Bonnie C. Yankaskas

Individual and Combined Effects of Age, Breast Density, and Hormone Replacement Therapy Use on the Accuracy of Screening Mammography

Context High breast density increases breast cancer risk and the difficulty of reading mammograms. Breast density decreases with age and increases with postmenopausal hormone therapy use. The interplay of breast density, age, and hormone therapy use on the accuracy of mammography is uncertain. Contribution For women with fatty breasts, the sensitivity of mammography was 87% and the specificity was 96.9%. For women with extremely dense breasts, the sensitivity of mammography was 62.9% and the specificity was 89.1%. Sensitivity increased with age. Hormone therapy use was not an independent predictor of accuracy. Implications The accuracy of screening mammography is best in older women and in women with fatty breasts. Postmenopausal hormone therapy affects mammography accuracy only through its effects on breast density. The Editors Mammographic breast density may be the most undervalued and underused risk factor in studies investigating breast cancer occurrence (1). The risk for breast cancer is four to six times higher in women with dense breasts (2, 3). Breast density may also decrease the sensitivity and, thus, the accuracy of mammography. Radiographically dense breast tissue may obscure tumors, which increases the difficulty of detecting breast cancer. In addition, dense breast tissue may mimic breast cancer on mammography (4), which increases recall rates (4-12), reduces specificity, and compromises the benefit of screening in women with dense breasts (such as women who use HRT or who are premenopausal) (6, 8, 13). Breast density is affected by age, use of hormone replacement therapy (HRT), menstrual cycle phase, parity, body mass index, and familial or genetic tendency (4, 5, 14-21). Studies show that the sensitivity of mammography increases with age (6-8), especially in postmenopausal women whose breasts are less dense (8). Earlier research has examined the individual effect of each factor we have described, but most studies could not adequately examine the interaction of these factors because of insufficient sample size (4-15). Studies conducted in the 1970s with data from the Breast Cancer Detection Demonstration Project (22) and New York Health Insurance Plan (23) are based on mammographic examinations that are very different from those performed using current technology. The Mammography Quality Standards Act (24) and the standardized reporting efforts of the American College of Radiology (25) have resulted in important improvements in mammography that necessitate reexamination. We used data from the National Cancer Institutes Breast Cancer Surveillance Consortium (BCSC) (26) on 329 495 women in the United States who had 463 372 screening mammograms, which were linked to 2223 cases of breast cancer. Our goal was to examine the individual and combined effects of age, breast density, and HRT use on mammographic accuracy. This large data set provides a unique opportunity to examine these issues in women undergoing screening mammography in the United States, especially women younger than 50 years of age and older than 80 years of age. We chose to study a sample that had been recently screened (within the previous 2 years) so that the risk for breast cancer would be similar to that in women who receive routine mammographic screening. Methods Data Collection Initially, we included data on women 40 to 89 years of age who underwent screening mammography between 1996 and 1998, as submitted by seven registries in the BCSC (North Carolina; New Mexico; New Hampshire; Vermont; Colorado; Seattle, Washington; and San Francisco, California). We included women who reported having previous mammography or who had a previous mammographic examination recorded in a registry within 2 years of the index mammogram. Women with breast implants or a personal history of breast cancer were excluded. In addition, women with missing data for age (<1%), breast density (27%), or HRT use (21%) were excluded (36% of all data). Demographic characteristics, clinical characteristics, and accuracy measures for women missing any of this information were very similar to those for women with complete data. All registries obtained institutional review board approval for data collection and linkage procedures, and careful data management, processing, and security procedures were followed (27). Consortium mammography registries and data collection procedures are described elsewhere (26). Briefly, seven institutions in seven states receive funding from the National Cancer Institute to maintain mammography registries that cover complete or contiguous portions of each state. Data are collected similarly at each registry. Demographic and history information is collected from women at the time of mammography by using a self-administered survey or face-to-face interview methods. Variables include date of birth, history of previous mammography, race or ethnicity, current use of HRT (prescription medication used to treat perimenopausal and postmenopausal symptoms), and menopausal status. We assumed that women 55 years of age and older were perimenopausal or postmenopausal. For women 40 to 54 years of age, premenopausal status was defined as having regular menstrual periods with no HRT use; perimenopausal or postmenopausal status was defined as either removal of both ovaries or uncertainty about whether periods had stopped permanently. This latter category was further classified into HRT users and nonusers. These definitions recognize that HRT users with intact uteri may have menstrual-like bleeding. Additional data, including mammographic breast density, mammographic assessment, and recommended follow-up (based on the American College of Radiology Breast Imaging Reporting and Data System [BI-RADS]), are collected from the technologist and radiologist at the time of mammography (25). Pathology data are collected from one or more sources: regional Surveillance, Epidemiology, and End Results (SEER) programs, state cancer registries, or pathology laboratories. Design We included all screening examinations for women who met the described criteria and who had at least one screening mammogram in 1996, 1997, or 1998. These years were chosen to ensure 1-year follow-up for cancer reporting and to account for routine reporting schedules in obtaining data from SEER and state cancer registries. We classified mammography as screening if a radiologist indicated that the examination was a bilateral, two-view (craniocaudal and mediolateral) examination. To avoid including diagnostic examinations, we excluded any breast imaging study performed within the previous 9 months. Because our goal was to study routine screening, mammographic accuracy was calculated on the basis of the initial assessment of the screening views alone (only 6% required supplemental imaging). Interpretation codes included BI-RADS assessments of 0 (incomplete), 1 (negative), 2 (negative, benign), 3 (probably benign), 4 (suspicious abnormality), or 5 (highly suggestive of malignancy). In cases in which the initial screening visit included both a screening examination and additional imaging to determine an assessment, the initial screening assessment was assigned a 0 (incomplete assessment) for analysis. When a woman had different assessments by breast, we chose the highest-level assessment for the woman as a whole (woman-level assessment) on the basis of the following hierarchy of overall level of radiologic concern: 1 < 2 < 3 < 0 < 4 < 5. We defined a screening examination as positive if it was assigned a BI-RADS assessment code of 0, 4, or 5. An assessment code of 3 associated with a recommendation for immediate additional imaging, biopsy, or surgical evaluation was also classified as positive. Although the BI-RADS recommendation for a code 3 (probably benign) is short-interval follow-up, immediate work-up was recommended in 37% of code 3s in the pooled BCSC data; therefore, this assessment is more consistent with a BI-RADS code of 0 (incomplete assessment) (28). We defined a screening examination as negative if it received a BI-RADS assessment code of 1, 2, or 3 when associated with short-interval follow-up only or routine follow-up. We classified breast pathology outcomes as cancer if pathology or cancer registry data identified a diagnosis of invasive or ductal carcinoma in situ. Lobular carcinoma in situ (<0.01% of cancer cases in our pooled data) was not considered a diagnosis of cancer in our analyses because it cannot be detected by mammography and is not treated. Examinations were classified as false-positive when the assessment was positive and breast cancer was not diagnosed within the follow-up period (365 days after the index screening examination or until the next examination, whichever occurred first). Examinations were classified as true-positive when the assessment was positive and cancer was diagnosed. A false-negative examination was a negative assessment with a diagnosis of cancer within the follow-up period. A true-negative examination was a negative assessment with no subsequent diagnosis of cancer within the follow-up period. Radiographic breast density was defined according to BI-RADS as follows: 1) almost entirely fatty, 2) scattered fibroglandular tissue, 3) heterogeneously dense, and 4) extremely dense (25). We excluded one registry that collects two categories of breast density (dense or not dense) at some facilities. Statistical Analysis For age, breast density, and HRT groups, we calculated rates of incident breast cancer, rates of breast cancer detected by mammography, and rates of missed cancer. To examine the nonlinear effects of age, we categorized age into 10-year groups, except for ages 40 to 59, which were divided into 5-year groups to explore changes around menopause. Accuracy indices included sensitivity and specificity. Sensitivity was calculated as true-positive/(true-positive + false-negative). Specificity was calculated as true-negative/(true-negative + false

Cumulative Probability of False-Positive Recall or Biopsy Recommendation After 10 Years of Screening Mammography: A Cohort Study

BACKGROUND 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. OBJECTIVE 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. DESIGN Prospective cohort study. SETTING 7 mammography registries in the National Cancer Institute-funded Breast Cancer Surveillance Consortium. PARTICIPANTS 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. MEASUREMENTS False-positive recalls and biopsy recommendations stage distribution of incident breast cancer. RESULTS 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. LIMITATIONS 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. CONCLUSION 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. PRIMARY FUNDING SOURCE National Cancer Institute.

Comparative Effectiveness of Digital Versus Film-Screen Mammography in Community Practice in the United States: A Cohort Study

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.

Contrast-limited adaptive histogram equalization: speed and effectiveness

An experiment intended to evaluate the clinical application of contrast-limited adaptive histogram equalization (CLAHE) to chest computer tomography (CT) images is reported. A machine especially designed to compute CLAHE in a few seconds is discussed. It is shown that CLAHE can be computed in 4 s after 5-s loading time using the specially designed parallel engine made from a few thousand dollars worth of off-the-shelf components. The processing appears to be useful for a wide range of medical images, but the limitations of observer calibration make it impossible to demonstrate such usefulness by agreement experiments.<<ETX>>

Prognostic Characteristics of Breast Cancer Among Postmenopausal Hormone Users in a Screened Population

PURPOSE We determined the risk of breast cancer and tumor characteristics among current postmenopausal hormone therapy users compared with nonusers, by duration of use. METHODS 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. RESULTS 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). CONCLUSION 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.

Epidemiology of Breast Cancer in Young Women

Breast cancer is a rare disease in young women, yet is the leading cause of cancer deaths in all ethnic groups in the United States and many parts of the world. The epidemiology for breast cancer in young women is reviewed, focusing on women under 40, prior to the recommended screening age. Specific age comparison groups used and results for young women vary in the literature, yet there are some common results. Young women have low incidence rates of breast cancer compared to older women. However, cancer incidence increases at a faster rate with increasing age in young women. Their cancers tend to be larger and higher grade with poorer prognostic characteristics, resulting in a higher risk of recurrence and death from breast cancer when compared to older women. Many of the usual risk factors for breast cancer in older women also increase risk in younger women including increasing age, Black race, family history, later age at first birth and menarche, radiation exposure and lack of physical activity. Risk factors that have specific relevance to young women include reproductive factors, history of induced abortion or miscarriage, oral contraceptive use, smoking, and radiation exposure, most specifically for treatment of Hodgkin Disease.

International comparison of performance measures for screening mammography: can it be done?

Objective: Published screening mammography performance measures vary across countries. An international study was undertaken to assess the comparability of two performance measures: the recall rate and positive predictive value (PPV). These measures were selected because they do not require identification of all cancers in the screening population, which is not always possible. Setting: The screening mammography programs or data registries in 25 member countries of the International Breast Cancer Screening Network (IBSN). Methods: In 1999 an assessment form was distributed to IBSN country representatives in order to obtain information on how screening mammography was performed and what specific data related to recall rates and PPV were collected. Participating countries were then asked to provide data to allow calculation of recall rates, PPV and cancer detection rates for screening mammography by age group for women screened in the period 1997–1999. Results: Twenty-two countries completed the assessment form and 14 countries provided performance data. Differences in screening mammography delivery and data collection were evident. For most countries, recall rates were higher for initial than for subsequent mammograms. There was no consistent relationship of initial to subsequent PPV, although PPV generally decreased as the recall rate increased. Recall rates decreased with increasing age, while PPV increased as age increased. Conclusion: Similar patterns for mammography performance measures were evident across countries. However, the development of a more standardized approach to defining and collecting data would allow more valid international comparisons, with the potential to optimize mammography performance. At present, international comparisons of performance should be made with caution due to differences in defining and collecting mammography data.

Patterns of Breast Magnetic Resonance Imaging Use in Community Practice

IMPORTANCE 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. OBJECTIVE To describe patterns of breast MRI use in US community practice during the period 2005 through 2009. DESIGN, SETTING, AND PARTICIPANTS 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. MAIN OUTCOMES AND MEASURES 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. RESULTS 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. CONCLUSIONS AND RELEVANCE 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.

The use of census data for determining race and education as SES indicators: a validation study.

PURPOSE Little research has examined the validity of using census data to determine an individuals socio-economic status (SES), as measured by race and educational level. This study assessed the accuracy of using aggregate level data from United States Census Block Groups in determining race and education SES indicators in a cohort of women from North Carolina. METHODS The study analyzed patient data from the Carolina Mammography Registry and 1990 United States Census in 21 North Carolina counties. Women (n = 39,546) were geocoded to their census block group and their block group characteristics (surrogate measures) were validated with their self-reported values on race and education. An analysis was performed to explore whether using these surrogate measures would affect measured associations with the self-reported values. RESULTS Whites were accurately identified (84.8%) more consistently than Blacks (14.1%) regardless of their urban/rural status. Women without a high school diploma or equivalent were accurately identified (56.2%) more often than those with higher education levels (45.9%). Analyses using the surrogate measures were significantly different than the true values according to chi-square statistics. CONCLUSIONS Use of census data to derive SES indicators tends to be more accurate for the majority than the minority population. Researchers must be sensitive to the ecologic fallacy when using aggregate level data such as the census to determine individual level characteristics.

Sensitivity and specificity of computed tomography for the detection of adrenal metastatic lesions among 91 autopsied lung cancer patients

The ability of computed tomography (CT) to detect metastatic lesions in adrenal glands was evaluated on 91 autopsied lung cancer patients who died in 11 hospitals in the eastern United States and Canada from January 1983 to February 1988. Abdominal CT scans within 90 days of death were reviewed twice by two radiologists blinded to the autopsy diagnosis. The likelihood of metastatic spread in each adrenal gland was scored on a five‐level scale. Histopathologic findings at autopsy were used to establish the presence or absence of metastases. The sensitivity of CT was low. Among 53 adrenal glands with proven metastatic lesions, the proportion with positive CT scans varied from 20.0% to 41.1%, according to the positivity threshold. In contrast, the specificity of CT was high, even at relaxed positivity thresholds, from 84.5% to 99.4%. The relatively low sensitivity of CT to detect adrenal metastatic lesions is explained to a large extent by the lack of substantial structural changes in many adrenal glands found to have metastases at autopsy. With a strongly positive CT scan, the probability of an adrenal metastatic lesion is high, and confirmatory adrenal biopsy may not be needed in patients with adenocarcinoma and large cell carcinoma.