Assessing breast cancer risk within the general screening population: developing a breast cancer risk model to identify higher risk women at mammographic screening.

OBJECTIVES: To develop a breast cancer risk model to identify women at mammographic screening who are at higher risk of breast cancer within the general screening population. METHODS: This retrospective nested case-control study used data from a population-based breast screening program (2009-2015). All women aged 40-75 diagnosed with screen-detected or interval breast cancer (n = 1882) were frequency-matched 3:1 on age and screen-year with women without screen-detected breast cancer (n = 5888). Image-derived risk factors from the screening mammogram (percent mammographic density [PMD], breast volume, age) were combined with core biopsy history, first-degree family history, and other clinical risk factors in risk models. Model performance was assessed using the area under the receiver operating characteristic curve (AUC). Classifiers assigning women to low- versus high-risk deciles were derived from risk models. Agreement between classifiers was assessed using a weighted kappa. RESULTS: The AUC was 0.597 for a risk model including only image-derived risk factors. The successive addition of core biopsy and family history significantly improved performance (AUC = 0.660, p < 0.001 and AUC = 0.664, p = 0.04, respectively). Adding the three remaining risk factors did not further improve performance (AUC = 0.665, p = 0.45). There was almost perfect agreement (kappa = 0.97) between risk assessments based on a classifier derived from image-derived risk factors, core biopsy, and family history compared with those derived from a model including all available risk factors. CONCLUSIONS: Women in the general screening population can be risk-stratified at time of screen using a simple model based on age, PMD, breast volume, and biopsy and family history. KEY POINTS: • A breast cancer risk model based on three image-derived risk factors as well as core biopsy and first-degree family history can provide current risk estimates at time of screen. • Risk estimates generated from a combination of image-derived risk factors, core biopsy history, and first-degree family history may be more valid than risk estimates that rely on extensive self-reported risk factors. • A simple breast cancer risk model can avoid extensive clinical risk factor data collection.

The burden of false-positive results in analog and digital screening mammography: experience of the Nova Scotia Breast Screening Program.

PURPOSE: The Canadian Task Force on Preventive Health Care released recommendations for breast cancer screening, in part, based on harms associated with screening. The purpose of this study was to describe the rate of false-positive (FP) screening mammograms and to describe the extent of the investigations after an FP. METHODS: A cohort was identified that consisted of all screening mammograms performed through the Screening Program (2000-2011) with patients ages 40-69 years at screening. Rates of FP screening mammograms were calculated as well as rates of further investigations required, including additional imaging, needle core biopsy, and surgery. Analyses were stratified by 10-year age group, screening status (first vs rescreen), and technology. RESULTS: A total of 608,088 screening mammograms were included. The FP rate varied by age group, and decreased with increasing age (digital, 40-49 years old, FP = 8.0%; 50-59 years old, FP = 6.3%; 60-69 years old, FP = 4.6%). The FP rate also varied by screening status (digital, first screen, FP = 12.0%; rescreen, FP = 5.6%), and this difference was consistent across age groups. The need for further investigation varied by age group, with invasive procedures being more heavily used as women age (digital, rescreen group, surgery: 40-49 years old, 1.1%; 50-59 years old 1.6%, 60-69 years old, 1.8%). CONCLUSIONS: Both the FP screening mammogram rate and the degree to which further investigation was required varied by age group and screening status. Reporting on these rates should form part of the evaluation of screening performance.

A review of interval breast cancers diagnosed among participants of the Nova Scotia Breast Screening Program.

PURPOSE: To conduct a radiologic review of interval breast cancer cases to determine rates of true interval and missed cancers in Nova Scotia, Canada. MATERIALS AND METHODS: This quality assurance project was exempt from institutional review board approval. Interval cancer cases were identified among women aged 40-69 years who were participants in the Nova Scotia Breast Screening Program from 1991 to 2004. For each case, the index negative screening mammogram was reviewed blindly by three radiologists from a pool of experienced radiologists. Cases were identified as those with normal or abnormal findings, the latter being a case that required further investigation. True interval cases were identified as cases in which a minimum of two radiologists reviewed the findings as normal. True interval and missed cancer rates were calculated separately for women according to age group and screening interval (for ages 40-49 years, a 1-year interval; for ages 50-69 years, a 1-year and a 2-year interval). RESULTS: The rate of missed cancers per 1000 women screened was one-half of the true interval rate among women screened annually (for ages 40-49 years, 0.45 vs 0.93; for ages 50-69 years, 1.08 vs 2.22). Among women aged 50-69 years who were screened biennially, the rate of missed cancers per 1000 women screened was one-third of the true interval rate (0.90 vs 3.15). Similarly, the rate of missed cancers per 10,000 screening examinations was one-half of the true interval rate among those 40-49 years old (1.95 vs 3.99) and one-third of the true interval rate among those 50-69 years old (3.34 vs 10.44). CONCLUSION: In screening programs, true interval cancer rates should be differentiated from missed cancer rates as part of ongoing quality assurance.

Breast density scales: the metric matters.

OBJECTIVE: Measures of percent mammographic density (PMD) are often categorized using various density scales. The purpose of this study was to examine information loss associated with the use of categorical density scales. METHODS: Baseline PMD was assessed at 1% precision for 2,374 females. The data were used to create 21-category, 4-category and 2-category density scales. R-squared and root mean square error were used to evaluate the effect of categorizing PMD. The area under the receiver operator characteristic curves were compared between cancer risk models employing solely categorical PMD scales and solely baseline PMD for a subset of females (424 cases, 848 controls). RESULTS: R-squared value decreased from 1.00 (1% PMD) to 0.56 (2-category scale), while root mean square error increased from 0.00 (1% PMD) to 10.83 (2-category scale). The area under the receiver operator characteristic curve decreased from 0.64 for a cancer risk model using 1% PMD to 0.58 for a risk model using a 21-category density scale (p < 0.0001), 0.55 for a 4-category Breast Imaging, Reporting and Data System-like scale (p < 0.0001) and 0.50 for a 2-category Breast Imaging, Reporting and Data System-like scale (high vs low) (p < 0.0001). CONCLUSION: Categorizing PMD measures into categorical density scales leads to a significant loss of information. Indeed, a simple high versus low split of PMD using a 50% cut point yields a cancer risk model with no discriminatory power. Advances in knowledge: Use of categorical mammographic density scales rather than continuous percent mammographic density measures leads to significant loss of information. Breast cancer risk models using categorical mammographic density scales perform more poorly than models using continuous PMD measures.

Consistency of visual assessments of mammographic breast density from vendor-specific "for presentation" images.

Discussions of percent breast density (PD) and breast cancer risk implicitly assume that visual assessments of PD are comparable between vendors despite differences in technology and display algorithms. This study examines the extent to which visual assessments of PD differ between mammograms acquired from two vendors. Pairs of "for presentation" digital mammography images were obtained from two mammography units for 146 women who had a screening mammogram on one vendor unit followed by a diagnostic mammogram on a different vendor unit. Four radiologists independently visually assessed PD from single left mediolateral oblique view images from the two vendors. Analysis of variance, intra-class correlation coefficients (ICC), scatter plots, and Bland-Altman plots were used to evaluate PD assessments between vendors. The mean radiologist PD for each image was used as a consensus PD measure. Overall agreement of the PD assessments was excellent between the two vendors with an ICC of 0.95 (95% confidence interval: 0.93 to 0.97). Bland-Altman plots demonstrated narrow upper and lower limits of agreement between the vendors with only a small bias (2.3 percentage points). The results of this study support the assumption that visual assessment of PD is consistent across mammography vendors despite vendor-specific appearances of "for presentation" images.

Utility of relative and absolute measures of mammographic density vs clinical risk factors in evaluating breast cancer risk at time of screening mammography.

OBJECTIVE: Various clinical risk factors, including high breast density, have been shown to be associated with breast cancer. The utility of using relative and absolute area-based breast density-related measures was evaluated as an alternative to clinical risk factors in cancer risk assessment at the time of screening mammography. METHODS: Contralateral mediolateral oblique digital mammography images from 392 females with unilateral breast cancer and 817 age-matched controls were analysed. Information on clinical risk factors was obtained from the provincial breast-imaging information system. Breast density-related measures were assessed using a fully automated breast density measurement software. Multivariable logistic regression was conducted, and area under the receiver-operating characteristic (AUROC) curve was used to evaluate the performance of three cancer risk models: the first using only clinical risk factors, the second using only density-related measures and the third using both clinical risk factors and density-related measures. RESULTS: The risk factor-based model generated an AUROC of 0.535, while the model including only breast density-related measures generated a significantly higher AUROC of 0.622 (p < 0.001). The third combined model generated an AUROC of 0.632 and performed significantly better than the risk factor model (p < 0.001) but not the density-related measures model (p = 0.097). CONCLUSION: Density-related measures from screening mammograms at the time of screen may be superior predictors of cancer compared with clinical risk factors. ADVANCES IN KNOWLEDGE: Breast cancer risk models based on density-related measures alone can outperform risk models based on clinical factors. Such models may support the development of personalized breast-screening protocols.

Statistical evaluation of a fully automated mammographic breast density algorithm.

Visual assessments of mammographic breast density by radiologists are used in clinical practice; however, these assessments have shown weaker associations with breast cancer risk than area-based, quantitative methods. The purpose of this study is to present a statistical evaluation of a fully automated, area-based mammographic density measurement algorithm. Five radiologists estimated density in 5% increments for 138 "For Presentation" single MLO views; the median of the radiologists' estimates was used as the reference standard. Agreement amongst radiologists was excellent, ICC = 0.884, 95% CI (0.854, 0.910). Similarly, the agreement between the algorithm and the reference standard was excellent, ICC = 0.862, falling within the 95% CI of the radiologists' estimates. The Bland-Altman plot showed that the reference standard was slightly positively biased (+1.86%) compared to the algorithm-generated densities. A scatter plot showed that the algorithm moderately overestimated low densities and underestimated high densities. A box plot showed that 95% of the algorithm-generated assessments fell within one BI-RADS category of the reference standard. This study demonstrates the effective use of several statistical techniques that collectively produce a comprehensive evaluation of the algorithm and its potential to provide mammographic density measures that can be used to inform clinical practice.

Comparison of clinical-pathologic characteristics and outcomes of true interval and screen-detected invasive breast cancer among participants of a Canadian breast screening program: a nested case-control study.

BACKGROUND: Previous analyses of interval breast cancers have been limited because of a lack of control for screening interval length and patient age, failure to restrict the interval group to 'true' intervals, and incomplete descriptions of pathology, adjuvant therapies and clinical outcomes. PATIENTS AND METHODS: A nested case-control study within the population-based Nova Scotia Breast Screening Program was performed. All true interval cases between 1991 and 2004 were identified, matched 1:2 to screen-detected cases (age, screening interval, time period), and compared in terms of pathologic characteristics and adjuvant therapies via logistic regression. Disease-free and overall survival was estimated, controlling for pathology and adjuvant chemotherapy receipt. RESULTS: A total of 241 true interval invasive cases were matched to 481 screen-detected cases. Interval cases were more likely to be > 1 cm (odds ratio [OR] = 1.76; 95% CI, 1.10-2.83), grade 3 (OR = 2.71; 95% CI, 1.49-4.92), and have lymphovascular invasion (OR = 3.06; 95% CI, 1.85-5.07). Interval cases received more adjuvant chemotherapy (OR = 4.37; 95% CI, 3.03-6.30) and radiation (OR = 1.43; 95% CI, 1.02-2.00). The 5-year Kaplan-Meier estimates of disease-free and overall survival rates for true intervals and screens were 0.830 (95% CI, 0.770-0.875) versus 0.926 (95% CI, 0.898-0.947) and 0.860 (95% CI, 0.804-0.901) versus 0.937 (95% CI, 0.910-0.956), respectively. CONCLUSION: True interval breast cancers have more adverse prognostic factors compared with screen-detected cases and, despite receiving more adjuvant chemotherapy, are associated with significantly poorer survival outcomes.

Ductal carcinoma in situ in core biopsies containing invasive breast cancer: correlation with extensive intraductal component and lumpectomy margins.

BACKGROUND AND OBJECTIVES: The diagnosis of invasive breast cancer is most commonly made on image-guided core biopsy (CB). The presence of extensive intraductal component (EIC), as identified on subsequent lumpectomy, is associated with an increased risk of positive margins and need for further surgery. CBs demonstrating invasive breast cancer may also contain ductal carcinoma in situ (DCIS), although the significance of this finding is unclear. The objective of this study was to examine the implications of DCIS found in the original CB, specifically related to the risk of EIC and/or positive lumpectomy margins. METHODS: All patients at a single academic institution who underwent initial breast conserving surgery for invasive breast cancer diagnosed on image-guided CB between 05/00 and 04/02 were included in the study. A systematic, blinded review of all CB and lumpectomy specimens was performed using standardized criteria for DCIS, EIC, and margins. RESULTS: A total of 95 patients were included in the study, with a mean of 5 (median 5) CB/patient. Of these, 43 (45%) patients had DCIS identified in their CB; in 34 (79%) of these patients, the DCIS was mixed with the invasive cancer. No differences in tumor size or lumpectomy volume were identified between patients with or without DCIS on CB. However, patients with DCIS were noted to be significantly younger. Overall, EIC was identified in 13 (14%) patients; the risk of EIC was significantly higher in patients with DCIS identified in CB than in those with invasive carcinoma alone (30% vs. 0%, respectively; P < 0.0001). Expectedly, the incidence of positive margins on lumpectomy was higher in patients with EIC (38% vs. 16%; P = 0.05). A trend, although not statistically significant, towards positive margins was also noted in patients with DCIS on CB compared to those with invasive carcinoma alone (24% vs. 15%, P = 0.3). CONCLUSIONS: The identification of DCIS in conjunction with invasive cancer on CB appears important; the absence of DCIS in a CB sample excludes the possibility of eventually identifying EIC. Knowledge of DCIS in CBs with invasive carcinoma may be helpful for surgeons in planning gross resection margins at lumpectomy.

Ten years of breast screening in the Nova Scotia Breast Screening Program, 1991-2001. experience: use of an adaptable stereotactic device in the diagnosis of screening-detected abnormalities.

OBJECTIVE: To evaluate and present 10-year outcomes of the Nova Scotia Breast Screening Program (NSBSP), a population-based screening program in the province of Nova Scotia, Canada, total population 900 000. SETTING: Organized Breast Screening Program in Nova Scotia, Canada. METHODS: Rates of participation, abnormal referrals, cancer detection rates, and benign:malignant (B:M) rates for core biopsy and surgical biopsy were calculated for asymptomatic women receiving a mammogram through the NSBSP 1991-2001. RESULTS: Of 192 454 mammograms performed on 71 317 women, 33% were aged 40 to 49 years, 39% aged 50 to 59 years, 23% aged 60 to 69 years, and 5% aged 70 years and over. Cancer detection rate increased in each age group respectively: 3.7, 5.8, 9.7, and 13.5 per 1000 population on first-time screens. The positive predictive value of an abnormal screen increased with increasing age groups. Benign breast surgery decreased with increased use of needle core breast biopsy (NCBB). Open surgery decreased from 25 to 6 surgeries per 1000 screens. Of 1519 open surgical procedures (1328 women), 878 cancers were removed, with 37% 10 mm or less, and 61% 15 mm or less. In 613 women in whom the node status was assessed, 79% were negative. CONCLUSION: A quality screening program incorporating NCBB in the diagnostic work-up is effective in the early detection of breast cancer and results in less open surgery, particularly in younger women.

Patient navigation: improving timeliness in the diagnosis of breast abnormalities.

OBJECTIVE: Patient navigation is a process that provides assistance to referring physicians in arranging further investigations and consultation for defined patient groups. This can facilitate timely investigations and potentially minimize delays. The purpose of this study was to determine the impact of patient navigation on timeliness in the diagnosis of breast abnormalities. METHODS: We retrospectively studied a cohort of 536 women who underwent breast core biopsy at our institution during comparable 6-month periods in 1999 and 2000 to determine the effects of patient navigation, age, and biopsy result on the wait for a biopsy after diagnostic imaging. Patient navigation was used for all women referred through the provincial breast cancer screening program. Navigation was unavailable to patients directly referred by physicians in 1999. In 2000, the program was expanded to encompass all patients. RESULTS: From 1999 to 2000, the median wait for a biopsy remained relatively stable for "navigated" screening patients at 12 days (n = 97) and 13 days (n = 133), respectively. The introduction of patient navigation for directly referred patients resulted in a statistically significant decrease in waiting times, from 20 days (n = 144) in 1999 to 14 days (n = 162) in 2000. Age and biopsy results were statistically significant variables, but their effect on the group data was negligible relative to that of navigation. CONCLUSIONS: Patient navigation significantly improves timeliness in the diagnosis of breast abnormalities and can potentially improve quality of life with more timely reassurance for women with benign conditions and earlier treatment for those with malignancy.