Relationship of circulating insulin-like growth factor-I and binding proteins 1-7 with mammographic density among women undergoing image-guided diagnostic breast biopsy.

BACKGROUND: Mammographic density (MD) is a strong breast cancer risk factor that reflects fibroglandular and adipose tissue composition, but its biologic underpinnings are poorly understood. Insulin-like growth factor binding proteins (IGFBPs) are markers that may be associated with MD given their hypothesized role in breast carcinogenesis. IGFBPs sequester IGF-I, limiting its bioavailability. Prior studies have found positive associations between circulating IGF-I and the IGF-I:IGFBP-3 ratio and breast cancer risk. We evaluated the associations of IGF-I, IGFBP-3, and six other IGFBPs with MD. METHODS: Serum IGF measures were quantified in 296 women, ages 40-65, undergoing diagnostic image-guided breast biopsy. Volumetric density measures (MD-V) were assessed in pre-biopsy digital mammograms using single X-ray absorptiometry. Area density measures (MD-A) were estimated by computer-assisted thresholding software. Age, body mass index (BMI), and BMI2-adjusted linear regression models were used to examine associations of serum IGF measures with MD. Effect modification by BMI was also assessed. RESULTS: IGF-I and IGFBP-3 were not strongly associated with MD after BMI adjustment. In multivariable analyses among premenopausal women, IGFBP-2 was positively associated with both percent MD-V (ß = 1.49, p value = 0.02) and MD-A (ß = 1.55, p value = 0.05). Among postmenopausal women, positive relationships between IGFBP-2 and percent MD-V (ß = 2.04, p = 0.003) were observed; the positive associations between IGFBP-2 and percent MD-V were stronger among lean women (BMI < 25 kg/m2) (ß = 5.32, p = 0.0002; p interaction = 0.0003). CONCLUSIONS: In this comprehensive study of IGFBPs and MD, we observed a novel positive association between IGFBP-2 and MD, particularly among women with lower BMI. In concert with in vitro studies suggesting a dual role of IGFBP-2 on breast tissue, promoting cell proliferation as well as inhibiting tumorigenesis, our findings suggest that further studies assessing the role of IGFBP-2 in breast tissue composition, in addition to IGF-1 and IGFBP-3, are warranted.

Time-varying risks of second events following a DCIS diagnosis in the population-based Vermont DCIS cohort.

PURPOSE: Long-term disease-free survival patterns following surgical, radiation, and endocrine therapy treatments for ductal carcinoma in situ (DCIS) are not well characterized in general US practice. METHODS: We identified 1252 women diagnosed with DCIS in Vermont during 1994-2012 using data from the Vermont Breast Cancer Surveillance System, a statewide registry of breast imaging and pathology records. Poisson regression and Cox regression with time-varying hazards were used to evaluate disease-free survival among self-selected treatment groups. RESULTS: With 7.8 years median follow-up, 192 cases experienced a second breast cancer diagnosis. For women treated with breast-conserving surgery (BCS) alone, the annual rate of second events decreased from 3.1% (95% CI 2.2-4.2%) during follow-up years 1-5 to 1.7% (95% CI 0.7-3.5%) after 10 years. In contrast, the annual rate of second events among women treated with BCS plus adjuvant radiation therapy increased from 1.8% (95% CI 1.1-2.6%) during years 1-5 to 2.8% (95% CI 1.6-4.7%) after 10 years (P < 0.05 for difference in trend compared to BCS alone). Annual rates of second events also increased over time among women treated with BCS plus adjuvant radiation and endocrine therapy (P = 0.01 for difference in trend compared to BCS alone). The rate of contralateral events increased after 10 years for all groups with adjuvant treatments. The rate of second events did not vary over time among women who underwent ipsilateral mastectomy (P = 0.62). CONCLUSIONS: Long-term risk of a second event after DCIS varies over time in a manner dependent on initial treatment.

Second opinion strategies in breast pathology: a decision analysis addressing over-treatment, under-treatment, and care costs.

PURPOSE: To estimate the potential near-term population impact of alternative second opinion breast biopsy pathology interpretation strategies. METHODS: Decision analysis examining 12-month outcomes of breast biopsy for nine breast pathology interpretation strategies in the U.S. health system. Diagnoses of 115 practicing pathologists in the Breast Pathology Study were compared to reference-standard-consensus diagnoses with and without second opinions. Interpretation strategies were defined by whether a second opinion was sought universally or selectively (e.g., 2nd opinion if invasive). Main outcomes were the expected proportion of concordant breast biopsy diagnoses, the proportion involving over- or under-interpretation, and cost of care in U.S. dollars within one-year of biopsy. RESULTS: Without a second opinion, 92.2% of biopsies received a concordant diagnosis. Concordance rates increased under all second opinion strategies, and the rate was highest (95.1%) and under-treatment lowest (2.6%) when all biopsies had second opinions. However, over-treatment was lowest when second opinions were sought selectively for initial diagnoses of invasive cancer, DCIS, or atypia (1.8 vs. 4.7% with no 2nd opinions). This strategy also had the lowest projected 12-month care costs ($5.907 billion vs. $6.049 billion with no 2nd opinions). CONCLUSIONS: Second opinion strategies could lower overall care costs while reducing both over- and under-treatment. The most accurate cost-saving strategy required second opinions for initial diagnoses of invasive cancer, DCIS, or atypia.

Pathologists' Use of Second Opinions in Interpretation of Melanocytic Cutaneous Lesions: Policies, Practices, and Perceptions.

BACKGROUND: Research examining the role of second opinions in pathology for diagnosis of melanocytic lesions is limited. OBJECTIVE: To assess current laboratory policies, clinical use of second opinions, and pathologists' perceptions of second opinions for melanocytic lesions. MATERIALS AND METHODS: Cross-sectional data collected from 207 pathologists in 10 US states who diagnose melanocytic lesions. The web-based survey ascertained pathologists' professional information, laboratory second opinion policy, use of second opinions, and perceptions of second opinion value for melanocytic lesions. RESULTS: Laboratory policies required second opinions for 31% of pathologists and most commonly required for melanoma in situ (26%) and invasive melanoma (30%). In practice, most pathologists reported requesting second opinions for melanocytic tumors of uncertain malignant potential (85%) and atypical Spitzoid lesions (88%). Most pathologists perceived that second opinions increased interpretive accuracy (78%) and protected them from malpractice lawsuits (62%). CONCLUSION: Use of second opinions in clinical practice is greater than that required by laboratory policies, especially for melanocytic tumors of uncertain malignant potential and atypical Spitzoid lesions. Quality of care in surgical interventions for atypical melanocytic proliferations critically depends on the accuracy of diagnosis in pathology reporting. Future research should examine the extent to which second opinions improve accuracy of melanocytic lesion diagnosis.

Association between breast cancer genetic susceptibility variants and terminal duct lobular unit involution of the breast.

Terminal duct lobular units (TDLUs) are the predominant source of future breast cancers, and lack of TDLU involution (higher TDLU counts, higher acini count per TDLU and the product of the two) is a breast cancer risk factor. Numerous breast cancer susceptibility single nucleotide polymorphisms (SNPs) have been identified, but whether they are associated with TDLU involution is unknown. In a pooled analysis of 872 women from two studies, we investigated 62 established breast cancer SNPs and relationships with TDLU involution. Poisson regression models with robust variance were used to calculate adjusted per-allele relative risks (with the non-breast cancer risk allele as the referent) and 95% confidence intervals between TDLU measures and each SNP. All statistical tests were two-sided; P < 0.05 was considered statistically significant. Overall, 36 SNPs (58.1%) were related to higher TDLU counts although this was not statistically significant (p = 0.25). Six of the 62 SNPs (9.7%) were nominally associated with at least one TDLU measure: rs616488 (PEX14), rs11242675 (FOXQ1) and rs6001930 (MKL1) were associated with higher TDLU count (p = 0.047, 0.045 and 0.031, respectively); rs1353747 (PDE4D) and rs6472903 (8q21.11) were associated with higher acini count per TDLU (p = 0.007 and 0.027, respectively); and rs1353747 (PDE4D) and rs204247 (RANBP9) were associated with the product of TDLU and acini counts (p = 0.024 and 0.017, respectively). Our findings suggest breast cancer SNPs may not strongly influence TDLU involution. Agnostic genome-wide association studies of TDLU involution may provide new insights on its biologic underpinnings and breast cancer susceptibility.

Diagnostic Reproducibility: What Happens When the Same Pathologist Interprets the Same Breast Biopsy Specimen at Two Points in Time?

BACKGROUND: Surgeons may receive a different diagnosis when a breast biopsy is interpreted by a second pathologist. The extent to which diagnostic agreement by the same pathologist varies at two time points is unknown. METHODS: Pathologists from eight U.S. states independently interpreted 60 breast specimens, one glass slide per case, on two occasions separated by ≥9 months. Reproducibility was assessed by comparing interpretations between the two time points; associations between reproducibility (intraobserver agreement rates); and characteristics of pathologists and cases were determined and also compared with interobserver agreement of baseline interpretations. RESULTS: Sixty-five percent of invited, responding pathologists were eligible and consented; 49 interpreted glass slides in both study phases, resulting in 2940 interpretations. Intraobserver agreement rates between the two phases were 92% [95% confidence interval (CI) 88-95] for invasive breast cancer, 84% (95% CI 81-87) for ductal carcinoma-in-situ, 53% (95% CI 47-59) for atypia, and 84% (95% CI 81-86) for benign without atypia. When comparing all study participants' case interpretations at baseline, interobserver agreement rates were 89% (95% CI 84-92) for invasive cancer, 79% (95% CI 76-81) for ductal carcinoma-in-situ, 43% (95% CI 41-45) for atypia, and 77% (95% CI 74-79) for benign without atypia. CONCLUSIONS: Interpretive agreement between two time points by the same individual pathologist was low for atypia and was similar to observed rates of agreement for atypia between different pathologists. Physicians and patients should be aware of the diagnostic challenges associated with a breast biopsy diagnosis of atypia when considering treatment and surveillance decisions.

Variability in Pathologists' Interpretations of Individual Breast Biopsy Slides: A Population Perspective.

BACKGROUND: The effect of physician diagnostic variability on accuracy at a population level depends on the prevalence of diagnoses. OBJECTIVE: To estimate how diagnostic variability affects accuracy from the perspective of a U.S. woman aged 50 to 59 years having a breast biopsy. DESIGN: Applied probability using Bayes' theorem. SETTING: B-Path (Breast Pathology) Study comparing pathologists' interpretations of a single biopsy slide versus a reference consensus interpretation from 3 experts. PARTICIPANTS: 115 practicing pathologists (6900 total interpretations from 240 distinct cases). MEASUREMENTS: A single representative slide from each of the 240 cases was used to estimate the proportion of biopsies with a diagnosis that would be verified if the same slide were interpreted by a reference group of 3 expert pathologists. Probabilities of confirmation (predictive values) were estimated using B-Path Study results and prevalence of biopsy diagnoses for women aged 50 to 59 years in the Breast Cancer Surveillance Consortium. RESULTS: Overall, if 1 representative slide were used per case, 92.3% (95% CI, 91.4% to 93.1%) of breast biopsy diagnoses would be verified by reference consensus diagnoses, with 4.6% (CI, 3.9% to 5.3%) overinterpreted and 3.2% (CI, 2.7% to 3.6%) underinterpreted. Verification of invasive breast cancer and benign without atypia diagnoses is highly probable; estimated predictive values were 97.7% (CI, 96.5% to 98.7%) and 97.1% (CI, 96.7% to 97.4%), respectively. Verification is less probable for atypia (53.6% overinterpreted and 8.6% underinterpreted) and ductal carcinoma in situ (DCIS) (18.5% overinterpreted and 11.8% underinterpreted). LIMITATIONS: Estimates are based on a testing situation with 1 slide used per case and without access to second opinions. Population-adjusted estimates may differ for women from other age groups, unscreened women, or women in different practice settings. CONCLUSION: This analysis, based on interpretation of a single breast biopsy slide per case, predicts a low likelihood that a diagnosis of atypia or DCIS would be verified by a reference consensus diagnosis. This diagnostic grey zone should be considered in clinical management decisions in patients with these diagnoses. PRIMARY FUNDING SOURCE: National Cancer Institute.

Relationships between mammographic density, tissue microvessel density, and breast biopsy diagnosis.

BACKGROUND: Women with high levels of mammographic density (MD) have a four- to six-fold increased risk of developing breast cancer; however, most neither have a prevalent tumor nor will they develop one. Magnetic resonance imaging (MRI) studies suggest that background parenchymal enhancement, an indicator of vascularity, is related to increased breast cancer risk. Correlations of microvessel density (MVD) in tissue, MD and biopsy diagnosis have not been defined, and we investigated these relationships among 218 women referred for biopsy. METHODS: MVD was determined by counting CD31-positive vessels in whole sections of breast biopsies in three representative areas; average MVD was transformed to approximate normality. Using digital mammograms, we quantified MD volume with single X-ray absorptiometry. We used linear regression to evaluate associations between MVD and MD adjusted for age and body mass index (BMI) overall, and stratified by biopsy diagnosis: cases (in situ or invasive cancer, n = 44) versus non-cases (non-proliferative or proliferative benign breast disease, n = 174). Logistic regression adjusted for age, BMI, and MD was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs) for associations between MVD and biopsy diagnosis. We also assessed whether the MVD-breast cancer association varied by MD. RESULTS: MVD and MD were not consistently associated. Higher MVD was significantly associated with higher odds of in situ/invasive disease (ORAdjusted = 1.69, 95 % CI = 1.17-2.44). MVD-breast cancer associations were strongest among women with greater non-dense volume. CONCLUSIONS: Increased MVD in tissues is associated with breast cancer, independently of MD, consistent with MRI findings suggestive of its possible value as a radiological cancer biomarker.

Circulating insulin-like growth factor-I, insulin-like growth factor binding protein-3 and terminal duct lobular unit involution of the breast: a cross-sectional study of women with benign breast disease.

BACKGROUND: Terminal duct lobular units (TDLUs) are the primary structures from which breast cancers and their precursors arise. Decreased age-related TDLU involution and elevated mammographic density are both correlated and independently associated with increased breast cancer risk, suggesting that these characteristics of breast parenchyma might be linked to a common factor. Given data suggesting that increased circulating levels of insulin-like growth factors (IGFs) factors are related to reduced TDLU involution and increased mammographic density, we assessed these relationships using validated quantitative methods in a cross-sectional study of women with benign breast disease. METHODS: Serum IGF-I, IGFBP-3 and IGF-I:IGFBP-3 molar ratios were measured in 228 women, ages 40-64, who underwent diagnostic breast biopsies yielding benign diagnoses at University of Vermont affiliated centers. Biopsies were assessed for three separate measures inversely related to TDLU involution: numbers of TDLUs per unit of tissue area ("TDLU count"), median TDLU diameter ("TDLU span"), and number of acini per TDLU ("acini count"). Regression models, stratified by menopausal status and adjusted for potential confounders, were used to assess the associations of TDLU count, median TDLU span and median acini count per TDLU with tertiles of circulating IGFs. Given that mammographic density is associated with both IGF levels and breast cancer risk, we also stratified these associations by mammographic density. RESULTS: Higher IGF-I levels among postmenopausal women and an elevated IGF-I:IGFBP-3 ratio among all women were associated with higher TDLU counts, a marker of decreased lobular involution (P-trend = 0.009 and <0.0001, respectively); these associations were strongest among women with elevated mammographic density (P-interaction <0.01). Circulating IGF levels were not significantly associated with TDLU span or acini count per TDLU. CONCLUSIONS: These results suggest that elevated IGF levels may define a sub-group of women with high mammographic density and limited TDLU involution, two markers that have been related to increased breast cancer risk. If confirmed in prospective studies with cancer endpoints, these data may suggest that evaluation of IGF signaling and its downstream effects may have value for risk prediction and suggest strategies for breast cancer chemoprevention through inhibition of the IGF system.

Ages at menarche- and menopause-related genetic variants in relation to terminal duct lobular unit involution in normal breast tissue.

Reduced levels of terminal duct lobular unit (TDLU) involution, as reflected by higher numbers of TDLUs and acini per TDLU, have been associated with higher breast cancer risk. Younger age at menarche and older age at menopause have been previously related to lower levels of TDLU involution. To determine a possible genetic link, we examined whether single-nucleotide polymorphisms (SNPs) previously established in genome-wide association studies (GWAS) for ages at menarche and menopause are associated with TDLU involution. We conducted a pooled analysis of 862 women from two studies. H&E tissue sections were assessed for numbers of TDLUs and acini/TDLU. Poisson regression models were used to estimate associations of 36 menarche- and 21 menopause-SNPs with TDLU counts, acini counts/TDLU, and the product of these two measures, adjusting for age and study site. Fourteen percent of evaluated SNPs (eight SNPs) were associated with TDLU counts at p < 0.05, suggesting an enrichment of associations with TDLU counts. However, only menopause-SNPs had >50 % that were either significantly or nonsignificantly associated with TDLU measures in the directions consistent with their relationships shown in GWAS. Among ten SNPs that were statistically significantly associated with at least one TDLU involution measure (p < 0.05), seven SNPs (rs466639: RXRG; rs2243803: SLC14A2; rs2292573: GAB2; rs6438424: 3q13.32; rs7606918: METAP1D; rs11668344: TMEM150B; rs1635501: EXO1) were associated in the consistent directions. Our data suggest that the loci associated with ages at menarche and menopause may influence TDLU involution, suggesting some shared genetic mechanisms. However, larger studies are needed to confirm the results.

Identifying and processing the gap between perceived and actual agreement in breast pathology interpretation.

We examined how pathologists' process their perceptions of how their interpretations on diagnoses for breast pathology cases agree with a reference standard. To accomplish this, we created an individualized self-directed continuing medical education program that showed pathologists interpreting breast specimens how their interpretations on a test set compared with a reference diagnosis developed by a consensus panel of experienced breast pathologists. After interpreting a test set of 60 cases, 92 participating pathologists were asked to estimate how their interpretations compared with the standard for benign without atypia, atypia, ductal carcinoma in situ and invasive cancer. We then asked pathologists their thoughts about learning about differences in their perceptions compared with actual agreement. Overall, participants tended to overestimate their agreement with the reference standard, with a mean difference of 5.5% (75.9% actual agreement; 81.4% estimated agreement), especially for atypia and were least likely to overestimate it for invasive breast cancer. Non-academic affiliated pathologists were more likely to more closely estimate their performance relative to academic affiliated pathologists (77.6 vs 48%; P=0.001), whereas participants affiliated with an academic medical center were more likely to underestimate agreement with their diagnoses compared with non-academic affiliated pathologists (40 vs 6%). Before the continuing medical education program, nearly 55% (54.9%) of participants could not estimate whether they would overinterpret the cases or underinterpret them relative to the reference diagnosis. Nearly 80% (79.8%) reported learning new information from this individualized web-based continuing medical education program, and 23.9% of pathologists identified strategies they would change their practice to improve. In conclusion, when evaluating breast pathology specimens, pathologists do a good job of estimating their diagnostic agreement with a reference standard, but for atypia cases, pathologists tend to overestimate diagnostic agreement. Many participants were able to identify ways to improve.

How concerns and experiences with medical malpractice affect dermatopathologists' perceptions of their diagnostic practices when interpreting cutaneous melanocytic lesions.

OBJECTIVE: We sought to identify characteristics associated with past malpractice lawsuits and how malpractice concerns may affect interpretive practices. METHODS: We surveyed 207 of 301 (68.8%) eligible dermatopathologists who interpret melanocytic skin lesions in 10 states. The survey assessed dermatopathologists' demographic and clinical practice characteristics, perceptions of how medical malpractice concerns could influence their interpretive practices, and past malpractice lawsuits. RESULTS: Of dermatopathologists, 33% reported past malpractice experiences. Factors associated with being sued included older age (57 vs 48 years, P < .001), lack of board certification or fellowship training in dermatopathology (76.5% vs 53.2%, P = .001), and greater number of years interpreting melanocytic lesions (>20 years: 52.9% vs 20.1%, P < .001). Of participants, 64% reported being moderately or extremely confident in their melanocytic interpretations. Although most dermatopathologists believed that malpractice concerns increased their likelihood of ordering specialized pathology tests, obtaining recuts, and seeking a second opinion, none of these practices were associated with past malpractice. Most dermatopathologists reported concerns about potential harms to patients that may result from their assessments of melanocytic lesions. LIMITATIONS: Limitations of this study include lack of validation of and details about the malpractice suits experienced by participating dermatopathologists. In addition, the study assessed perceptions of practice rather than actual practices that might be associated with malpractice incidents. CONCLUSIONS: Most dermatopathologists reported apprehension about how malpractice affects their clinical practice and are concerned about patient safety irrespective of whether they had actually experienced a medical malpractice suit.

Achieving consensus for the histopathologic diagnosis of melanocytic lesions: use of the modified Delphi method.

OBJECTIVE: To understand the sophisticated nature of coming to consensus when diagnosing complex melanocytic lesions among a panel of experienced dermatopathologists. METHODS: A total of 240 melanocytic lesions were assessed independently by three experienced dermatopathologists with their diagnoses mapped into one of five Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-DX) categories: (I) nevus/mild atypia, (II) moderate atypia, (III) severe atypia/melanoma in situ, (IV) T1a invasive melanoma and (V) ≥ T1b invasive melanoma. The dermatopathologists then discussed the cases, using a modified Delphi method to facilitated consensus building for cases with discordant diagnoses. RESULTS: For most cases, a majority of interpretations (two or three of three) agreed with the consensus diagnosis in 95% of Category I, 64% of Category II, 84% of Category III, 88% for Category IV and 100% of Category V cases. Disagreements were typically due to diagnostic threshold differences (64.5%), differing contents on slides even though the slides were sequential cuts (18.5%), and missed findings (15.3%). Disagreements were resolved via discussion of histopathologic features and their significance while reviewing the slides using a multi-headed microscope, considering treatment recommendations, citing existing literature, reviewing additional slides for a case, and choosing a provisional/borderline diagnosis to capture diverse opinions. All experienced pathologists participating in this study reported that the process of coming to consensus was challenging for borderline cases and may have represented compromise rather than consensus. They also reported the process changed their approaches to diagnosing complex melanocytic lesions. CONCLUSIONS: The most frequent reason for disagreement of experienced dermatopathologists was differences in diagnostic thresholds related to observer viewpoints. A range of approaches was needed to come to consensus, and this may guide pathology groups who do not currently hold consensus conferences.

Use of Digital Whole Slide Imaging in Dermatopathology.

Digital whole slide imaging (WSI) is an emerging technology for pathology interpretation, with specific challenges for dermatopathology, yet little is known about pathologists' practice patterns or perceptions regarding WSI for interpretation of melanocytic lesions. A national sample of pathologists (N = 207) was recruited from 864 invited pathologists from ten US states (CA, CT, HI, IA, KY, LA, NJ, NM, UT, and WA). Pathologists who had interpreted melanocytic lesions in the past year were surveyed in this cross-sectional study. The survey included questions on pathologists' experience, WSI practice patterns and perceptions using a 6-point Likert scale. Agreement was summarized with descriptive statistics to characterize pathologists' use and perceptions of WSI. The majority of participating pathologists were between 40 and 59 years of age (62%) and not affiliated with an academic medical center (71%). Use of WSI was seen more often among dermatopathologists and participants affiliated with an academic medical center. Experience with WSI was reported by 41%, with the most common type of use being for education and testing (CME, board exams, and teaching in general, 71%), and clinical use at tumor boards and conferences (44%). Most respondents (77%) agreed that accurate diagnoses can be made with this technology, and 59% agreed that benefits of WSI outweigh concerns. However, 78% of pathologists reported that digital slides are too slow for routine clinical interpretation. The respondents were equally split as to whether they would like to adopt WSI (49%) or not (51%). The majority of pathologists who interpret melanocytic lesions do not use WSI, but among pathologists who do, use is largely for CME, licensure/board exams, and teaching. Positive perceptions regarding WSI slightly outweigh negative perceptions. Understanding practice patterns with WSI as dissemination advances may facilitate concordance of perceptions with adoption of the technology.

Trends in breast biopsy pathology diagnoses among women undergoing mammography in the United States: a report from the Breast Cancer Surveillance Consortium.

BACKGROUND: Current data on the pathologic diagnoses of breast biopsy after mammography can inform patients, clinicians, and researchers about important population trends. METHODS: Breast Cancer Surveillance Consortium data on 4,020,140 mammograms between 1996 and 2008 were linked to 76,567 pathology specimens. Trends in diagnoses in biopsies by time and risk factors (patient age, breast density, and family history of breast cancer) were examined for screening and diagnostic mammography (performed for a breast symptom or short-interval follow-up). RESULTS: Of the total mammograms, 88.5% were screening and 11.5% diagnostic; 1.2% of screening and 6.8% of diagnostic mammograms were followed by biopsies. The frequency of biopsies over time was stable after screening mammograms, but increased after diagnostic mammograms. For biopsies obtained after screening, frequencies of invasive carcinoma increased over time for women ages 40-49 and 60-69, Ductal carcinoma in situ (DCIS) increased for those ages 40-69, whereas benign diagnoses decreased for all ages. No trends in pathology diagnoses were found following diagnostic mammograms. Dense breast tissue was associated with high-risk lesions and DCIS relative to nondense breast tissue. Family history of breast cancer was associated with DCIS and invasive cancer. CONCLUSIONS: Although the frequency of breast biopsy after screening mammography has not changed over time, the percentages of biopsies with DCIS and invasive cancer diagnoses have increased. Among biopsies following mammography, women with dense breasts or family history of breast cancer were more likely to have high-risk lesions or invasive cancer. These findings are relevant to breast cancer screening and diagnostic practices.

Breast cancer detection with short-interval follow-up compared with return to annual screening in patients with benign stereotactic or US-guided breast biopsy results.

PURPOSE: To compare the cancer detection rate and stage after benign stereotactic or ultrasonography (US)-guided core breast biopsy between patients with short-interval follow-up (SIFU) and those who return to annual screening. MATERIALS AND METHODS: The Breast Cancer Surveillance Consortium (BCSC) registry and the BCSC Statistical Coordinating Center received institutional review board approval for active and passive consent processes and a waiver of consent. All procedures were HIPAA compliant. BCSC data for 1994-2010 were used to compare ipsilateral breast cancer detection rates and tumor characteristics for diagnoses within 3 months after SIFU (3-8 months) versus return to annual screening (RTAS) mammography (9-18 months) after receiving a benign pathology result from image-guided breast biopsy. RESULTS: In total, 17 631 biopsies with benign findings were identified with SIFU or RTAS imaging. In the SIFU group, 27 ipsilateral breast cancers were diagnosed in 10 715 mammographic examinations (2.5 cancers per 1000 examinations) compared with 16 cancers in 6916 mammographic examinations in the RTAS group (2.3 cancers per 1000 examinations) (P = .88). Sixteen cancers after SIFU (59%; 95% confidence interval [CI]: 39%, 78%) were invasive versus 12 after RTAS (75%; 95% CI: 48%, 93%). The invasive cancer rate was 1.5 per 1000 examinations after SIFU (95% CI: 0.9, 2.4) and 1.7 per 1000 examinations (95% CI: 0.9, 3.0) after RTAS (P = .70). Among invasive cancers, 25% were late stage (stage 2B, 3, or 4) in the SIFU group (95% CI: 7%, 52%) versus 27% in the RTAS group (95% CI: 6%, 61%). Positive lymph nodes were found in seven (44%; 95% CI: 20%, 70%) invasive cancers after SIFU and in three (25%; 95% CI: 5%, 57%) invasive cancers after RTAS. CONCLUSION: Similar rates of cancer detection were found between SIFU and RTAS after benign breast biopsy with no significant differences in stage, tumor size, or nodal status, although the present study was limited by sample size. These findings suggest that patients with benign radiologic-pathologic-concordant percutaneous breast biopsy results could return to annual screening.

Leukocyte telomere length and its association with mammographic density and proliferative diagnosis among women undergoing diagnostic image-guided breast biopsy.

BACKGROUND: Elevated mammographic density (MD) is a strong breast cancer risk factor but the mechanisms underlying the association are poorly understood. High MD and breast cancer risk may reflect cumulative exposures to factors that promote epithelial cell division. One marker of cellular replicative history is telomere length, but its association with MD is unknown. We investigated the relation of telomere length, a marker of cellular replicative history, with MD and biopsy diagnosis. METHODS: One hundred and ninety-five women, ages 40-65, were clinically referred for image-guided breast biopsies at an academic facility in Vermont. Relative peripheral blood leukocyte telomere length (LTL) was measured using quantitative polymerase chain reaction. MD volume was quantified in cranio-caudal views of the breast contralateral to the primary diagnosis in digital mammograms using a breast density phantom, while MD area (cm(2)) was measured using thresholding software. Associations between log-transformed LTL and continuous MD measurements (volume and area) were evaluated using linear regression models adjusted for age and body mass index. Analyses were stratified by biopsy diagnosis: proliferative (hyperplasia, in-situ or invasive carcinoma) or non-proliferative (benign or other non-proliferative benign diagnoses). RESULTS: Mean relative LTL in women with proliferative disease (n = 141) was 1.6 (SD = 0.9) vs. 1.2 (SD = 0.6) in those with non-proliferative diagnoses (n = 54) (P = 0.002). Mean percent MD volume did not differ by diagnosis (P = 0.69). LTL was not associated with MD in women with proliferative (P = 0.89) or non-proliferative (P = 0.48) diagnoses. However, LTL was associated with a significant increased risk of proliferative diagnosis (adjusted OR = 2.46, 95% CI: 1.47, 4.42). CONCLUSIONS: Our analysis of LTL did not find an association with MD. However, our findings suggest that LTL may be a marker of risk for proliferative pathology among women referred for biopsy based on breast imaging.

Diagnostic concordance among pathologists interpreting breast biopsy specimens.

IMPORTANCE: A breast pathology diagnosis provides the basis for clinical treatment and management decisions; however, its accuracy is inadequately understood. OBJECTIVES: To quantify the magnitude of diagnostic disagreement among pathologists compared with a consensus panel reference diagnosis and to evaluate associated patient and pathologist characteristics. DESIGN, SETTING, AND PARTICIPANTS: Study of pathologists who interpret breast biopsies in clinical practices in 8 US states. EXPOSURES: Participants independently interpreted slides between November 2011 and May 2014 from test sets of 60 breast biopsies (240 total cases, 1 slide per case), including 23 cases of invasive breast cancer, 73 ductal carcinoma in situ (DCIS), 72 with atypical hyperplasia (atypia), and 72 benign cases without atypia. Participants were blinded to the interpretations of other study pathologists and consensus panel members. Among the 3 consensus panel members, unanimous agreement of their independent diagnoses was 75%, and concordance with the consensus-derived reference diagnoses was 90.3%. MAIN OUTCOMES AND MEASURES: The proportions of diagnoses overinterpreted and underinterpreted relative to the consensus-derived reference diagnoses were assessed. RESULTS: Sixty-five percent of invited, responding pathologists were eligible and consented to participate. Of these, 91% (N = 115) completed the study, providing 6900 individual case diagnoses. Compared with the consensus-derived reference diagnosis, the overall concordance rate of diagnostic interpretations of participating pathologists was 75.3% (95% CI, 73.4%-77.0%; 5194 of 6900 interpretations). Among invasive carcinoma cases (663 interpretations), 96% (95% CI, 94%-97%) were concordant, and 4% (95% CI, 3%-6%) were underinterpreted; among DCIS cases (2097 interpretations), 84% (95% CI, 82%-86%) were concordant, 3% (95% CI, 2%-4%) were overinterpreted, and 13% (95% CI, 12%-15%) were underinterpreted; among atypia cases (2070 interpretations), 48% (95% CI, 44%-52%) were concordant, 17% (95% CI, 15%-21%) were overinterpreted, and 35% (95% CI, 31%-39%) were underinterpreted; and among benign cases without atypia (2070 interpretations), 87% (95% CI, 85%-89%) were concordant and 13% (95% CI, 11%-15%) were overinterpreted. Disagreement with the reference diagnosis was statistically significantly higher among biopsies from women with higher (n = 122) vs lower (n = 118) breast density on prior mammograms (overall concordance rate, 73% [95% CI, 71%-75%] for higher vs 77% [95% CI, 75%-80%] for lower, P < .001), and among pathologists who interpreted lower weekly case volumes (P < .001) or worked in smaller practices (P = .034) or nonacademic settings (P = .007). CONCLUSIONS AND RELEVANCE: In this study of pathologists, in which diagnostic interpretation was based on a single breast biopsy slide, overall agreement between the individual pathologists' interpretations and the expert consensus-derived reference diagnoses was 75.3%, with the highest level of concordance for invasive carcinoma and lower levels of concordance for DCIS and atypia. Further research is needed to understand the relationship of these findings with patient management.

Breast cancer screening in an era of personalized regimens: a conceptual model and National Cancer Institute initiative for risk-based and preference-based approaches at a population level.

Breast cancer screening holds a prominent place in public health, health care delivery, policy, and women's health care decisions. Several factors are driving shifts in how population-based breast cancer screening is approached, including advanced imaging technologies, health system performance measures, health care reform, concern for "overdiagnosis," and improved understanding of risk. Maximizing benefits while minimizing the harms of screening requires moving from a "1-size-fits-all" guideline paradigm to more personalized strategies. A refined conceptual model for breast cancer screening is needed to align women's risks and preferences with screening regimens. A conceptual model of personalized breast cancer screening is presented herein that emphasizes key domains and transitions throughout the screening process, as well as multilevel perspectives. The key domains of screening awareness, detection, diagnosis, and treatment and survivorship are conceptualized to function at the level of the patient, provider, facility, health care system, and population/policy arena. Personalized breast cancer screening can be assessed across these domains with both process and outcome measures. Identifying, evaluating, and monitoring process measures in screening is a focus of a National Cancer Institute initiative entitled PROSPR (Population-based Research Optimizing Screening through Personalized Regimens), which will provide generalizable evidence for a risk-based model of breast cancer screening, The model presented builds on prior breast cancer screening models and may serve to identify new measures to optimize benefits-to-harms tradeoffs in population-based screening, which is a timely goal in the era of health care reform.

Registry-based study of trends in breast cancer screening mammography before and after the 2009 U.S. Preventive Services Task Force recommendations.

PURPOSE: To determine whether the 2009 U.S. Preventive Services Task Force (USPSTF) guidelines for breast cancer mammography screening were followed by changes in screening utilization in the state of Vermont. MATERIALS AND METHODS: This retrospective study was HIPAA compliant and approved by the institutional review board, with waiver of informed consent. Trends in screening mammography utilization during 1997-2011 were examined among approximately 150,000 women aged 40 years and older in the state of Vermont using statewide mammography registry data. RESULTS: The percentage of Vermont women aged 40 years and older screened in the past year declined from 45.3% in 2009% to 41.6% in 2011 (an absolute decrease of -3.7 percentage points; 95% confidence interval [CI]: -3.3, -4.1). The largest decline in utilization was among women aged 40-49 years (-4.8 percentage points; 95% CI: -4.1, -5.4), although substantial declines were also observed among women aged 50-74 years (-3.0 percentage points; 95% CI: -2.6, -3.5) and women aged 75 years and older (-3.1 percentage points; 95% CI: -2.3, -4.0). The percentage of women aged 50-74 years screened within the past 2 years declined by -3.4 percentage points (95% CI: -3.0, -3.9) from 65.4% in 2009 to 61.9% in 2011. CONCLUSION: After years of increasing screening mammography utilization in Vermont, there was a decline in screening, which coincided with the release of the 2009 USPSTF recommendations. The age-specific patterns in utilization were generally consistent with the USPSTF recommendations, although there was also evidence that the percentage of women aged 50-74 years screened in the past 2 years declined since 2009.