age, baseline vs subsequent screening round, and breast density category.This comparative effectiveness study assessed 1 584 079 screening examinations of women aged 40 to 79 years without prior history of breast cancer, mastectomy, or breast augmentation undergoing screening mammography at 46 participating Breast Cancer Surveillance Consortium facilities from January 2010 to April 2018.Age, Breast Imaging Reporting and Data System breast density category, screening round, and modality.Absolute rates and relative risks (RRs) of screening recall and cancer detection.Of 1 273 492 DM and 310 587 DBT examinations analyzed, 1 028 891 examinations (65.0%) were of white non-Hispanic women; 399 952 women (25.2%) were younger than 50 years; and 671 136 women (42.4%) had heterogeneously dense or extremely dense breasts. Adjusted differences in DM vs DBT performance were largest on baseline examinations: for example, per 1000 baseline examinations in women ages 50 to 59, recall rates decreased from 241 examinations for DM to 204 examinations for DBT (RR, 0.84; 95% CI, 0.73-0.98), and cancer detection rates increased from 5.9 with DM to 8.8 with DBT (RR, 1.50; 95% CI, 1.10-2.08). On subsequent examinations, women aged 40 to 79 years with heterogeneously dense breasts had improved recall rates and improved cancer detection with DBT. For example, per 1000 examinations in women aged 50 to 59 years, the number of recall examinations decreased from 102 with DM to 93 with DBT (RR, 0.91; 95% CI, 0.84-0.98), and cancer detection increased from 3.7 with DM to 5.3 with DBT (RR, 1.42; 95% CI, 1.23-1.64). Women aged 50 to 79 years with scattered fibroglandular density also had improved recall and cancer detection rates with DBT. Women aged 40 to 49 years with scattered fibroglandular density and women aged 50 to 79 years with almost entirely fatty breasts benefited from improved recall rates without change in cancer detection rates. No improvements in recall or cancer detection rates were observed in women with extremely dense breasts on subsequent examinations for any age group.This study found that improvements in recall and cancer detection rates with DBT were greatest on baseline mammograms. On subsequent screening mammograms, the benefits of DBT varied by age and breast density. Women with extremely dense breasts did not benefit from improved recall or cancer detection with DBT on subsequent screening rounds.

PURPOSE To evaluate comparative associations of breast magnetic resonance imaging (MRI) background parenchymal enhancement (BPE) and mammographic breast density with subsequent breast cancer risk. PATIENTS AND METHODS We examined women undergoing breast MRI in the Breast Cancer Surveillance Consortium from 2005 to 2015 (with one exam in 2000) using qualitative BPE assessments of minimal, mild, moderate, or marked. Breast density was assessed on mammography performed within 5 years of MRI. Among women diagnosed with breast cancer, the first BPE assessment was included if it was more than 3 months before their first diagnosis. Breast cancer risk associated with BPE was estimated using Cox proportional hazards regression. RESULTS Among 4,247 women, 176 developed breast cancer (invasive, n = 129; ductal carcinoma in situ,n = 47) over a median follow-up time of 2.8 years. More women with cancer had mild, moderate, or marked BPE than women without cancer (80% v 66%, respectively). Compared with minimal BPE, increasing BPE levels were associated with significantly increased cancer risk (mild: hazard ratio [HR], 1.80; 95% CI, 1.12 to 2.87; moderate: HR, 2.42; 95% CI, 1.51 to 3.86; and marked: HR, 3.41; 95% CI, 2.05 to 5.66). Compared with women with minimal BPE and almost entirely fatty or scattered fibroglandular breast density, women with mild, moderate, or marked BPE demonstrated elevated cancer risk if they had almost entirely fatty or scattered fibroglandular breast density (HR, 2.30; 95% CI, 1.19 to 4.46) or heterogeneous or extremely dense breasts (HR, 2.61; 95% CI, 1.44 to 4.72), with no significant interaction ( P = .82). Combined mild, moderate, and marked BPE demonstrated significantly increased risk of invasive cancer (HR, 2.73; 95% CI, 1.66 to 4.49) but not ductal carcinoma in situ (HR, 1.48; 95% CI, 0.72 to 3.05). CONCLUSION BPE is associated with future invasive breast cancer risk independent of breast density. BPE should be considered for risk prediction models for women undergoing breast MRI.

Purpose To identify phenotypes of mammographic parenchymal complexity by using radiomic features and to evaluate their associations with breast density and other breast cancer risk factors. Materials and Methods Computerized image analysis was used to quantify breast density and extract parenchymal texture features in a cross-sectional sample of women screened with digital mammography from September 1, 2012, to February 28, 2013 (n = 2029; age range, 35–75 years; mean age, 55.9 years). Unsupervised clustering was applied to identify and reproduce phenotypes of parenchymal complexity in separate training (n = 1339) and test sets (n = 690). Differences across phenotypes by age, body mass index, breast density, and estimated breast cancer risk were assessed by using Fisher exact, χ2, and Kruskal-Wallis tests. Conditional logistic regression was used to evaluate preliminary associations between the detected phenotypes and breast cancer in an independent case-control sample (76 women diagnosed with breast cancer and 158 control participants) matched on age. Results Unsupervised clustering in the screening sample identified four phenotypes with increasing parenchymal complexity that were reproducible between training and test sets (P = .001). Breast density was not strongly correlated with phenotype category (R2 = 0.24 for linear trend). The low- to intermediate-complexity phenotype (prevalence, 390 of 2029 [19%]) had the lowest proportion of dense breasts (eight of 390 [2.1%]), whereas similar proportions were observed across other phenotypes (from 140 of 291 [48.1%] in the high-complexity phenotype to 275 of 511 [53.8%] in the low-complexity phenotype). In the independent case-control sample, phenotypes showed a significant association with breast cancer (P = .001), resulting in higher discriminatory capacity when added to a model with breast density and body mass index (area under the curve, 0.84 vs 0.80; P = .03 for comparison). Conclusion Radiomic phenotypes capture mammographic parenchymal complexity beyond conventional breast density measures and established breast cancer risk factors. © RSNA, 2018 Online supplemental material is available for this article. See also the editorial by Pinker in this issue.

Screening mammography and magnetic resonance imaging (MRI) are recommended for women with ATM, CHEK2, and PALB2 pathogenic variants. However, there are few data to guide screening regimens for these women.To estimate the benefits and harms of breast cancer screening strategies using mammography and MRI at various start ages for women with ATM, CHEK2, and PALB2 pathogenic variants.This comparative modeling analysis used 2 established breast cancer microsimulation models from the Cancer Intervention and Surveillance Modeling Network (CISNET) to evaluate different screening strategies. Age-specific breast cancer risks were estimated using aggregated data from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium for 32 247 cases and 32 544 controls in 12 population-based studies. Data on screening performance for mammography and MRI were estimated from published literature. The models simulated US women with ATM, CHEK2, or PALB2 pathogenic variants born in 1985.Screening strategies with combinations of annual mammography alone and with MRI starting at age 25, 30, 35, or 40 years until age 74 years.Estimated lifetime breast cancer mortality reduction, life-years gained, breast cancer deaths averted, total screening examinations, false-positive screenings, and benign biopsies per 1000 women screened. Results are reported as model mean values and ranges.The mean model-estimated lifetime breast cancer risk was 20.9% (18.1%-23.7%) for women with ATM pathogenic variants, 27.6% (23.4%-31.7%) for women with CHEK2 pathogenic variants, and 39.5% (35.6%-43.3%) for women with PALB2 pathogenic variants. Across pathogenic variants, annual mammography alone from 40 to 74 years was estimated to reduce breast cancer mortality by 36.4% (34.6%-38.2%) to 38.5% (37.8%-39.2%) compared with no screening. Screening with annual MRI starting at 35 years followed by annual mammography and MRI at 40 years was estimated to reduce breast cancer mortality by 54.4% (54.2%-54.7%) to 57.6% (57.2%-58.0%), with 4661 (4635-4688) to 5001 (4979-5023) false-positive screenings and 1280 (1272-1287) to 1368 (1362-1374) benign biopsies per 1000 women. Annual MRI starting at 30 years followed by mammography and MRI at 40 years was estimated to reduce mortality by 55.4% (55.3%-55.4%) to 59.5% (58.5%-60.4%), with 5075 (5057-5093) to 5415 (5393-5437) false-positive screenings and 1439 (1429-1449) to 1528 (1517-1538) benign biopsies per 1000 women. When starting MRI at 30 years, initiating annual mammography starting at 30 vs 40 years did not meaningfully reduce mean mortality rates (0.1% [0.1%-0.2%] to 0.3% [0.2%-0.3%]) but was estimated to add 649 (602-695) to 650 (603-696) false-positive screenings and 58 (41-76) to 59 (41-76) benign biopsies per 1000 women.This analysis suggests that annual MRI screening starting at 30 to 35 years followed by annual MRI and mammography at 40 years may reduce breast cancer mortality by more than 50% for women with ATM, CHEK2, and PALB2 pathogenic variants. In the setting of MRI screening, mammography prior to 40 years may offer little additional benefit.

Diagnostic delays in breast cancer detection may be associated with later-stage disease and higher anxiety, but data on multilevel factors associated with diagnostic delay are limited.To evaluate individual-, neighborhood-, and health care-level factors associated with differences in time from abnormal screening to biopsy among racial and ethnic groups.This prospective cohort study used data from women aged 40 to 79 years who had abnormal results in screening mammograms conducted in 109 imaging facilities across 6 US states between 2009 and 2019. Data were analyzed from February 21 to November 4, 2021.Individual-level factors included self-reported race and ethnicity, age, family history of breast cancer, breast density, previous breast biopsy, and time since last mammogram; neighborhood-level factors included geocoded education and income based on residential zip codes and rurality; and health care-level factors included mammogram modality, screening facility academic affiliation, and facility onsite biopsy service availability. Data were also assessed by examination year.The main outcome was unadjusted and adjusted relative risk (RR) of no biopsy within 30, 60, and 90 days using sequential log-binomial regression models. A secondary outcome was unadjusted and adjusted median time to biopsy using accelerated failure time models.A total of 45 186 women (median [IQR] age at screening, 56 [48-65] years) with 46 185 screening mammograms with abnormal results were included. Of screening mammograms with abnormal results recommended for biopsy, 15 969 (34.6%) were not resolved within 30 days, 7493 (16.2%) were not resolved within 60 days, and 5634 (12.2%) were not resolved within 90 days. Compared with White women, there was increased risk of no biopsy within 30 and 60 days for Asian (30 days: RR, 1.66; 95% CI, 1.31-2.10; 60 days: RR, 1.58; 95% CI, 1.15-2.18), Black (30 days: RR, 1.52; 95% CI, 1.30-1.78; 60 days: 1.39; 95% CI, 1.22-1.60), and Hispanic (30 days: RR, 1.50; 95% CI, 1.24-1.81; 60 days: 1.38; 95% CI, 1.11-1.71) women; however, the unadjusted risk of no biopsy within 90 days only persisted significantly for Black women (RR, 1.28; 95% CI, 1.11-1.47). Sequential adjustment for selected individual-, neighborhood-, and health care-level factors, exclusive of screening facility, did not substantially change the risk of no biopsy within 90 days for Black women (RR, 1.27; 95% CI, 1.12-1.44). After additionally adjusting for screening facility, the increased risk for Black women persisted but showed a modest decrease (RR, 1.20; 95% CI, 1.08-1.34).In this cohort study involving a diverse cohort of US women recommended for biopsy after abnormal results on screening mammography, Black women were the most likely to experience delays to diagnostic resolution after adjusting for multilevel factors. These results suggest that adjustment for multilevel factors did not entirely account for differences in time to breast biopsy, but unmeasured factors, such as systemic racism and other health care system factors, may impact timely diagnosis.

<h3>Importance</h3> Digital breast tomosynthesis (DBT) was developed with the expectation of improving cancer detection in women with dense breasts. Studies are needed to evaluate interval invasive and advanced breast cancer rates, intermediary outcomes related to breast cancer mortality, by breast density and breast cancer risk. <h3>Objective</h3> To evaluate whether DBT screening is associated with a lower likelihood of interval invasive cancer and advanced breast cancer compared with digital mammography by extent of breast density and breast cancer risk. <h3>Design, Setting, and Participants</h3> Cohort study of 504 427 women aged 40 to 79 years who underwent 1 003 900 screening digital mammography and 375 189 screening DBT examinations from 2011 through 2018 at 44 US Breast Cancer Surveillance Consortium (BCSC) facilities with follow-up for cancer diagnoses through 2019 by linkage to state or regional cancer registries. <h3>Exposures</h3> Breast Imaging Reporting and Data System (BI-RADS) breast density; BCSC 5-year breast cancer risk. <h3>Main Outcomes and Measures</h3> Rates per 1000 examinations of interval invasive cancer within 12 months of screening mammography and advanced breast cancer (prognostic pathologic stage II or higher) within 12 months of screening mammography, both estimated with inverse probability weighting. <h3>Results</h3> Among 504 427 women in the study population, the median age at time of mammography was 58 years (IQR, 50-65 years). Interval invasive cancer rates per 1000 examinations were not significantly different for DBT vs digital mammography (overall, 0.57 vs 0.61, respectively; difference, −0.04; 95% CI, −0.14 to 0.06;<i>P</i> = .43) or among all the 836 250 examinations with BCSC 5-year risk less than 1.67% (low to average-risk) or all the 413 061 examinations with BCSC 5-year risk of 1.67% or higher (high risk) across breast density categories. Advanced cancer rates were not significantly different for DBT vs digital mammography among women at low to average risk or at high risk with almost entirely fatty, scattered fibroglandular densities, or heterogeneously dense breasts. Advanced cancer rates per 1000 examinations were significantly lower for DBT vs digital mammography for the 3.6% of women with extremely dense breasts and at high risk of breast cancer (13 291 examinations in the DBT group and 31 300 in the digital mammography group; 0.27 vs 0.80 per 1000 examinations; difference, −0.53; 95% CI, −0.97 to −0.10) but not for women at low to average risk (10 611 examinations in the DBT group and 37 796 in the digital mammography group; 0.54 vs 0.42 per 1000 examinations; difference, 0.12; 95% CI, −0.09 to 0.32). <h3>Conclusions and Relevance</h3> Screening with DBT vs digital mammography was not associated with a significant difference in risk of interval invasive cancer and was associated with a significantly lower risk of advanced breast cancer among the 3.6% of women with extremely dense breasts and at high risk of breast cancer. No significant difference was observed in the 96.4% of women with nondense breasts, heterogeneously dense breasts, or with extremely dense breasts not at high risk.

Breast cancer screening with digital breast tomosynthesis may decrease false-positive results compared with digital mammography.To estimate the probability of receiving at least 1 false-positive result after 10 years of screening with digital breast tomosynthesis vs digital mammography in the US.An observational comparative effectiveness study with data collected prospectively for screening examinations was performed between January 1, 2005, and December 31, 2018, at 126 radiology facilities in the Breast Cancer Surveillance Consortium. Analysis included 903 495 individuals aged 40 to 79 years. Data analysis was conducted from February 9 to September 7, 2021.Screening modality, screening interval, age, and Breast Imaging Reporting and Data System breast density.Cumulative risk of at least 1 false-positive recall for further imaging, short-interval follow-up recommendation, and biopsy recommendation after 10 years of annual or biennial screening with digital breast tomosynthesis vs digital mammography, accounting for competing risks of breast cancer diagnosis and death.In this study of 903 495 women, 2 969 055 nonbaseline screening examinations were performed with interpretation by 699 radiologists. Mean (SD) age of the women at the time of the screening examinations was 57.6 (9.9) years, and 58% of the examinations were in individuals younger than 60 years and 46% were performed in women with dense breasts. A total of 15% of examinations used tomosynthesis. For annual screening, the 10-year cumulative probability of at least 1 false-positive result was significantly lower with tomosynthesis vs digital mammography for all outcomes: 49.6% vs 56.3% (difference, -6.7; 95% CI, -7.4 to -6.1) for recall, 16.6% vs 17.8% (difference, -1.1; 95% CI, -1.7 to -0.6) for short-interval follow-up recommendation, and 11.2% vs 11.7% (difference, -0.5; 95% CI, -1.0 to -0.1) for biopsy recommendation. For biennial screening, the cumulative probability of a false-positive recall was significantly lower for tomosynthesis vs digital mammography (35.7% vs 38.1%; difference, -2.4; 95% CI, -3.4 to -1.5), but cumulative probabilities did not differ significantly by modality for short-interval follow-up recommendation (10.3% vs 10.5%; difference, -0.1; 95% CI, -0.7 to 0.5) or biopsy recommendation (6.6% vs 6.7%; difference, -0.1; 95% CI, -0.5 to 0.4). Decreases in cumulative probabilities of false-positive results with tomosynthesis vs digital mammography were largest for annual screening in women with nondense breasts (differences for recall, -6.5 to -12.8; short-interval follow-up, 0.1 to -5.2; and biopsy recommendation, -0.5 to -3.1). Regardless of modality, cumulative probabilities of false-positive results were substantially lower for biennial vs annual screening (overall recall, 35.7 to 38.1 vs 49.6 to 56.3; short-interval follow-up, 10.3 to 10.5 vs 16.6 to 17.8; and biopsy recommendation, 6.6 to 6.7 vs 11.2 to 11.7); older vs younger age groups (eg, among annual screening in women ages 70-79 vs 40-49, recall, 39.8 to 47.0 vs 60.8 to 68.0; short-interval follow-up, 13.3 to 14.2 vs 20.7 to 20.9; and biopsy recommendation, 9.1 to 9.3 vs 13.2 to 13.4); and women with entirely fatty vs extremely dense breasts (eg, among annual screening in women aged 50-59 years, recall, 29.1 to 36.3 vs 58.8 to 60.4; short-interval follow-up, 8.9 to 11.6 vs 19.5 to 19.8; and biopsy recommendation, 4.9 to 8.0 vs 15.1 to 15.3).In this comparative effectiveness study, 10-year cumulative probabilities of false-positive results were lower on digital breast tomosynthesis vs digital mammography. Biennial screening interval, older age, and nondense breasts were associated with larger reductions in false-positive probabilities than screening modality.

PURPOSE Artificial intelligence (AI) algorithms improve breast cancer detection on mammography, but their contribution to long-term risk prediction for advanced and interval cancers is unknown. METHODS We identified 2,412 women with invasive breast cancer and 4,995 controls matched on age, race, and date of mammogram, from two US mammography cohorts, who had two-dimensional full-field digital mammograms performed 2-5.5 years before cancer diagnosis. We assessed Breast Imaging Reporting and Data System density, an AI malignancy score (1-10), and volumetric density measures. We used conditional logistic regression to estimate odds ratios (ORs), 95% CIs, adjusted for age and BMI, and C-statistics (AUC) to describe the association of AI score with invasive cancer and its contribution to models with breast density measures. Likelihood ratio tests (LRTs) and bootstrapping methods were used to compare model performance. RESULTS On mammograms between 2-5.5 years prior to cancer, a one unit increase in AI score was associated with 20% greater odds of invasive breast cancer (OR, 1.20; 95% CI, 1.17 to 1.22; AUC, 0.63; 95% CI, 0.62 to 0.64) and was similarly predictive of interval (OR, 1.20; 95% CI, 1.13 to 1.27; AUC, 0.63) and advanced cancers (OR, 1.23; 95% CI, 1.16 to 1.31; AUC, 0.64) and in dense (OR, 1.18; 95% CI, 1.15 to 1.22; AUC, 0.66) breasts. AI score improved prediction of all cancer types in models with density measures ( P LRT values &lt; .001); discrimination improved for advanced cancer (ie, AUC for dense volume increased from 0.624 to 0.679, Δ AUC 0.065, P = .01) but did not reach statistical significance for interval cancer. CONCLUSION AI imaging algorithms coupled with breast density independently contribute to long-term risk prediction of invasive breast cancers, in particular, advanced cancer.

Importance The effects of breast cancer incidence changes and advances in screening and treatment on outcomes of different screening strategies are not well known. Objective To estimate outcomes of various mammography screening strategies. Design, Setting, and Population Comparison of outcomes using 6 Cancer Intervention and Surveillance Modeling Network (CISNET) models and national data on breast cancer incidence, mammography performance, treatment effects, and other-cause mortality in US women without previous cancer diagnoses. Exposures Thirty-six screening strategies with varying start ages (40, 45, 50 years) and stop ages (74, 79 years) with digital mammography or digital breast tomosynthesis (DBT) annually, biennially, or a combination of intervals. Strategies were evaluated for all women and for Black women, assuming 100% screening adherence and “real-world” treatment. Main Outcomes and Measures Estimated lifetime benefits (breast cancer deaths averted, percent reduction in breast cancer mortality, life-years gained), harms (false-positive recalls, benign biopsies, overdiagnosis), and number of mammograms per 1000 women. Results Biennial screening with DBT starting at age 40, 45, or 50 years until age 74 years averted a median of 8.2, 7.5, or 6.7 breast cancer deaths per 1000 women screened, respectively, vs no screening. Biennial DBT screening at age 40 to 74 years (vs no screening) was associated with a 30.0% breast cancer mortality reduction, 1376 false-positive recalls, and 14 overdiagnosed cases per 1000 women screened. Digital mammography screening benefits were similar to those for DBT but had more false-positive recalls. Annual screening increased benefits but resulted in more false-positive recalls and overdiagnosed cases. Benefit-to-harm ratios of continuing screening until age 79 years were similar or superior to stopping at age 74. In all strategies, women with higher-than-average breast cancer risk, higher breast density, and lower comorbidity level experienced greater screening benefits than other groups. Annual screening of Black women from age 40 to 49 years with biennial screening thereafter reduced breast cancer mortality disparities while maintaining similar benefit-to-harm trade-offs as for all women. Conclusions This modeling analysis suggests that biennial mammography screening starting at age 40 years reduces breast cancer mortality and increases life-years gained per mammogram. More intensive screening for women with greater risk of breast cancer diagnosis or death can maintain similar benefit-to-harm trade-offs and reduce mortality disparities.

Ductal carcinoma in situ (DCIS) recurs in the same breast following breast-conserving surgery in 5%-25% of patients, with the rate influenced by the presence or absence of involved surgical margins, tumor size and nuclear grade, and whether or not radiation therapy was performed. A recurrent lesion arising soon after excision of an initial DCIS may reflect residual disease, whereas in situ tumors arising after longer periods are sometimes considered to be second independent events. The purpose of this study was to determine the clonal relationship between initial DCIS lesions and their recurrences.Comparative genomic hybridization (CGH) was used to compare chromosomal alterations in 18 initial DCIS lesions (presenting in the absence of invasive disease) and in their subsequent ipsilateral DCIS recurrences (detected from 16 months to 9.3 years later).Of the 18 tumor pairs, 17 showed a high concordance in their chromosomal alterations (median = 81%; range = 65%-100%), while one case showed no agreement between the paired samples (having two and 20 alterations, respectively). Morphologic characterization of the DCIS pairs showed clear similarities. The mean number of CGH changes was greater in the recurrent tumors than in the initial lesions (10.7 versus 8.8; P =.019). The most common changes in both the initial and the recurrent in situ lesions were gains involving chromosome 17q and losses involving chromosomes 8p and 17p. The degree of concordance was independent of the time interval before recurrence and of the presence of positive surgical margins.In this study, DCIS recurrences were clonally related to their primary lesions in most cases. This finding is consistent with treatment paradigms requiring wide surgical margins and/or postoperative radiation therapy.

Although contemporary guidelines suggest that the intervals between Papanicolaou tests can be extended to three years among low-risk women with previous negative tests, the excess risk of cervical cancer associated with less frequent than annual screening is uncertain.We determined the prevalence of biopsy-proven cervical neoplasia among 938,576 women younger than 65 years of age, stratified according to the number of previous consecutive negative Papanicolaou tests. Using a Markov model that estimates the rate at which dysplasia will progress to cancer, we estimated the risk of cancer within three years after one or more negative Papanicolaou tests, as well as the number of additional Papanicolaou tests and colposcopic examinations that would be required to avert one case of cancer given a particular interval between screenings.Among 31,728 women 30 to 64 years of age who had had three or more consecutive negative tests, the prevalence of biopsy-proven cervical intraepithelial neoplasia of grade 2 was 0.028 percent and the prevalence of grade 3 neoplasia was 0.019 percent; none of the women had invasive cervical cancer. According to our model, the estimated risk of cancer with annual Papanicolaou tests for three years was 2 in 100,000 among women 30 to 44 years of age, 1 in 100,000 among women 45 to 59 years of age, and 1 in 100,000 among women 60 to 64 years of age; these risks would be 5 in 100,000, 2 in 100,000, and 1 in 100,000, respectively, if screening were performed once three years after the last negative test. To avert one additional case of cancer by screening 100,000 women annually for three years rather than once three years after the last negative test, an average of 69,665 additional Papanicolaou tests and 3861 colposcopic examinations would be needed in women 30 to 44 years of age and an average of 209,324 additional Papanicolaou tests and 11,502 colposcopic examinations in women 45 to 59 years of age.As compared with annual screening for three years, screening performed once three years after the last negative test in women 30 to 64 years of age who have had three or more consecutive negative Papanicolaou tests is associated with an average excess risk of cervical cancer of approximately 3 in 100,000.

The performance of diagnostic mammography for women with signs or symptoms of breast cancer has not been well studied. We evaluated whether age, breast density, self-reported breast lump, and previous mammography influence the performance of diagnostic mammography.From January 1996 through March 1998, prospective diagnostic mammography data from women aged 25-89 years with no previous breast cancer were linked to cancer outcomes data in six mammography registries participating in the Breast Cancer Surveillance Consortium. We used the final mammographic assessment at the end of the imaging work-up to determine abnormal mammographic examination rate, positive predictive value (PPV), sensitivity, specificity, and area under the receiver operating characteristic (ROC) curve. We used age, breast density, prior mammogram, and self-reported breast lump jointly as predictors of performance. All statistical tests were two-sided.Of 41 427 diagnostic mammograms, 6279 (15.2%) were judged abnormal. The overall PPV was 21.8%, sensitivity was 85.8%, and specificity was 87.7%. Multivariate analysis showed that sensitivity and specificity generally declined as breast density increased (P =.007 and P<.001, respectively), that previous mammography decreased sensitivity (odds ratio [OR] = 0.52, 95% confidence interval [CI] = 0.36 to 0.74; P<.001) but increased specificity (OR = 1.43, 95% CI = 1.31 to 1.57; P<.001), and that a self-reported breast lump increased sensitivity (OR = 1.64, 95% CI = 1.13 to 2.38; P =.013) but decreased specificity (OR = 0.54, 95% CI = 0.49 to 0.59; P<.001). ROC analysis showed that higher breast density and previous mammography were negatively related to accuracy (P<.001 for both).Diagnostic mammography in women with signs or symptoms of breast cancer shows higher sensitivity and lower specificity than screening mammography does. Higher breast density and previous mammographic examination appear to impair performance.

Breast augmentation is not associated with an increased risk of breast cancer; however, implants may interfere with the detection of breast cancer thereby delaying cancer diagnosis in women with augmentation.To determine whether mammography accuracy and tumor characteristics are different for women with and without augmentation.A prospective cohort of 137 women with augmentation and 685 women without augmentation diagnosed with breast cancer between January 1, 1995, and October 15, 2002, matched (1:5) by age, race/ethnicity, previous mammography screening, and mammography registry, and 10 533 women with augmentation and 974 915 women without augmentation and without breast cancer among 7 mammography registries in Denver, Colo; Lebanon, NH; Albuquerque, NM; Chapel Hill, NC; San Francisco, Calif; Seattle, Wash; and Burlington, Vt.Comparison between women with and without augmentation of mammography performance measures and cancer characteristics, including invasive carcinoma or ductal carcinoma in situ, tumor stage, nodal status, size, grade, and estrogen-receptor status.Among asymptomatic women, the sensitivity of screening mammography based on the final assessment was lower in women with breast augmentation vs women without (45.0% [95% confidence interval [CI], 29.3%-61.5%] vs 66.8% [95% CI, 60.4%-72.8%]; P =.008), and specificity was slightly higher in women with augmentation (97.7% [95% CI, 97.4%-98.0%] vs 96.7% [95% CI, 96.6%-96.7%]; P<.001). Among symptomatic women, both sensitivity and specificity were lower for women with augmentation compared with women without but these differences were not significant. Tumors were of similar stage, size, estrogen-receptor status, and nodal status but tended to be lower grade (P =.052) for women with breast augmentation vs without.Breast augmentation decreases the sensitivity of screening mammography among asymptomatic women but does not increase the false-positive rate. Despite the lower accuracy of mammography in women with augmentation, the prognostic characteristics of tumors are not influenced by augmentation.

To determine if use of postmenopausal hormone replacement therapy (HRT) increases the risk of invasive epithelial ovarian carcinoma.English-language articles published from January 1966 to June 1997 examining HRT and ovarian cancer were found by using MEDLINE, searching the bibliographies of relevant articles and by consulting experts.Of 327 articles identified, nine provided data on the risk of invasive cancer among ever-users of HRT and were selected for inclusion by consensus of two independent reviewers. Studies were included if cases were age-matched to controls or results were age-adjusted and if women with bilateral salpingo-oophorectomy were excluded.Two independent unblinded reviewers abstracted data regarding risk of developing epithelial ovarian carcinoma and use of HRT. A general variance-based, fixed-effects model was used to calculate summary relative risks. Ever-use of HRT was associated with an increased risk of developing invasive epithelial ovarian carcinoma (odds ratio [OR] 1.15; 95% confidence interval [CI] 1.05, 1.27). Use of HRT for more than 10 years was associated with the greatest risk of ovarian cancer (OR 1.27; 95% CI 1.00, 1.61).Prolonged use of hormone therapy by postmenopausal women may be associated with an increased risk of developing epithelial carcinoma of the ovary.

<h3>Objective.</h3> —To determine the efficacy of screening mammography by age, number of mammographic views per screen, screening interval, and duration of follow-up. <h3>Design.</h3> —Literature review and meta-analysis. <h3>Data Identification and Analysis.</h3> —Literature search of English-language studies reported from January 1966 to October 31, 1993, using MEDLINE, manual literature review, and consultation with experts. A total of 13 studies were selected, and their results were combined using meta-analytic techniques based on the assumption of fixed effects. <h3>Main Results.</h3> —The overall summary relative risk (RR) estimate for breast cancer mortality for women aged 50 to 74 years undergoing screening mammography compared with those who did not was 0.74 (95% confidence interval [CI], 0.66 to 0.83). The magnitude of the benefit in this age group was similar regardless of number of mammographic views per screen, screening interval, or duration of follow-up. In contrast, none of the summary RR estimates for women aged 40 to 49 years was significantly less than 1.0, irrespective of screening intervention or duration of follow-up. The overall summary RR estimate in women aged 40 to 49 years was 0.93 (95% CI, 0.76 to 1.13); the summary RR estimate for those studies that used two-view mammography was 0.87 (95% CI, 0.68 to 1.12) compared with 1.02 (95% CI, 0.73 to 1.44) for those studies that used one-view mammography, and for those studies with 7 to 9 years of follow-up, the summary RR estimate was 1.02 (95% CI, 0.82 to 1.27) compared with 0.83 (95% CI, 0.65 to 1.06) for those studies with 10 to 12 years of follow-up. <h3>Conclusion.</h3> —Screening mammography significantly reduces breast cancer mortality in women aged 50 to 74 years after 7 to 9 years of follow-up, regardless of screening interval or number of mammographic views per screen. There is no reduction in breast cancer mortality in women aged 40 to 49 years after 7 to 9 years of follow-up. Screening mammography may be effective in reducing breast cancer mortality in women aged 40 to 49 years after 10 to 12 years of follow-up, but the same benefit could probably be achieved by beginning screening at menopause or 50 years of age. (<i>JAMA</i>. 1995;273:149-154)

The association between physician experience and the accuracy of screening mammography in community practice is not well studied. We identified characteristics of U.S. physicians associated with the accuracy of screening mammography.Data were obtained from the Breast Cancer Surveillance Consortium and the American Medical Association Master File. Unadjusted mammography sensitivity and specificity were calculated according to physician characteristics. We modeled mammography sensitivity and specificity by multivariable logistic regression as a function of patient and physician characteristics. All statistical tests were two-sided.We studied 209 physicians who interpreted 1,220,046 screening mammograms from January 1, 1995, through December 31, 2000, of which 7143 (5.9 per 1000 mammograms) were associated with breast cancer within 12 months of screening. Each physician interpreted a mean of 6011 screening mammograms (95% confidence interval [CI] = 4998 to 6677), including a mean of 34 (95% CI = 28 to 40) from women diagnosed with breast cancer. The mean sensitivity was 77% (range = 29%-97%), and the mean false-positive rate was 10% (range = 1%-29%). After adjustment for the patient characteristics of those whose mammograms they interpreted, physician characteristics were strongly associated with specificity. Higher specificity was associated with at least 25 years (versus less than 10 years) since receipt of a medical degree (for physicians practicing for 25-29 years, odds ratio [OR] = 1.54, 95% CI = 1.14 to 2.08; P = .006), interpretation of 2500-4000 (versus 481-750) screening mammograms annually (OR = 1.30, 95% CI = 1.06 to 1.59; P = .011) and a high focus on screening mammography compared with diagnostic mammography (OR = 1.59, 95% CI = 1.37 to 1.82; P<.001). Higher overall accuracy was associated with more experience and with a higher focus on screening mammography. Compared with physicians who interpret 481-750 mammograms annually and had a low screening focus, physicians who interpret 2500-4000 mammograms annually and had a high screening focus had approximately 50% fewer false-positive examinations and detected a few less cancers.Raising the annual volume requirements in the Mammography Quality Standards Act might improve the overall quality of screening mammography in the United States.

In randomized controlled trials, screening mammography has been shown to reduce mortality from breast cancer about 25% to 30% among women aged 50 to 69 years after only five to six years from the initiation of screening. Among women aged 40 to 49 years, trials have reported no reduction in breast cancer mortality after seven to nine years from the initiation of screening; after 10 to 14 years there is a 16% reduction in breast cancer mortality. Given that the incidence of breast cancer for women aged 40 to 49 years is lower and the potential benefit from mammography screening smaller and delayed, the absolute number of deaths prevented by screening women aged 40 to 49 years is much less than in screening women aged 50 to 69 years. Because the absolute benefit of screening women aged 40 to 49 years is small and there is concern that the harms are substantial, the focus should be to help these women make informed decisions about screening mammography by educating them of their true risk of breast cancer and the potential benefits and risks of screening.

The association between mammographic breast density and breast cancer risk may be the result of genetic and/or environmental factors that determine breast density. We reasoned that if the genetic factors that underlie breast density increase breast cancer risk, then breast density should be associated with family history of breast cancer. Therefore, we determined the association between mammographic density and family history of breast cancer among women in the San Francisco Mammography Registry. Mammographic density was classified using the four BI-RADS criteria: 1 = almost entirely fatty, 2 = scattered fibroglandular tissue, 3 = heterogeneously dense, and 4 = extremely dense. We adjusted for age, body mass index, hormone replacement therapy use, menopause status, and personal history of breast cancer. Compared with women with BI-RADS 1 readings, women with higher breast density were more likely to have first-degree relatives with breast cancer (BI-RADS 2, odds ratio [OR] = 1.37, 95% confidence interval [CI] = 0.96 to 1.89; BI-RADS 3, OR = 1.70, 95% CI = 1.19 to 2.40; BI-RADS 4, OR = 1.70, 95% CI = 1.05 to 2.71). Thus, the genetic factors that determine breast density may determine breast cancer risk.

Background: Because approximately 1 in 10 women with a breast lump or abnormal mammography result will have breast cancer, a series of decisions must be taken by a primary care practitioner to exclude or establish a diagnosis of breast cancer among these women. Purpose: To determine the most accurate and least invasive means to evaluate an abnormal mammography result and a palpable breast abnormality. Data Source: MEDLINE search (January 1966 to March 2003) for articles and reviews describing the accuracy of clinical examination, biopsy procedures, and radiographic examination for patients with abnormal mammography results or palpable breast abnormalities. Study Selection: The authors reviewed abstracts and selected articles that provided relevant primary data. Studies were included if 1) mammography, fine-needle aspiration biopsy, or core-needle biopsy was performed before a definitive diagnosis was obtained; 2) the study sample included 100 or more women; and 3) breast cancer status was determined from histopathology review of excisional biopsy specimens, from linkage with a state cancer registry or the Surveillance, Epidemiology, and End Results program, or from clinical follow-up of 95% or more of the study sample. Data Extraction: One investigator abstracted results. Methods were evaluated for major potential biases, but methodologic scoring was not performed. Data Synthesis: Likelihood ratios for first screening mammography were 0.1 for the Breast Imaging Reporting and Data System (BI-RADS) assessment category negative or benign finding, 1.2 for probably benign finding, 7 for need additional imaging evaluation, 125 for suspicious abnormality, and 2200 for highly suggestive of malignancy. For fine-needle aspiration biopsy of a palpable lump performed by formally trained physicians, the likelihood ratio was infinity for an assessment of malignant, 2.6 for atypical/suspicious, and 0.02 for benign. When diagnostic mammography was used to evaluate a palpable lump or nonpalpable breast abnormality, the positive likelihood ratios were 5.6 and 9.4, and the negative likelihood ratios were 0.15 and 0.19, respectively. Conclusions: Women whose screening mammography results are interpreted as suspicious abnormality or highly suggestive of malignancy have a high risk for breast cancer and should undergo core-needle biopsy or needle localization with surgical biopsy. Women whose screening mammography results are interpreted as need additional imaging evaluation have a moderate risk for breast cancer and should undergo diagnostic mammography or ultrasonography to decide whether a nonpalpable breast lesion should be biopsied. Women whose screening mammography results are interpreted as probably benign finding have a low risk for breast cancer and can undergo follow-up mammography in 6 months. Either fine-needle aspiration biopsy or ultrasonography is recommended as the first diagnostic test of a palpable breast abnormality to distinguish simple cysts from solid masses. Fine-needle aspiration biopsy also allows characterization of a solid mass. Diagnostic mammography does not help determine whether a palpable breast mass should be biopsied and should not affect the decision to perform a biopsy.

We determined the risk of breast cancer and tumor characteristics among current postmenopausal hormone therapy users compared with nonusers, by duration of use.From January 1996 to December 2000, data were collected prospectively on 374,465 postmenopausal women aged 50 to 79 years who underwent screening mammography. We calculated the relative risk (RR) of breast cancer (invasive or ductal carcinoma-in-situ) and type of breast cancer within 12 months of postmenopausal therapy use among current hormone users with a uterus (proxy for estrogen and progestin use) and without a uterus (proxy for estrogen use), compared with nonusers.Compared with nonusers, women using estrogen and progestin for >/= 5 years were at increased risk of breast tumors of stage 0 or I (RR, 1.51; 95% CI, 1.37 to 1.66), stage II or higher (RR, 1.46; 95% CI, 1.30 to 1.63), size </= 20 mm (RR, 1.59; 95% CI, 1.43 to 1.76), size greater than 20 mm (RR, 1.24; 95% CI, 1.09 to 1.42), grade 1 or 2 (RR, 1.60; 95% CI, 1.44 to 1.77), grade 3 or 4 (RR, 1.54; 95% CI, 1.37 to 1.73), and estrogen receptor-positive (RR, 1.72; 95% CI, 1.55 to 1.90). Estrogen-only users were slightly more likely to have estrogen receptor-positive breast cancer compared with nonusers (RR, 1.14; 95% CI, 1.06 to 1.23).Use of estrogen and progestin postmenopausal hormone therapy for five years or more increased the likelihood of developing breast cancer, including both tumors with favorable prognostic features and tumors with unfavorable prognostic features.

A major health priority is to increase colorectal cancer screening, and colonoscopy has become an increasingly important method of screening. The Medicare program began coverage for colonoscopy for average risk individuals in 2001.We sought to examine whether overall colorectal cancer screening increased over time and whether these increases were a result of increased utilization of all methods or a result of greater use of colonoscopy but reduced use of other methods, whether the enactment of Medicare coverage was associated with an increase in colonoscopy among Medicare enrollees, and whether these trends equally affected subpopulations.We used nationally representative data from the 2000 and 2003 National Health Interview Surveys and analyzed data using used chi, difference-in-differences tests, and logistic regression analyses to examine whether screening rates differed between 2000 and 2003.The percentage of individuals being screened for colorectal cancer using any method increased modestly from 2000 to 2003 (3%), with increases a result of increased use of colonoscopy and a reduction in the use of other methods. Increases in colonoscopy use were significant among all populations except the insured, non-Medicare population with low incomes. Among Medicare enrollees with high/middle incomes, colonoscopy use increased 14% from 2000 to 2003 compared with an increase of only 7% among low-income groups, which was a significant difference (P < 0.01). Similarly, among insured, non-Medicare enrollees with high/middle incomes, colonoscopy use increased 11% from 2000 to 2003 compared with an increase of only 4% among low-income groups, which also was a significant difference (P < 0.01).Colorectal cancer screening utilization increased modestly from 2000 to 2003, with the increases that primarily were the result of increased colonoscopy use. Increases in colonoscopy use, however, were primarily among high/middle income groups. Although Medicare coverage may have indirectly facilitated the increase in colonoscopy, we could not determine that coverage directly increased screening rates. Screening rates remain modest and lower income individuals continue to be screened less. Topics for future research include approaches to facilitating screening among low-income individuals and evaluating the impact of policy coverage decisions.

To determine whether patient race was associated with timeliness of follow-up after abnormal screening mammography, a retrospective record review of diagnostic tests for women with abnormal screening mammography from a Northern California mobile van program was conducted.The study included 317 women between the ages of 33 and 85 who were reported to have abnormal screening mammography between July 1993 and May 1994. Measurements included patient demographics, screening mammography interpretation, follow-up diagnostic tests, and dates of diagnostic evaluation.Women with abnormal screening mammography underwent a wide variety of diagnostic evaluations. Nonwhite women had significantly longer time (median time, 19 days) from date of index abnormal screening mammography to final disposition compared with white women (median time, 12 days). This racial difference was primarily due to the longer interval between index abnormal screening mammography and first diagnostic test (median time, 15 days for nonwhite women versus 7 days for white women, P < 0.001). The difference persisted when adjusting for patient age, family history of breast cancer, report of palpable mass, and income. The racial difference was similarly significant for each nonwhite subgroup (African American, Latina, and Asian) when compared with white women (P < 0.01).Reasons for less timely follow-up of abnormal mammography among nonwhite women need to be identified. Delays that may be instigated by the patient or be due to her physician or system of care need to be explored further.

Abstract Purpose: Ductal carcinoma in situ (DCIS) is thought to be a nonobligate precursor of invasive cancer. Genomic changes specific to pure DCIS versus invasive cancer, as well as alterations unique to individual DCIS subtypes, have not been fully defined. Experimental Design: Chromosomal copy number alterations were examined by comparative genomic hybridization in 34 cases of pure DCIS and compared with 12 cases of paired synchronous DCIS and invasive ductal cancer, as well as to 146 additional cases of invasive breast cancer of ductal or lobular histology. Genomic differences between high-grade and low/intermediate-grade DCIS, as well as between pure DCIS and invasive cancer, were identified. Results: Pure DCIS showed almost the same degree of chromosomal instability as invasive ductal cancers. A higher proportion of low/intermediate-grade versus high-grade DCIS had loss of 16q (65 versus 12%, respectively; P = 0.002). When compared with lower grade DCIS, high-grade DCIS exhibited more frequent gain of 17q (65 versus 41%; P = 0.15) and higher frequency loss of 8p (77 versus 41%; P = 0.04). Chromosomal alterations in those cases with synchronous DCIS and invasive ductal cancer showed a high degree of shared changes within the two components. Conclusions: DCIS is genetically advanced, showing a similar degree of chromosomal alterations as invasive ductal cancer. The pattern of alterations differed between high- and low/intermediate-grade DCIS, supporting a model in which different histological grades of DCIS are associated with distinct genomic changes. These regions of chromosomal alterations may be potential targets for treatment and/or markers of prognosis.

Ductal carcinoma in situ (DCIS) accounts for approximately 12% of newly diagnosed breast cancers. Knowledge of the factors that predict who will be diagnosed with DCIS is very limited.The goal of this study was to determine risk factors associated with DCIS and whether these risk factors are similar to those associated with invasive breast cancer.We conducted a cross-sectional study of 39,542 women aged 30 years and older who underwent a screening mammographic examination at the University of California San Francisco Mobile Mammography Screening Program from April 1985 through September 1995. A breast cancer risk profile and clinical history were obtained for each woman. Follow-up after abnormal mammography was performed to determine the presence of DCIS or invasive breast cancer by contacting the women's physicians and by linkage to the regional Surveillance, Epidemiology, and End Results cancer registry. Multivariate analysis was performed by the use of polytomous logistic regression. Two-sided statistical tests were used to determine P values.Among women aged 30-49 years, a family history of breast cancer (i.e., at least one affected first degree relative) was associated with an increased risk of DCIS (Odds ratio [OR] = 2.4; 95% confidence interval [CI] = 1.1-4.9) and body mass index greater than or equal to 25 kg/m2 was associated with a decreased risk of DCIS (OR = 0.4, 95% CI = 0.2 to 0.9). For each of these factors, there was a trend in the same direction bordering on statistical significance for invasive cancer (ORs = 1.7 [95% CI = 0.9-3.4] and 0.6 [95% CI = 0.3-1.1], respectively). Report of a palpable mass was associated with an increased risk of invasive cancer among women aged 30-49 years (OR = 12.0; 95% CI = 7.1-20.0); there was a trend in the same direction for DCIS (OR = 2.0; 95% CI = 0.8-5.1), but the association was much stronger for invasive disease than for DCIS (OR = 6.0; 95% CI = 2.1-18.0; P = .001). Among women aged 50 years and older, family history of breast cancer and nulliparity or age at birth of first child of 30 years or older increased the risk of both DCIS (ORs = 2.2 [95% CI = 1.0-4.2] and 2.3 [95% CI = 1.3-3.8], respectively) and invasive breast cancer (ORs = 1.5 [95% CI = 1.0-2.2] and 1.6 [95% CI = 1.2-2.1], respectively). Report of a palpable mass was not associated with an increased risk of DCIS among women 50 years and older, but it was strongly associated with an increased risk of invasive cancer (OR = 9.3; 95% CI = 6.0-14.0). Increasing age was associated with an increased risk of both DCIS and invasive cancer among women aged 30-49 years, but the association was stronger for invasive disease; a trend in the same direction bordering on statistical significance was observed for women aged 50 years and older.Risk factors for DCIS are similar to those for invasive breast cancer.More research is needed to better understand the malignant potential of DCIS lesions and factors that predict which lesions will become invasive breast cancer if left untreated.

To determine the efficacy of periabortal antibiotics in preventing postabortal upper genital tract infection using data from published trials.We performed a literature search of all studies published from January 1966 to September 1, 1994, using MEDLINE, and we manually searched bibliographies of published articles. MEDLINE search terms included: abortion, infection, prophylaxis, antibiotics, pelvic inflammatory disease (PID), and suction curettage.Randomized, controlled trials comparing antibiotics with placebo in women undergoing suction curettage abortion before 16 weeks' gestation were identified.Data were extracted independently by two reviewers, one of whom was blinded to journal, year of publication, authors, and institution. Data from 12 studies were combined using meta-analytic techniques based on a fixed-effects model. The overall summary relative risk (RR) estimate for developing postabortal upper genital tract infection in women receiving antibiotic therapy compared with those receiving placebo was 0.58 (95% confidence interval [CI] 0.47-0.71). Of high-risk women, those with a history of PID had a summary RR estimate of 0.56 (95% CI 0.37-0.84); women with a positive chlamydia culture at abortion had a summary RR estimate of 0.38 (95% CI 0.15-0.92). Of low-risk women, those with no reported history of PID had a summary RR estimate of 0.65 (95% CI 0.47-0.90); in women with a negative chlamydia culture, the summary RR estimate was 0.63 (95% CI 0.42-0.97). The lowest summary RR estimate was among women drawn from populations with a low incidence (5-6%) of postabortal infection (summary RR estimate 0.22, 95% CI 0.11-0.42). The overall 42% decreased risk of infection in women given periabortal antibiotics is similar to the risk reduction demonstrable when only studies published before 1985 are combined (summary RR estimate 0.63, 95% CI 0.44-0.89).Our meta-analysis revealed a substantial protective effect of antibiotics in all subgroups of women undergoing therapeutic abortion, even women in low-risk groups. No more placebo-controlled trials should be performed, because women assigned to placebo are exposed to preventable risk. Routine use of periabortal antibiotics in the United States may prevent up to half of all cases of postabortal infections.

Abstract BACKGROUND To the authors' knowledge, a comprehensive analysis of pathology outcomes after screening mammography, as it is practiced clinically in the U.S. general population, has not been performed. METHODS Breast Cancer Surveillance Consortium data from 1996–2001 were used to identify pathology specimens that were obtained within 1 year of screening mammograms performed on 786,846 women ages 40–89 years. The pathology results were classified as invasive carcinoma, ductal carcinoma in situ (DCIS), or benign. The associations between overall pathology outcomes and invasive tumor size and lymph node status were analyzed by age and mammography assessment category. RESULTS The rates of both recommending and performing a biopsy varied little with age. The 1,664,032 screening mammograms were followed by 26,748 known biopsies (1.6%) and 8815 diagnoses of breast carcinoma (0.53%). Overall, 81% of carcinomas were invasive, and 78% of those were pathologically lymph node‐negative tumors, in contrast to the 66% prevalence observed in the Surveillance, Epidemiology, and End Results (SEER) data during the same period. Most invasive tumors measured between 0 mm and 10 mm (35%) or between 11 mm and 20 mm (36%) in greatest dimension, and 92% and 78% were lymph node‐negative tumors, respectively: Biopsy results that were classified as malignant increased with age ( P &lt; 0.0001) and were most likely to follow Breast Imaging, Reporting, and Diagnosis System Category 5 and 4 assessments, respectively. Ductal hyperplasia (19.6%), fibroadenoma (18.5%), and other benign findings (56.1%) were the most common benign diagnoses. CONCLUSIONS Pathologically negative lymph nodes were more prevalent in this mammographically screened population than in the overall SEER population. The prevalence of invasive carcinoma, DCIS, and benign findings presented herein establish a range of expected biopsy outcomes for women after screening mammography in the general U.S. population. Cancer 2006. © 2006 American Cancer Society.

The density of breast tissue on a mammogram is a strong predictor of breast cancer risk and may reflect cumulative estrogen effect on breast tissue. Endogenous and exogenous estrogen exposure increases the risk of estrogen receptor (ER)-positive breast cancer. We determined if mammographic density is associated more strongly with ER-positive breast cancer than with ER-negative breast cancer.We analyzed data from 44,811 participants in the San Francisco Mammography Registry of whom 701 developed invasive breast cancer. Mammographic density was measured using the Breast Imaging Reporting and Data System (BI-RADS) classification system (1 = almost entirely fat, 2 = scattered fibroglandular, 3 = heterogeneously dense, 4 = extremely dense). We tested for associations between mammographic density and ER-positive and ER-negative breast cancer separately. Analyses were adjusted for age, body mass index, postmenopausal hormone use, family history of breast cancer, menopausal status, parity, and race/ethnicity.Mammographic density was strongly associated with both ER-positive and ER-negative breast cancers. Compared with women with BI-RADS 2, women with BI-RADS 1 (lowest density) had a lower risk of ER-positive cancer [adjusted hazard ratio (HR), 0.28; 95% confidence interval (95% CI), 0.16-0.50] and ER-negative cancer (adjusted HR, 0.17; 95% CI, 0.04-0.70). Women with BI-RADS 4 (highest density) had an increased risk of ER-positive breast cancer (adjusted HR, 2.21; 95% CI, 1.64-3.04) and an increased risk of ER-negative breast cancer (adjusted HR, 2.21; 95% CI, 1.16-4.18).Surprisingly, women with high mammographic density have an increased risk of both ER-positive and ER-negative breast cancers. The association between mammographic density and breast cancer may be due to factors besides estrogen exposure.

To determine the prevalence of Mycobacterium tuberculosis infection and the incidence of tuberculosis in HIV-infected and uninfected urban Rwandan women, 460 HIV-positive and 998 HIV-negative childbearing women were recruited from pediatric and prenatal care clinics and were enrolled in a prospective study in 1988 and followed for 2 yr. Tuberculin testing was administered 12 to 18 months after enrollment. Fifty-three percent of HIV-negative women had positive tuberculin tests (induration > or = 10 mm), with higher rates among older women and among women who had received BCG vaccine. Only 21% of HIV-positive women had positive tuberculin tests, with no relationship to BCG vaccine. Follow-up was available for 93% of subjects. Tuberculosis was diagnosed in 20 HIV-positive women and in two HIV-negative women. Features associated with an increased risk of tuberculosis among HIV-positive women included: age > or = 30, body mass index in the lowest quartile, low income, erythrocyte sedimentation rate > 75, positive tuberculin test, and chronic cough, chronic fever, and weight loss. Among Rwandan women who are infected with HIV, approximately half of those who are infected with M. tuberculosis do not have positive tuberculin tests. The rate ratio for development of tuberculosis among HIV-positive women was 22 (95% CI, 5 to 92). New algorithms are needed to improve the early detection of tuberculosis among HIV-positive patients in Africa.This study determines the prevalence of Mycobacterium tuberculosis (TB) infection and the incidence among HIV infected and uninfected women in urban Rwanda. The sample population includes 460 HIV-positive women and 998 HIV-negative women who were recruited from pediatric and prenatal care clinics at the Centre Hospitalier de Kigali. The sample is considered representative of childbearing women from the capital city. Initial interviews were conducted in 1988 and followed-up in 1990. HIV-1 diagnosis was determined on the basis of enzyme immunoassay and western blot tests or indirect immunofluorescence that showed reactivity to both a core protein and an envelope protein. A positive tuberculin test was defined as induration of 10 mm or more. Routine visits were made every 6 months. Comparisons were made between women who were HIV positive at their first HIV test (250 women), women who were negative at their first test but seroconverted between the first HIV test and the TB test 3 years later (80 women), and women who were HIV negative at the time of TB testing (687). 55% of HIV-negative women had positive tests with induration of more than 10 mm. 25% of HIV-positive women and 66% of HIV-negative women had TB tests with over 5 mm induration. 31% of HIV-positive women and 70% of HIV-negative women had induration of over 2 mm. 77% of women had TB vaccine scars. Prevalence of a positive test was significantly higher in the HIV-negative vaccinated group than in the nonvaccinated group. The proportion with low white cell counts, low lymphocyte counts, and high sedimentation rates was higher among HIV-positive women than HIV-negative women. During the 2-year follow-up period, 20 of the 401 HIV-positive women and 2 of the 917 HIV-negative women were diagnosed with TB. The risk ratio was 22.9. The incidence of TB was 3 times higher among women who had been infected with HIV at least 18 months than among women who had been infected less than 18 months. Low income and low body mass were associated with an increased risk of TB. 9 out of 17 HIV-infected women with TB had negative TB tests.

To examine changes in screening mammogram interpretation as radiologists with and radiologists without fellowship training in breast imaging gain clinical experience.In an institutional review board-approved HIPAA-compliant study, the performance of 231 radiologists who interpreted screen-film screening mammograms from 1996 to 2005 at 280 facilities that contribute data to the Breast Cancer Surveillance Consortium was examined. Radiologists' demographic data and clinical experience levels were collected by means of a mailed survey. Mammograms were grouped on the basis of how many years the interpreting radiologist had been practicing mammography, and the influence of increasing experience on performance was examined separately for radiologists with and those without fellowship training in breast imaging, taking into account case-mix and radiologist-level differences.A total of 1 599 610 mammograms were interpreted during the study period. Performance for radiologists without fellowship training improved most during their 1st 3 years of clinical practice, when the odds of a false-positive reading dropped 11%-15% per year (P < .015) with no associated decrease in sensitivity (P > .89). The number of women recalled per breast cancer detected decreased from 33 for radiologists in their 1st year of practice to 24 for radiologists with 3 years of experience to 19 for radiologists with 20 years of experience. Radiologists with fellowship training in breast imaging experienced no learning curve and reached desirable goals during their 1st year of practice.Radiologists' interpretations of screening mammograms improve during their first few years of practice and continue to improve throughout much of their careers. Additional residency training and targeted continuing medical education may help reduce the number of work-ups of benign lesions while maintaining high cancer detection rates.

To examine whether U.S. radiologists' interpretive volume affects their screening mammography performance.Annual interpretive volume measures (total, screening, diagnostic, and screening focus [ratio of screening to diagnostic mammograms]) were collected for 120 radiologists in the Breast Cancer Surveillance Consortium (BCSC) who interpreted 783 965 screening mammograms from 2002 to 2006. Volume measures in 1 year were examined by using multivariate logistic regression relative to screening sensitivity, false-positive rates, and cancer detection rate the next year. BCSC registries and the Statistical Coordinating Center received institutional review board approval for active or passive consenting processes and a Federal Certificate of Confidentiality and other protections for participating women, physicians, and facilities. All procedures were compliant with the terms of the Health Insurance Portability and Accountability Act.Mean sensitivity was 85.2% (95% confidence interval [CI]: 83.7%, 86.6%) and was significantly lower for radiologists with a greater screening focus (P = .023) but did not significantly differ by total (P = .47), screening (P = .33), or diagnostic (P = .23) volume. The mean false-positive rate was 9.1% (95% CI: 8.1%, 10.1%), with rates significantly higher for radiologists who had the lowest total (P = .008) and screening (P = .015) volumes. Radiologists with low diagnostic volume (P = .004 and P = .008) and a greater screening focus (P = .003 and P = .002) had significantly lower false-positive and cancer detection rates, respectively. Median invasive tumor size and proportion of cancers detected at early stages did not vary by volume.Increasing minimum interpretive volume requirements in the United States while adding a minimal requirement for diagnostic interpretation could reduce the number of false-positive work-ups without hindering cancer detection. These results provide detailed associations between mammography volumes and performance for policymakers to consider along with workforce, practice organization, and access issues and radiologist experience when reevaluating requirements.