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 Institute's 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