Citations

PURPOSE To determine the sensitivity and specificity of genetic testing criteria for the detection of germline pathogenic variants in women with breast cancer. MATERIALS AND METHODS Women with breast cancer enrolled in a breast cancer registry at a tertiary cancer center between 2000 and 2016 were evaluated for germline pathogenic variants in 9 breast cancer predisposition genes ( ATM , BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53). The performance of the National Comprehensive Cancer Network (NCCN) hereditary cancer testing criteria was evaluated relative to testing of all women as recommended by the American Society of Breast Surgeons. RESULTS Of 3,907 women, 1,872 (47.9%) meeting NCCN criteria were more likely to carry a pathogenic variant in 9 predisposition genes compared with women not meeting criteria (9.0% v 3.5%; P < .001). Of those not meeting criteria (n = 2,035), 14 (0.7%) had pathogenic variants in BRCA1 or BRCA2. The sensitivity of NCCN criteria was 70% for 9 predisposition genes and 87% for BRCA1 and BRCA2, with a specificity of 53%. Expansion of the NCCN criteria to include all women diagnosed with breast cancer at ≤ 65 years of age achieved > 90% sensitivity for the 9 predisposition genes and > 98% sensitivity for BRCA1 and BRCA2. CONCLUSION A substantial proportion of women with breast cancer carrying germline pathogenic variants in predisposition genes do not qualify for testing by NCCN criteria. Expansion of NCCN criteria to include all women diagnosed at ≤ 65 years of age improves the sensitivity of the selection criteria without requiring testing of all women with breast cancer.

6531 Background: Annual mammography is recommended to screen residual breast tissue for new cancers and recurrent disease after treatment for early stage breast cancer. This study aimed to assess mammography rates over time in breast cancer survivors. Methods: We used administrative claims data from a large U.S. commercial insurance database, OptumLabs, to retrospectively identify privately- and Medicare Advantage-insured women with operable breast cancer who had residual breast tissue after definitive breast surgery between 2006 and 2015. We required coverage for at least 13 months following surgery. For each subsequent 13-month time period, we only included women without a loss of coverage, bilateral mastectomy, metastatic breast cancer diagnosis, or non-breast cancer diagnosis. We calculated the proportion of patients who had a mammogram during each 13-month period following breast surgery. We used multivariable logistic regression to test for factors associated with mammography in the first 13 months. Results: The cohort included 26,011 women followed for a median of 2.9 years (IQR 1.9-4.6) after surgery; 63.1% were less than 65 years of age, and 74.4% were white. In their first year of follow-up, 86% underwent mammography, but by year 7, this decreased to 73%. Fewer than 1% underwent MRI instead of mammography. In multivariable analysis, mammograms were less likely during the first year after surgery among women aged < 50 years (odds ratio [OR], 0.7; 95% confidence interval [CI], 0.6 to 0.8), African Americans (OR, 0.7; 95% CI, 0.7 to 0.8), patients who underwent mastectomy (OR, 0.7; 95% CI, 0.6 to 0.7), and patients residing in the Western part of the country (OR, 0.9; 95% CI, 0.7 to 0.9). Those with 1-2 comorbidities were more likely (OR, 1.1; 95% CI 1.1-1.2) than those with none to have a mammogram during that period. Mammography use did not differ significantly by year of diagnosis (2006-2015). Conclusions: Even in an insured cohort, a substantial proportion of breast cancer survivors do not undergo annual surveillance mammography. Mammography use falls as the time from the early stage breast cancer diagnosis increases. Understanding factors associated with lack of mammographic screening may help improve survivorship care.

Abstract Purpose: With improvements in breast cancer imaging, there has been a corresponding increase in false-positives and avoidable biopsies. There is a need to better differentiate when a breast biopsy is warranted and determine appropriate follow-up. This study describes the design and clinical performance of a combinatorial proteomic biomarker assay (CPBA), Videssa Breast, in women over age 50 years. Experimental Design: A BI-RADS 3, 4, or 5 assessment was required for clinical trial enrollment. Serum was collected prior to breast biopsy and subjects were followed for 6–12 months and clinically relevant outcomes were recorded. Samples were split into training (70%) and validation (30%) cohorts with an approximate 1:4 case:control ratio in both arms. Results: A CPBA that combines biomarker data with patient clinical data was developed using a training cohort (469 women, cancer incidence: 18.5%), resulting in 94% sensitivity and 97% negative predictive value (NPV). Independent validation of the final algorithm in 194 subjects (breast cancer incidence: 19.6%) demonstrated a sensitivity of 95% and a NPV of 97%. When combined with previously published data for women under age 50, Videssa Breast achieves a comprehensive 93% sensitivity and 98% NPV in a population of women ages 25–75. Had Videssa Breast results been incorporated into the clinical workflow, approximately 45% of biopsies might have been avoided. Conclusions: Videssa Breast combines serum biomarkers with clinical patient characteristics to provide clinicians with additional information for patients with indeterminate breast imaging results, potentially reducing false-positive breast biopsies.

Background More than 1.5 million women per year have a benign breast biopsy resulting in concern about their future breast cancer (BC) risk. This study examined the performance of 2 BC risk models that integrate clinical and histologic findings in this population. Methods The BC risk at 5 and 10 years was estimated with the Breast Cancer Surveillance Consortium (BCSC) and Benign Breast Disease to Breast Cancer (BBD‐BC) models for women diagnosed with benign breast disease (BBD) at the Mayo Clinic from 1997 to 2001. Women with BBD were eligible for the BBD‐BC model, but the BCSC model also required a screening mammogram. Calibration and discrimination were assessed. Results Fifty‐six cases of BC were diagnosed among the 2142 women with BBD (median age, 50 years) within 5 years (118 were diagnosed within 10 years). The BBD‐BC model had slightly better calibration at 5 years (0.89; 95% confidence interval [CI], 0.71‐1.21) versus 10 years (0.81; 95% CI, 0.70‐1.00) but similar discrimination in the 2 time periods: 0.68 (95% CI, 0.60‐0.75) and 0.66 (95% CI, 0.60‐0.71), respectively. In contrast, among the 1089 women with screening mammograms (98 cases of BC within 10 years), the BCSC model had better calibration (0.94; 95% CI, 0.85‐1.43) and discrimination (0.63; 95% CI, 0.56‐0.71) at 10 years versus 5 years (calibration, 1.31; 95% CI, 0.94‐2.25; discrimination, 0.59; 95% CI, 0.46‐0.71) where discrimination was not different from chance. Conclusions The BCSC and BBD‐BC models were validated in the Mayo BBD cohort, although their performance differed by 5‐year risk versus 10‐year risk. Further enhancement of these models is needed to provide accurate BC risk estimates for women with BBD.

Purpose Women with atypical hyperplasia (AH) on breast biopsy have an aggregate increased risk of breast cancer (BC), but existing risk prediction models do not provide accurate individualized estimates of risk in this subset of high-risk women. Here, we used the Mayo benign breast disease cohort to develop and validate a model of BC risk prediction that is specifically for women with AH, which we have designated as AH-BC. Patients and Methods Retrospective cohorts of women age 18 to 85 years with pathologically confirmed benign AH from Rochester, MN, and Nashville, TN, were used for model development and external validation, respectively. Clinical risk factors and histologic features of the tissue biopsy were selected using L1-penalized Cox proportional hazards regression. Identified features were included in a Fine and Gray regression model to estimate BC risk, with death as a competing risk. Model discrimination and calibration were assessed in the model-building set and an external validation set. Results The model-building set consisted of 699 women with AH, 142 of whom developed BC (median follow-up, 8.1 years), and the external validation set consisted of 461 women with 114 later BC events (median follow-up, 11.4 years). The final AH-BC model included three covariates: age at biopsy, age at biopsy squared, and number of foci of AH. At 10 years, the AH-BC model demonstrated good discrimination (0.63 [95% CI, 0.57 to 0.70]) and calibration (0.87 [95% CI, 0.66 to 1.24]). In the external validation set, the model showed acceptable discrimination (0.59 [95% CI, 0.51 to 0.67]) and calibration (0.91 [95% CI, 0.65 to 1.42]). Conclusion We have created a new model with which to refine BC risk prediction for women with AH. The AH-BC model demonstrates good discrimination and calibration, and it validates in an external data set.

25 Background: Women with diabetes are at an increased risk of developing breast cancer, present with later stage disease, and experience higher breast cancer-specific mortality compared to nondiabetic women. Thus, it is imperative that diabetic women undergo routine screening mammography. Previous studies have shown conflicting results with smaller studies showing lower screening mammography rates among diabetics while a study using national self-report data showed that diabetic women were equally likely to be screened compared to nondiabetic women. Given the conflicting data and limitations of previous studies, we aimed to study receipt of mammography in diabetic women using a nationally representative administrative claims database. Methods: This was a retrospective study using a nationally representative administrative claims database from January 1, 2010, through December 31, 2012. We compared rates of receipt of mammography within a 2-year time frame in diabetic and nondiabetic women ages 40 to 64. We used Healthcare Effectiveness Data and Information Set (HEDIS) logic to define women with diabetes. We used CPT and ICD-9 codes to identify mammogram services received. We calculated odds ratios with 95% confidence intervals to compare mammogram rates among diabetics compared to nondiabetics. Results: 1,723,674 nondiabetic women and 133,973 diabetic women were identified. Among women ages 40 to 49, diabetic women had significantly decreased mammography rates compared to nondiabetic women (OR 0.84; 95% CI 0.83, 0.85). Rates were also lower in diabetic women ages 50 to 64 (OR 0.88; 95% CI 0.88, 0.91). Despite lower mammography rates among diabetics, diabetic women had 1.78 times more visits than nondiabetic women. Conclusions: Women with diabetes are less likely to undergo routine screening mammography than women without diabetes, despite having more encounters with health care providers. This study serves as a reminder to provide timely preventive health services to all patients regardless of medical comorbidities.

2 Background: Women with atypical hyperplasia (AH) on breast biopsy have an aggregate increased risk of breast cancer (BC), but accurate personalized risk prediction is desirable to facilitate individual clinical management decisions. Currently used models provide poor BC risk prediction for women with AH. Our goal was to develop and validate an improved risk prediction model for women with AH. Methods: From a cohort of 13,538 women with benign breast disease from 1967-2001, pathology review confirmed 699 with AH. Clinical risk factors and histologic features of the tissue biopsy were recorded, and BC events were ascertained from study questionnaires, tumor registry, and review of medical records. Using a lasso approach, 23 variables were assessed for model inclusion. Lasso-identified features were then fit in a Cox regression model to estimate BC risk. Model discrimination was assessed with C-statistics in the model-building set and in a separate external validation set. Calibration was assessed by comparing observed to predicted breast cancer counts. Results: The model-building set comprised 699 women with 142 BC events (median follow-up 8.1 years), and the external validation set comprised 461 women with 114 BC events (median follow-up 11.4 years). The final model included three covariates: age at biopsy, age squared, and number of foci of AH. Model performance was good, with a C-statistic of 0.622 (SE = 0.027) in the model-building set and 0.594 (SE = 0.029) in the external validation set. The model is well-calibrated, with observed to expected numbers of BCs nearly equal across all post-biopsy follow-up years. Conclusions: We propose a new model for predicting BC risk in women with AH based on age at biopsy and number of foci of atypia. This model provides absolute risk estimates for women with AH, has good discriminatory ability, is well-calibrated, and validates in an external cohort.

BACKGROUNDWomen with atypical hyperplasia (AH) on breast biopsy have a substantially increased risk of breast cancer (BC). Here the BC risk for the extent and subtype of AH is reported for 2 separate cohorts.METHODSAll samples containing AH were included from 2 cohorts of women with benign breast disease (Mayo Clinic and Nashville). Histology review quantified the number of foci of atypical ductal hyperplasia (ADH) and atypical lobular hyperplasia (ALH). The BC risk was stratified for the number of AH foci within AH subtypes.RESULTSThe study included 708 Mayo AH subjects and 466 Nashville AH subjects. In the Mayo cohort, an increasing number of foci of AH was associated with a significant increase in the risk of BC both for ADH (relative risks of 2.61, 5.21, and 6.36 for 1, 2, and ≥3 foci, respectively; P for linear trend = .006) and for ALH (relative risks of 2.56, 3.50, and 6.79 for 1, 2, and ≥3 foci, respectively; P for linear trend = .001). In the Nashville cohort, the relative risks of BC for ADH were 2.70, 5.17, and 15.06 for 1, 2, and ≥3 foci, respectively (P for linear trend < .001); for ALH, the relative risks also increased but not significantly (2.61, 3.48, and 4.02, respectively; P = .148). When the Mayo and Nashville samples were combined, the risk increased significantly for 1, 2, and ≥3 foci: the relative risks were 2.65, 5.19, and 8.94, respectively, for ADH (P < .001) and 2.58, 3.49, and 4.97, respectively, for ALH (P = .001).CONCLUSIONSIn 2 independent cohort studies of benign breast disease, the extent of atypia stratified the long‐term BC risk for ADH and ALH. Cancer 2016;122:2971‐2978. © 2016 American Cancer Society.

Abstract: Malignant proliferating tricholemmal tumor (MPTT) is a rare adnexal neoplasm most commonly located on the scalp. We a 62-year-old woman who presented to her local physician with a palpable but not visible nodule of the left breast, initially diagnosed as squamous cell carcinoma. Histopathological evaluation of the reexcision specimen incidentally revealed ductal carcinoma in situ. On referral to our institution, the skin biopsy specimen was reviewed and interpreted as a low-grade MPTT. This patient and 2 previously reported cases of MPTT involving breast skin highlight presentation of a rare tumor at an unusual site and the potential for misdiagnosis as squamous cell carcinoma. Reexcision provided the unexpected benefit for our patient of early diagnosis of ductal carcinoma in situ not revealed by imaging.