Search

Background: Despite evidence of substantial breast cancer risk reduction, few high-risk women adopt chemopreventive medications such as selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs). Women with benign breast disease, such as atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS), have an increased risk of developing breast cancer and derive a greater benefit from antiestrogens compared to other high-risk women. Reasons for low uptake of chemoprevention include insufficient patient and clinician knowledge about antiestrogens, time constraints during the clinical encounter, and concerns about side effects. To address these barriers, we have developed patient and provider web-based decision support tools to improve informed choice about breast cancer chemoprevention among women with AH or LCIS. Study design: We are conducting a cluster-randomized controlled trial of clinical decision support to improve chemoprevention informed choice among women with AH or LCIS and their treating providers. Twenty-six U.S. sites through the SWOG Cancer Research Network were randomly assigned 1:1 to standard educational materials alone or in combination with the patient-centered decision aid (RealRisks) and provider decision support tool (BNAV). A total of 415 patients and 200 healthcare providers will be recruited from these sites. RealRisks consists of interactive modules to calculate personalized breast cancer risk and elicit preferences on chemoprevention. The modules are available in English and Spanish. BNAV is comprised of self-directed case-based learning modules on breast cancer risk assessment and chemoprevention. Patients complete questionnaires at baseline, 6 and 12 months. Providers complete surveys at baseline and after their enrolled patient’s 6-month clinical encounter. The primary endpoint is chemoprevention informed choice at 6 months, using a measure combining knowledge, attitude, and intention scales. Secondary endpoints include perceived breast cancer risk/worry, chemoprevention knowledge/intention, decision conflict/regret, shared decision-making, and chemoprevention uptake. For patients who begin chemoprevention, adherence and reasons for discontinuation are assessed annually for up to 5 years. Barriers and facilitators to implementing RealRisks and BNAV into clinic workflow will be assessed by conducting patient and provider interviews at baseline and mid-implementation. Eligibility criteria: Eligible patients include women, age 35-74 years, with AH or LCIS, no history of breast cancer, no prior use of SERMs or AIs, no bilateral mastectomies, English or Spanish-speaking, and access to the internet. Eligible providers include breast surgeons, medical oncologists, primary care providers, and physician extenders who see patients with AH or LCIS. Statistical methods: We have 90% power to detect a 15% increase in the frequency of chemoprevention informed choice with a 1-sided 0.025 level test, assuming an intraclass correlation (ICC) of 0.02 to account for clustering, roughly equal accrual at each site, 10% loss to follow-up, and ≤10% event rate in the control arm. Current/target accrual: The trial was activated on 9/1/2020. As of 7/7/2022, all 26 sites have been randomized, 157/200 providers and 184/415 patients have been enrolled. Discussion: Our hybrid effectiveness/implementation study seeks to evaluate the effectiveness of a multi-level intervention in promoting informed decision-making about breast cancer chemoprevention. Study results will provide valuable insights on how the decision support tools are integrated in diverse clinical settings. Citation Format: Katherine D. Crew, Garnet Anderson, Kathryn Arnold, Andrew Stieb, Jacquelyn N. Amenta, Cynthia Law, Ana Sandoval-Leon, Sarah Colonna, Tari King, Debra Mangino, Sandhya Pruthi, Maria Grosse Perdekamp, Christa Braun-Inglis, Stacy Krisher, Lisa Yee, Danielle Bertoni, Samantha Seaward, Kari B. Wisinski, Justin Floyd, Corrine Zarwan, Tarah J. Ballinger, Lindi VanderWalde, Masey M. Ross, Preston Steen, Shelly Lo, Alison Conlin, Kathleen Yost, John Ellerton, Erin Lin, Holly J. Pederson, Sagar Sardesai, Cheryl Jernigan, Dawn Hershman, Marian L. Neuhouser, Banu K. Arun, Rita Kukafka. SWOG 1904: Cluster-randomized controlled trial of patient and provider decision support to increase chemoprevention informed choice among women with atypical hyperplasia or lobular carcinoma in situ (MiCHOICE) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-15-01.

Historically, surgeons have provided subspecialty breast care. The development of a robust medical breast program in a large academic center staffed by trained primary care providers initially showed a shift in care of benign breast disease away from surgeons. In this review, we aim to revisit the practice after 20 years. Medical patients are defined as patients with symptomatic issues (eg, pain or lump), those at increased risk (due to family history, genetic mutations, or benign atypical lesions), or survivors in need of long-term care.Data for this review were collected retrospectively from an internal outpatient appointment dataset. The sample included data for 3 staff breast surgeons (2.6 clinical full-time employees [FTEs]), 3 staff medical breast physicians (2.4 clinical FTEs), and 2 medical breast advanced practice providers (2.0 clinical FTEs). Provider visit types were grouped into 1 of 4 categories (new medical, established medical, new surgical, and established surgical) in order to review the percentages of outpatient visits by provider group.Before the institution of the Medical Breast Service, 75% of breast surgeons' outpatient visits were for either new or established medical issues. Our most recent analyses show that between 2013 and 2017 breast surgeons averaged 19% of surgical outpatient visits for medical issues. Higher surgical outpatient visits have resulted in higher surgical volume, increased surgical productivity and time spent in the operating room, and decreased time to treatment at our institution. Both surgical and medical breast providers can be added and become rapidly productive with focus on their respective areas of expertise.The Medical Breast Service has met its expectations in providing access for symptomatic patients, personalized care for those at risk, and attentive care to long-term survivors. The program has allowed for surgeons to focus on surgical outpatient visits, driving surgical volume and productivity, and streamlining care.

Women at high inherited risk of ovarian cancer are offered risk-reducing salpingo-oophorectomy (RRSO) from age 35 to 45 years. Although potentially life-saving, RRSO may induce symptoms that negatively affect quality of life and impair long-term health. Clinical care following RRSO is often suboptimal. This scoping review describes how RRSO affects short- and long-term health and provides evidence-based international consensus recommendations for care from preoperative counselling to long-term disease prevention. This includes the efficacy and safety of hormonal and non-hormonal treatments for vasomotor symptoms, sleep disturbance and sexual dysfunction and effective approaches to prevent bone and cardiovascular disease.

Breast cancer remains the most common female malignancy in the United States. Reducing this cancer burden involves identification of high-risk individuals and personalized risk management. Because coronary artery disease remains the primary cause of death for women, any intervention to reduce breast cancer risk must be weighed against comorbidities and interventions affecting cardiovascular risk reduction. For select women at increased risk for breast cancer, preventive medication can greatly decrease risk and is vastly underutilized. Women's health clinicians are poised to evaluate risk, promote breast cancer risk reduction, and manage overall health.

Background: Personalized breast cancer (BC) risk assessment depends on known traditional risk factors, specific germline mutations, and genome-wide polygenic risk scores (PRS). PRS explains a substantial proportion of genetic BC susceptibility. Accuracy of BC risk prediction may be improved by combining a PRS with traditional risk factors. We recently developed and validated a 149-SNP PRS for women of diverse ancestries using ancestry-informative genetic markers and combined this with version 7 of the Tyrer-Cuzick (TC) model to generate a Combined Risk Score (CRS). Here, we describe a pre-specified prospective longitudinal clinical validation of CRS as a predictor of BC risk. Methods: Women in the U.S. who were referred for clinical genetic testing between January 2017 and February 2019 were matched to medical and hospital claims in an anonymized dataset. Women with a pathogenic mutation in a BC-related gene were excluded from analysis. Follow-up began 4 months after testing and extended to the earliest date of BC diagnosis, censoring at the time of BC preventive treatment, or November 1, 2019. Incident BC events were determined by an ICD10 code of C50.* and confirmed by relevant treatment codes. CRS calibration was evaluated by the ratio of observed (O) to expected (E) incident BCs for the full cohort, and for women split into event-based 5-year CRS risk deciles. Cox proportional hazards models were used to evaluate discriminatory accuracy in terms of hazard ratios (HR) with 95% confidence intervals (CI) and p-values from likelihood ratio chi-squared statistics. Kaplan-Meier analysis was used to examine risk for women split into high- or low-risk groups according to a 3% 5-year CRS risk threshold. Results: 130,058 women with 148,349 total patient years met study eligibility criteria and were matched to claims data. Over a median (range) follow-up of 12.1 (4.0-29.5) months, 340 incident BC events were observed. The CRS was well calibrated in the overall cohort with an O/E ratio of 1.11 (95% CI=0.99-1.23) and within deciles of predicted risk (Table). Importantly, in the highest risk decile, the O/E was 0.91 (95% CI=0.63-1.27) with CRS, but 0.67 (95% CI=0.46-0.94) with TC alone, illustrating the superior calibration of CRS. In a Cox model adjusted for age at testing, PRS had an HR per standard deviation (SD) of 1.48 (95% CI=1.33-1.64, p=2.55×10-13); the HR/SD was 1.43 (95% CI=1.29-1.59, p=1.61×10-11) after adjusting for family history. In a bivariate analysis using both CRS and TC to predict time to BC, CRS added significantly to the model after accounting for TC (HR/SD=2.89, 95% CI=2.12-3.94, p=1.20×10-11), whereas TC did not add significant information after accounting for CRS. 15,986 (12.3%) women were above the CRS high-risk threshold, including 123 with events. A total of 10,248 (7.9%) women were reclassified by the CRS model compared to the TC model. Among women who were classified as high-risk by TC, 32.6% were reclassified as low-risk by CRS; among those classified as low-risk by TC, 4.3% were reclassified as high-risk by CRS. The CRS high-risk group experienced events at over three times the rate of the low-risk group (HR=3.75, 95% CI=3.00-4.68, p=6.39×10-27). Conclusion: The CRS was well-calibrated in predicting BC and significantly improved upon a traditional risk factor model. Clinical use of the CRS may lead to improved BC prevention and screening strategies. Table: Absolute risk calibration by 5-year risk decile Incidence is reported per 1,000 women-years. 34 breast cancers were observed per decile. Citation Format: Brent Mabey, Elisha Hughes, Braden Probst, Holly J. Pederson, Timothy Simmons, Brian Morris, Brooke Hullinger, Susan Domchek, Charis Eng, Monique Gary, Jennifer Klemp, Semanti Mukherjee, Vijai Joseph, Kenneth Offit, Olufunmilayo I. Olopade, Sandhya Pruthi, Allison W. Kurian, Mark E. Robson, Pat Whitworth, Susanne Wagner, Jerry Lanchbury, Thomas Slavin, Alexander Gutin. PD14-05 Prospective longitudinal validation of a breast cancer risk prediction model in a cohort of 130,058 women [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD14-05.

Personalized management of patients at risk ideally should involve a multidisciplinary team of not only genetic counselors and surgeons, but also women's health or menopause specialists, knowledgeable psychologists, and primary care providers or obstetrician-gynecologists aware of the risks and fears "previvors" (survivors of a predisposition to cancer who have not had the disease) face as well as the issues that are common postoperatively. Identification of patients at risk for hereditary cancer, understanding of current genetic testing modalities and potential results, knowledge about screening and prevention including timing of surveillance, preventive medication and risk-reducing surgeries, understanding limitations and comorbidities associated with these risk management strategies and long-term psychological support are all important in hereditary cancer management. We describe issues surrounding the identification of the high-risk patient, universal testing in breast and ovarian cancer, and testing in special populations. We describe a simplified approach to understanding and communicating genetic testing results and nuances of testing including direct-to-consumer testing. We highlight concerns surrounding breast cancer screening during pregnancy and lactation. A framework for practical management and counseling of women who opt for risk-reducing salpingo-oophorectomy or risk-reducing mastectomy or both is provided. We provide an in-depth discussion of questions that arise in relation to timing of surgery, fertility preservation, management of menopausal symptoms, and surgical technique. Alternative choices in women who choose to delay bilateral salpingo-oophorectomy are reviewed. Finally, the psychosocial effects of carrying a genetic mutation and the issues that women face when undergoing to risk-reducing surgery including adjustment, sexuality issues, and cosmesis are addressed.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic or likely pathogenic variants associated with increased risk of breast, ovarian, and pancreatic cancer and recommended approaches to genetic testing/counseling and management strategies in individuals with these pathogenic or likely pathogenic variants. This manuscript focuses on cancer risk and risk management for BRCA-related breast/ovarian cancer syndrome and Li-Fraumeni syndrome. Carriers of a BRCA1/2 pathogenic or likely pathogenic variant have an excessive risk for both breast and ovarian cancer that warrants consideration of more intensive screening and preventive strategies. There is also evidence that risks of prostate cancer and pancreatic cancer are elevated in these carriers. Li-Fraumeni syndrome is a highly penetrant cancer syndrome associated with a high lifetime risk for cancer, including soft tissue sarcomas, osteosarcomas, premenopausal breast cancer, colon cancer, gastric cancer, adrenocortical carcinoma, and brain tumors.

Testing for hereditary predisposition to breast cancer is rapidly expanding in parallel with the emerging field of molecular genetics given the associated implications for screening, risk reduction and cancer therapeutics for identified gene mutation carriers. With the advent of next generation multigene panel testing for hereditary predisposition and decreasing cost for that testing, more breast cancer patients (and unaffected family members) are undergoing cancer genetic testing. With multiple genes being tested and the myriad of possible results and implications for patients and their families, the process of genetic counseling is of paramount importance in promoting understanding by both patients and providers of risks and options for risk management. Guidelines exist to facilitate a multidisciplinary approach to management of individuals identified as being at increased risk, and there must be an appreciation for flexibility as guidelines are applied to individual families. This update summarizes recommendations regarding who may benefit from breast cancer risk assessment and genetic counseling, controversies regarding inclusion for testing and provides a framework for the practical management of high risk gene carriers.

Objective Lynch syndrome is an inherited genetic disorder associated with a predisposition to early-onset colorectal and endometrial cancers, but breast cancer risk in these patients is debated. The aim of this study is to evaluate breast cancer rates in a cohort of Lynch syndrome patients, as well as to identify women who may be eligible for additional breast cancer specific genetic testing or enhanced breast surveillance (contrast-enhanced magnetic resonance imaging (MRI) screening). Materials and methods Using a hereditary colorectal cancer registry at a single academic institution for identification of patients with Lynch syndrome, a retrospective chart review was performed of 188 women with DNA mismatch repair (MMR) mutations. The Tyrer-Cuzick model was used to estimate breast cancer risk in patients without breast cancer. Results The prevalence of breast cancer differed based on mutation type (p=0.0043), as 27% of women with a PMS2 mutation were diagnosed with breast cancer, compared to 3%, 4%, and 9% in MLH1, MSH2, and MSH6 patients. The average age at diagnosis for women with a PMS2 mutation was 46.7 years. Additionally, 7.5% of unaffected women had an estimated lifetime risk of breast cancer greater than 20%. 46/188 (24.4%) of patients were eligible for breast specific genetic testing. Conclusion Our analysis suggests that Lynch syndrome patients with PMS2 mutations may be at higher risk of developing breast cancer. Additionally, the personal and family history of cancer suggests crossover in eligibility for breast specific genetic testing in a significant number of patients (16.5-24.4%). Also, many women are eligible for enhanced breast surveillance (7.5%) which would otherwise not be offered.

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic provide recommendations for genetic testing and counseling for hereditary cancer syndromes, and risk management recommendations for patients who are diagnosed with syndromes associated with an increased risk of these cancers. The NCCN panel meets at least annually to review comments, examine relevant new data, and reevaluate and update recommendations. These NCCN Guidelines Insights summarize the panel’s discussion and most recent recommendations regarding criteria for high-penetrance genes associated with breast and ovarian cancer beyond BRCA1/2, pancreas screening and genes associated with pancreatic cancer, genetic testing for the purpose of systemic therapy decision-making, and testing for people with Ashkenazi Jewish ancestry.

ImportanceIdentifying hereditary cancer predisposition facilitates high-risk organ-specific cancer surveillance and prevention. In PTEN hamartoma tumor syndrome (PHTS), longitudinal studies remain lacking, and there are insufficient data on cancers in children and young adults, as well as individuals with neurodevelopmental disorders (NDD).ObjectiveTo evaluate lifetime cancer risks, including second malignant neoplasms (SMN), among patients with PHTS.Design, Setting, and ParticipantsProspective longitudinal cohort study (September 1, 2005, through January 6, 2022). General population risks from the Surveillance, Epidemiology, and End Results database. Patients with PHTS, molecularly defined as carrying germline PTEN variants, were accrued from community and academic medical centers throughout North America, South America, Europe, Australia, and Asia. Data were analyzed from July 2022 to February 2023.ExposuresReview of physical and electronic medical records, and follow-up through clinical visits or telephone interviews.Main Outcomes and MeasuresLifetime cancer risks in PHTS relative to the general population.ResultsA total of 7302 patients were prospectively accrued, 701 of whom had germline PTEN variants (median [IQR] age at consent, 38 [12-52] years; 413 female patients [59%]). Longitudinal follow-up data could be obtained for 260 patients (37%), with a median (IQR) follow-up of 4 (2-8) years. Of the 701 patients, 341 (49%) received at least 1 cancer diagnosis, with 144 (42%) of those having SMN. The study found significantly elevated lifetime risks for breast (91%), endometrial (48%), thyroid (33%), kidney (30%), and colorectal cancers (17%), as well as melanoma (5%). Cancer diagnoses were also observed in children and young adults with PHTS (15%) and in patients with PHTS with neurodevelopmental disorders (11%). Elevated risks (P P Conclusions and RelevanceThis cohort study found consistently elevated lifetime cancer risks in PHTS. Organ-specific surveillance should continue in patients with PHTS. Additional study is required to ascertain elevated cancer risks in patients with PHTS with NDD.

BACKGROUND AND OBJECTIVES Screening for breast cancer in highly penetrant mutation carriers during pregnancy and lactation is challenging and consensus guidelines are lacking. This study evaluates the lapse in screening and the interval pregnancy-associated breast cancer rate. METHODS A single-institution retrospective cohort study of pregnant and lactating patients with known pathogenic germline mutations was performed. Lapse in screening was defined as the interval between the last screening imaging exam obtained before last menstrual period and the subsequent screening imaging. RESULTS Out of 685 patients, 42 had 1-3 evaluable pregnancies (54 total - 28 managed in High Risk Breast Clinic and 26 by OB/GYN). Mutations were observed in patients in BRCA1 (49%), BRCA2 (36%), CDH1 (5%), CHEK2 (2%), ATM (2%), NF1 (3%), and MSH2 (3%). The average screening lapse was 25 [19, 30] months for patients followed in the High Risk Clinic versus 32.5 [21, 65.75] months for patients followed with Routine Care (p = 0.035). We identified three cases of pregnancy-associated breast cancer (interval cancer rate 6%). CONCLUSIONS Patients with highly penetrant mutations are at risk for the development of interval pregnancy-associated breast cancer. Development of consistent screening guidelines and adherence to those guidelines is needed for this patient population.

Background: African American (AA) women are more likely to have breast cancer at a younger age and be diagnosed with triple negative breast cancer (TNBC), which is as yet unexplained. We examined results of multi-gene panel testing in AA women with TNBC tested at a large commercial laboratory to assess the utility of gene panels and findings in this group. Methods: We assessed individuals who had clinical hereditary cancer testing with a multi-gene panel between September 2013 and May 2018. Women were included for analysis if they had a personal history of TNBC and self-identified as having any AA ancestry (n=3,268) or only Caucasian (CA) ancestry (n=8,953). Clinical data was collected from provider-completed test request forms. Comparisons were performed using descriptive statistics, t-tests (continuous variables), and chi-square tests (categorical variables) adjusting for multiple testing when necessary. Results: In this cohort, AA women were significantly more likely than CA women to meet NCCN guidelines (97.5% vs. 96.6%, p=0.010) and significantly less likely to have an additional personal (16.2% vs. 21.8%, p1 VUS (8.6% vs. 2.6%, p Conclusions: In the era of multi-gene panel testing, this large cohort of patients with TNBC supports the use of panel testing in AA women with TNBC regardless of age or additional personal/family history of cancer. While additional research to the rate and pathogenicity of VUS in AA women is needed, genetic counseling is necessary to explain the possibility and meaning of a VUS in this group. Table 1.Distribution of PVs in BC-related genes according to ancestry AA WomenCA WomenGeneN (%)N (%)Any Breast Cancer-Related Gene347 (10.6)1104 (12.3)BRCA1132 (4.0)496 (5.5)BRCA297 (3.0)236 (2.6)ATM6 (0.2)25 (0.3)BARD119 (0.6)67 (0.7)BRIP120 (0.6)46 (0.5)CDH11 ( Citation Format: Pederson HJ, Heald B, Budd GT, Bernhisel R, Cummings S, Saam JR, Lancaster JM, Grobmyer SR, Eng C. Defining the spectrum of germline variants among African American patients with triple negative breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-10-01.

Early breast cancer detection decreases mortality. As a result, it is imperative that primary care physicians are able to identify those individuals who are at an increased risk for breast cancer and understand how to help the patients manage that risk. Hereditary cancer syndromes in particular are dangerous and under-recognized. Various risk assessment tools are available for patients who are not at hereditary risk to help determine who may be eligible for enhanced screening or those who may benefit from preventive medication, and many imaging centers have now incorporated a form of risk assessment with associated recommendations into their reporting structure. Some patients even wish to consider risk-reducing surgery, which requires special counseling and support. All women should be risk stratified as early as possible so that those at a high risk can benefit from risk-stratified care. The management of patients at increased risk for the development of breast cancer has become increasingly challenging and nuanced with the exploding field of germline genetic testing and its implications for personalized care, and an increasing number of available options for high-quality supplemental breast imaging, particularly for the patient with dense breast tissue. This chapter aims to outline the identification and management of the high-risk patient, focusing on salient genetic and nongenetic risk factors, available options for risk management, and recommendations for risk modification for all women.

Personalized management of patients at risk ideally should involve a multidisciplinary team of not only genetic counselors and surgeons, but also women's health or menopause specialists, knowledgeable psychologists, and primary care providers or obstetrician-gynecologists aware of the risks and fears "previvors" (survivors of a predisposition to cancer who have not had the disease) face as well as the issues that are common postoperatively. Identification of patients at risk for hereditary cancer, understanding of current genetic testing modalities and potential results, knowledge about screening and prevention including timing of surveillance, preventive medication and risk-reducing surgeries, understanding limitations and comorbidities associated with these risk management strategies and long-term psychological support are all important in hereditary cancer management. We describe issues surrounding the identification of the high-risk patient, universal testing in breast and ovarian cancer, and testing in special populations. We describe a simplified approach to understanding and communicating genetic testing results and nuances of testing including direct-to-consumer testing. We highlight concerns surrounding breast cancer screening during pregnancy and lactation. A framework for practical management and counseling of women who opt for risk-reducing salpingo-oophorectomy or risk-reducing mastectomy or both is provided. We provide an in-depth discussion of questions that arise in relation to timing of surgery, fertility preservation, management of menopausal symptoms, and surgical technique. Alternative choices in women who choose to delay bilateral salpingo-oophorectomy are reviewed. Finally, the psychosocial effects of carrying a genetic mutation and the issues that women face when undergoing to risk-reducing surgery including adjustment, sexuality issues, and cosmesis are addressed.

Background Bilateral nipple-sparing mastectomy (NSM) is a technically feasible operation and is associated with excellent cosmetic outcomes. The aim of this study was to evaluate trends in patient characteristics, indications for surgery and long-term outcomes of bilateral NSM for breast cancer risk reduction over time. Methods A review of a single-centre experience with bilateral NSM performed between 2001 and 2017 for breast cancer risk reduction in patients without breast cancer was performed. Trends in patient characteristics and indications for surgery were evaluated over four time intervals: 2001-2005, 2006-2009, 2010-2013 and 2014-2017. Statistical analysis was performed using χ2 tests. Results Over the study period, 272 NSMs were performed in 136 patients; their median age was 41 years. The number of bilateral NSMs performed increased over time. The most common indication was a mutation in breast cancer-associated genes (104 patients, 76·5 per cent), which included BRCA1 (62 patients), BRCA2 (35), PTEN (2), TP53 (3) and ATM (2). Other indications were family history of breast cancer (19 patients, 14·0 per cent), lobular carcinoma in situ (10, 7·4 per cent) and a history of mantle irradiation (3, 2·2 per cent). The proportion of patients having a bilateral NSM for mutation in a breast cancer-associated gene increased over time (2001-2005: 2 of 12; 2006-2009: 9 of 17; 2010-2013: 34 of 41; 2014-2017: 61 of 66; P

With the advent of multigene panel testing for breast cancer patients, germline mutations with unknown association with cancer risk, known as variants of uncertain significance (VUS), are being increasingly identified. Some studies have shown higher rates of contralateral prophylactic mastectomies (CPM) in these patients, despite lack of evidence to support this intervention. We analyzed surgical choices in patients who were identified to have VUS.A retrospective review was performed of patients with triple-negative breast cancer treated at a single institution after multigene panel tests became available (September 1, 2013 to February 28, 2017). Rates of genetic testing, results of testing, and surgical decision making were evaluated. Chi-square or Fisher's exact test was used to compare categorical variables. A p value0.05 was considered statistically significant.There were 477 triple-negative breast cancer patients identified; 331 met established criteria for genetic testing and 226 (68.3%) underwent genetic testing (multigene panel, n = 130 and BRCA1/2 testing, n = 96). All of them received risk-appropriate genetic counseling and follow-up. Of these, 29 (12.8%) patients had pathogenic mutations in BRCA1/2 or PALB2 (Mut+), 42 (18.6%) had VUS (VUS+), and 155 (68.6%) had no mutations identified (Mut-). Variants of uncertain significance in 6 of 42 patients (14.3%) were later reclassified as normal variants. Eighty-eight percent of Mut+ patients underwent CPM compared with 20.1% of Mut- and 21.4% of VUS+ patients (p0.001 for both). Rates of CPM were not significantly different between VUS+ and Mut- (p = 0.37). Multigene panel testing detected pathogenic mutations in non-breast cancer-associated genes in 6 patients, with significant management implications.When combined with risk-appropriate genetic counseling, detection of VUS did not lead to excessive CPM in this cohort of triple-negative breast cancer patients. Furthermore, panel testing detected mutations in non-breast cancer-associated genes, which had significant implications on management and outcomes.

Background Despite findings that the Tyrer-Cuzick (IBIS Breast Cancer Risk Evaluation Tool or TC) model is more predictive of breast cancer risk than the Gail model (NCI maintained Breast Cancer Risk Assessment Tool or BCRAT), BCRAT is commonly clinically used as per the United States Preventive Services Task Force (USPSTF), with a 5-year risk for breast cancer (BC) of greater than 3% on BCRAT, the benefits of preventive medication likely outweigh the risks. We aimed to compare the models, 1: to see if a 10 year risk estimate per the TC model reliably correlated with the 3% 5 year risk per BCRAT, and 2: to analyze the subset of patients with atypical hyperplasia (AH) and lobular carcinoma in situ (LCIS) who are known both to be at high risk for breast cancer and to benefit from chemoprevention. Our hypothesis is that BCRAT has limited utility in risk estimation, and the most comprehensive model for risk estimation and clinical decision making is TC. Methods 200 women ages 35-64 women followed in benign breast clinic were included. Risk estimations were run using BCRAT, TC version 7 (v7) and TC version 8 (v8). A Pearson's Correlation test was conducted to investigate the relationship between the TC models and the BCRAT model. A p-value < 0.05 was considered statistically significant. Results Analysis showed a positive moderate-strength relationship between the TC v7 10-year risk and the 5-year BCRAT risk for this population (R = 0.468, P A total of 36 patients were diagnosed with AH, 2 patients were diagnosed with LCIS and 7 patients were diagnosed with both AH and LCIS. 11 patients who had AH had an estimated 5-year risk per the BCRAT model of Of the 30 patients who had a BCRAT 5-year estimated risk of BC of >3% but no AH or LCIS, 12 had two first degree relatives with breast cancer and 16 had a first-degree relative with BC and at least two benign breast biopsies. Conclusion BCRAT is limited and caution is warranted with its use in assessing risk and for counseling around chemoprevention benefit. There is not reliable correlation between the 5 year BCRAT risk estimate and the 10 year TC risk estimate. Chemoprevention should be discussed for patients with AH, LCIS or 2+ first degree relatives with breast cancer. Further, BCRAT may underestimate risk in minority populations and others with AH. For a limited group of patients with moderate risk, dual modeling may be clinically useful in making chemopreventive recommendations. Citation Format: Pederson HJ, Yanda C, Kline M, Stephens M, Goraya ST, Grobmyer SR, Kattan MW. Assessing utility of breast cancer risk assessment tool in comparison to Tyrer-Cuzick model for determination of breast cancer risk and implications for chemoprevention [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-09-09.

BACKGROUND Breast cancer risk estimates for atypical lesions are based primarily on case-control studies of patients with open biopsies. The authors report the cumulative breast cancer incidence after a core biopsy diagnosis of atypical hyperplasia (ductal or lobular) or lobular carcinoma in situ. METHODS A cohort study with central pathology review was conducted on 393 patients who had core biopsy diagnoses of atypical hyperplasia and lobular carcinoma in situ from 1995 through 2010. Follow-up was available for 255 of 264 patients (97%) at a median of 87 months (range, 3-236 months). RESULTS There were 212 patients (54%) who were not upgraded on excision and had no personal history of breast cancer. Of these, 21 of 212 (9.9%) developed breast cancer, including 15 invasive carcinomas, 4 ductal carcinomas in situ, 1 pleomorphic lobular carcinoma in situ, and 1 unknown type. The prior core biopsy diagnoses were atypical ductal hyperplasia for 11 patients (52%) and atypical lobular hyperplasia/lobular carcinoma in situ in the remaining 10 patients (48%). The number of atypical foci in the core biopsy was not significantly associated with the subsequent development of breast cancer (P = .42). Of the 15 invasive carcinomas, 11 (73%) were ipsilateral, 11 (73%) were pathologic T1 tumors, 5 (33%) were pathologic N1 tumors, 13 (87%) were estrogen receptor-positive, and 1 (7%) was amplified for human epidermal growth factor receptor 2. CONCLUSIONS In patients who had an initial diagnosis of atypical hyperplasia or lobular carcinoma in situ on core biopsy, the 7-year cumulative breast cancer incidence was 9.9%. Most tumors were ipsilateral, stage I, estrogen receptor-positive, invasive carcinomas. The current data support close clinical and radiologic follow-up for more than 5 years in this patient population. Cancer 2018;124:459-65. © 2017 American Cancer Society.

Bilateral breast magnetic resonance imaging (MRI) is commonly used in the diagnostic workup of breast cancer (BC) to assess extent of disease and identify occult foci of disease. However, evidence for routine use of pre-operative MRI is lacking. Breast MRI is costly and can lead to unnecessary tests and treatment delays. Clinical care pathways (care paths) are value-based guidelines, which define management recommendations derived by expert consensus and available evidence based data. At Cleveland Clinic, care paths created for newly diagnosed BC patients recommend selective use of pre-operative MRI. We evaluated the number of pre-operative MRIs ordered before and after implementing an institution wide BC care paths in April 2014.A retrospective review was conducted of BC cases during the years 2012, 2014, and part of 2015. Patient, tumor and treatment characteristics were collected. Pre-operative MRI utilization was compared before and after care path implementation.We identified 1,515 BC patients during the study period. Patients were more likely to undergo pre-operative MRI in 2012 than 2014 (OR: 2.77; P0.001; 95% CI: 1.94-3.94) or 2015 (OR: 4.14; P0.001; 95% CI: 2.51-6.83). There was a significant decrease in pre-operative MRI utilization between 2012 and 2014 (P0.001) after adjustment for pre-operative MRIs ordered for care path indications.Implementation of online BC care paths at our institution was associated with a decreased use of pre-operative MRI overall and in patients without a BC care path indication, driving value based care through the reduction of pre-operative breast MRIs.

Background. Triple negative breast cancer (TNBC) has been associated with a relatively high rate of germline BRCA1/2 deleterious mutations (11-20%). With use of panel testing, additional predisposition genes are being identified. Among Caucasian (CC) patients (pts), pathogenic germline variants in BRCA1/2 are mainly associated with TNBC. However, these may not fully explain the higher incidence of TNBC among African Americans (AA). Additionally, partly due to under-testing among AA, the distribution of predisposition genes for AA TNBC pts is unknown, and a greater proportion of germline alterations may be classified as a variant of uncertain significance (VUS). We hypothesized that additional clinically significant germline mutations in genes, other than in BRCA1/2, may explain the increased incidence of TNBC among AA, which may be better elucidated by panel testing. Methods. A retrospective chart review was completed of all self-identified CC and AA TNBC pts who presented to two institutions from 10/2013 to 12/2016. A total of 596 pts were analyzed. 434 (73%) were CC and 162 (27%) were AA. Clinicopathologic features including histologic subtype, age, gender, bilateral disease and stage were examined. Patients were assessed for meeting the National Comprehensive Cancer Network (NCCN) criteria for genetic testing in TNBC, type of testing performed, and the results. The distribution of mutations in higher penetrance genes (BRCA1, BRCA2, and PALB2), pathogenic variants in other genes, and VUS in AA vs. CC were analyzed. Significance was determined using a two-tailed Fisher exact test with significance of p Results. 306/434 (71%) CC and 98/162 (60%) AA TNBC pts met criteria for genetic testing (p=0.023). For those who met NCCN criteria for testing, 216/306 (71%) CC and 66/98 (67%) AA TNBC pts underwent testing (p=0.61). For all pts, the average age of first diagnosis was 59.5 (SD 14) for CC vs. 62.4 (SD 12.9) for AA pts. For pts who underwent testing, regardless of meeting NCCN criteria, 18% (40/221) of CC vs.12% (8/68) of AA patients had a mutation in a higher penetrance gene (p=0.27), 1% (3/221) of CC vs. 3% (2/68) of AA had a mutation in other genes (BRIP1, Lynch genes; p=0.34), and 16% (36/221) of CC vs. 18% (12/68) of AA had a VUS (p=0.982). Of VUS, 42% (5/12) in AA vs. 19% (7/36) in CC were in higher penetrance breast cancer genes (p=0.14). Conclusion. More CC than AA TNBC pts met criteria for genetic testing. This difference may in part be explained by the later age at diagnosis for AA given that age is a major factor in determining genetic testing. Broadening eligibility for testing in AA may help to identify more patients with an underlying genetic predisposition to TNBC. No difference was seen in the frequency of higher penetrance genes, other genes, and VUS between AA and CC pts. However, important non-BRCA genes were identified with panel testing in both AA and CC pts. In addition to broadening testing criteria for existing multi-gene panels, further genetic analysis may be necessary to explain the predisposition to TNBC in AA pts. To our knowledge, this is the first report of evaluation of predisposition genes among AA TNBC pts using germline panel testing. Citation Format: Nizialek EA, Gopalakrishnan D, Yanda C, Abbas H, Kline M, Stephens M, Grobmyer SR, Eng C, Mitchell A, Pederson H, Vinayak S. Germline alterations in African-American versus Caucasian patients with triple-negative breast cancer in the era of multi-gene panel testing [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-06-04.

There have been rapid advances in precision medicine since the Human Genome Project was completed in 2003, including several noteworthy advances in Women's Health. This includes significant advances in predicting individualized cancer risk based on hereditary cancer genetic testing, with the number of known cancer-predisposition genes extending well beyond BRCA1 and BRCA2. This has been coupled with gene-specific management guidelines for several gynecologic cancers. In addition, genetic testing can also inform therapy selection for women with gynecologic cancers. Here we address hereditary cancer and practical cancer genetics as it relates to the practicing Obstetrician/Gynecologist.

Genitourinary syndrome of menopause is a condition describing the hypoestrogenic effects on the female genitals and lower urinary tract leading to symptoms such as vaginal dryness, vulvar and vaginal burning, dyspareunia and dysuria. Genitourinary syndrome of menopause is experienced by over half of postmenopausal women, and is even more pervasive in women with cancer. Due to treatments such as surgery, chemotherapy, radiation, and hormonal therapy, women may experience early menopause resulting in earlier and more severe symptoms. Understanding the scope of this issue in female breast and gynecologic cancer survivors and identifying treatment options for this complex patient population are paramount. Tailored patient treatments include nonhormonal therapies (vaginal moisturizers, lubricants, pelvic floor physical therapy, dilator therapy, counseling), systemic and local hormonal therapies. Consensus recommendations by medical societies and associated evidence are reviewed, with emphasis on safety and efficacy of local vaginal hormonal therapies, and management variations noted depending on cancer type and characteristics. With knowledge and understanding of the unmet need associated with under-recognition and under-treatment of genitourinary syndrome of menopause, providers caring for women with cancer are in a position to improve the quality of life of their patients by providing safe and effective treatments.

10502 Background: BC risk is influenced by single-nucleotide polymorphisms (SNPs) with small effects that can be aggregated into polygenic risk scores (PRSs). PRSs have primarily been developed and validated for populations of European descent. To make a PRS available for all women, we developed and validated a novel global PRS (gPRS) that utilizes individual ancestral genetic composition. Methods: Ancestry-specific PRSs corresponding to 3 continental ancestries were developed from 149 SNPs (93 BC and 56 ancestry-informative): an African PRS was developed using a cohort of 31,126 self-reported African American patients referred for hereditary cancer testing; an East Asian PRS was developed based on published data from the Asia Breast Cancer Consortium; and a European PRS was developed using data from the Breast Cancer Association Consortium and 24,259 European hereditary cancer testing patients. For each patient, ancestry-informative SNPs were used to calculate the fractional ancestry attributable to each of the 3 continents. The gPRS was the sum of ancestry specific PRSs weighted according to genetic ancestral composition. In an independent validation cohort (N = 62,707), we evaluated discrimination and calibration of gPRS, and compared performance against a previously described 86-SNP PRS for women of European ancestry. Associations of SNPs and PRSs with BC were analyzed using logistic regression adjusted for personal and family cancer history, age, and ancestry. Odds ratios (ORs) are reported per standard deviation within the corresponding patient population. P-values are reported as two-sided. Results: The gPRS was strongly associated with BC in the full validation cohort and in sub-cohorts defined by self-reported ancestry (Table). 95% (88/93) of BC SNPs had ≥1% frequency of risk alleles within each of the self-reported populations. Compared to the aforementioned 86-SNP PRS, the gPRS showed improved discrimination overall, and within each sub-cohort, with the exception of the Asian population where the sample size was too small to show superiority of either score. The 86-SNP PRS was calibrated for white non-Hispanic women but mis-calibrated for non-European ancestries. The gPRS was properly calibrated for all women. Conclusions: The 149-SNP gPRS is validated and calibrated for women of all ancestries. Combined with clinical and biological risk factors, this approach may offer improved risk stratification for all women, regardless of ancestry.[Table: see text]

Hereditary syndromes that increase the risk of breast cancer are not common, but it is critical to recognize and manage them appropriately. This paper reviews the management of patients with the most common hereditary breast cancer syndromes, ie, hereditary breast and ovarian cancer syndrome, hereditary diffuse gastric cancer, Cowden syndrome (PTEN hamartoma tumor syndrome), Peutz-Jeghers syndrome, and Li-Fraumeni syndrome.

Background: Work-up of patients with breast symptoms and radiographic abnormalities, risk management, and survivorship care are vital elements in a multidisciplinary breast cancer program. Breast surgeons have traditionally provided for these needs, but with intense clinical demands and with efforts to reduce treatment time, access for patients with these problems can be a challenge. The medical breast specialist (MBS) is defined as a primary care physician who has been provided with additional training in benign and malignant breast disease [Smedira, AIM 2008]. With increasing need for providers, a fellowship for training MBS was designed for board eligible or board certified internists, family practitioners, obstetricians/gynecologists, and has recently been expanded for board certified primary care nurse practitioners, one of the first of its kind in the country. In our practice, medical breast visits (MBV) are defined as clinical visits for evaluation or follow-up of patients with breast symptoms, high risk management, and/or survivorship. Methods: The MBS Program at our institution was established in 1997, with expansion involving a formalized training for Nurse Practitioners in 2013. The medical breast fellowship uses a defined curriculum and offers nurse practitioners a six month multidisciplinary program with multiple rotations including medical breast clinic, surgical breast clinic, breast imaging, medical oncology, radiation oncology, genetics, pathology, plastic surgery, physical therapy, and psych-oncology. We analyzed the impact of trained NPs on overall medical breast and breast center volumes and clinical workflow. Our prospectively maintained Electronic Medical Records (EMR) system, which allows the acquisition of volume and practice pattern data, was utilized for this analysis. Results: The number of MBV has significantly increased between 2008 and 2014 (p Conclusions: Medical breast visits account for a large percentage of patients seen within a multidisciplinary breast cancer program. The development of a curriculum for training NP medical breast specialists enables the rapid incorporation of a NP into a multidisciplinary cancer program. The training of a NP within the fellowship can increase patient access, timeliness of care, and can facilitate streamlining of a breast cancer practice to optimize patient care. Citation Format: Iyer PH, Kline M, Oliphant D, Crowe J, Grobmyer S, Pederson H. Education and integration of medical breast nurse practitioners in a multidisciplinary breast cancer program. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-09-03.

Attention to issues related to breast cancer survivorship is important to optimize oncologic outcomes and quality of life. Patients, cancer care providers, and primary care providers must work collaboratively to address these issues. Late and long-term effects can be related to surgery, radiation therapy, chemotherapy, and hormonal therapy. Common survivorship issues include fatigue, cognitive changes, cardiac dysfunction, sexuality, psychosocial issues, weight management, pain, fertility, and menopausal symptoms. Genetic and genomic testing will inform, stratify risk, and guide treatment options and management for appropriate personalized follow-up. Survivorship care plans are now mandated by national accrediting organizations, but require care models that have the ability to develop and deliver this tool and the necessary services to meet the needs of each survivor. This chapter aims to describe the scope of survivorship issues with advice on management of specific issues and stresses the importance of the creation of a multidisciplinary shared care practice model.

Breast cancer risk estimates for atypical lesions are based primarily on case-control studies of patients with open biopsies. The authors report the cumulative breast cancer incidence after a core biopsy diagnosis of atypical hyperplasia (ductal or lobular) or lobular carcinoma in situ.A cohort study with central pathology review was conducted on 393 patients who had core biopsy diagnoses of atypical hyperplasia and lobular carcinoma in situ from 1995 through 2010. Follow-up was available for 255 of 264 patients (97%) at a median of 87 months (range, 3-236 months).There were 212 patients (54%) who were not upgraded on excision and had no personal history of breast cancer. Of these, 21 of 212 (9.9%) developed breast cancer, including 15 invasive carcinomas, 4 ductal carcinomas in situ, 1 pleomorphic lobular carcinoma in situ, and 1 unknown type. The prior core biopsy diagnoses were atypical ductal hyperplasia for 11 patients (52%) and atypical lobular hyperplasia/lobular carcinoma in situ in the remaining 10 patients (48%). The number of atypical foci in the core biopsy was not significantly associated with the subsequent development of breast cancer (P = .42). Of the 15 invasive carcinomas, 11 (73%) were ipsilateral, 11 (73%) were pathologic T1 tumors, 5 (33%) were pathologic N1 tumors, 13 (87%) were estrogen receptor-positive, and 1 (7%) was amplified for human epidermal growth factor receptor 2.In patients who had an initial diagnosis of atypical hyperplasia or lobular carcinoma in situ on core biopsy, the 7-year cumulative breast cancer incidence was 9.9%. Most tumors were ipsilateral, stage I, estrogen receptor-positive, invasive carcinomas. The current data support close clinical and radiologic follow-up for more than 5 years in this patient population. Cancer 2018;124:459-65. © 2017 American Cancer Society.

Advances in the understanding of the genetics and biology of breast cancer are defining patients at increased risk for the development of breast cancer. Prophylactic risk-reducing mastectomy and bilateral salpingo-oophorectomy are very good options for reducing breast cancer risk in selected patients with elevated breast cancer risk. Technical approaches to prophylactic surgery are evolving and are leading to improved patient cosmetic outcomes and lower morbidity. Decisions regarding utilization of these procedures for patients should take into account a specific patient’s risk for developing breast cancer based on genetic, family, and personal medical history; patient age; and comorbid conditions. Limitations of prophylactic surgical approaches, alternatives, and side effects of prophylactic operations should also be considered carefully with patients who are considering these surgical interventions for breast cancer risk reduction.

Advances in the management of patients with HER-2+ breast cancer with combinatorial targeted therapies are leading to unprecedented rates of pathologic complete response. The high rates of complete pathologic response in the breast and the axillary lymph nodes following neoadjuvant therapy are raising new questions about the role of local therapies (surgery and radiation therapy) in treating these patients. The safe elimination of surgery and radiation therapy for selected breast cancer patients would ultimately reduce the short- and long-term morbidity associated with traditional breast cancer treatments and would represent a major step forward. However, numerous technical and clinical challenges remain which will be discussed in this chapter. Collaborative efforts to address these challenges are essential to improving current therapeutic approaches for patients with HER-2+ breast cancer.

e18324 Background: Understanding clinic-based resource utilization among breast cancer (BC) patients is critical for the development of bundled payment models, and redesigning efficient value based systems of care delivery. BC outpatient visits (OVs) are costly from a time and human resource perspective and warrant investigation. Methods: This observational study included patients who were diagnosed with BC (Stages 0 to 3) in 2012 and were followed within our health network. Frequencies of OVs were compared between years 1, 2 and 3 of follow-up across subgroups, using one-sample Kolmogorov-Smirnov test; p < 0.05 was considered significant. Results: Of 643 patients identified, 83% were Caucasian and 99.5 % were females. 99.4% had breast surgery, 60% received radiation, and 42% received chemotherapy. 66% of patients who had mastectomy had reconstruction (73% implants, 27% tissue flap). The average duration of follow-up was 3.2 yrs. The frequency of OVs was highest in the 1st year after diagnosis across all groups in the Table (all p < 0.001). Breast reconstruction was associated with high clinic resource utilization; tissue flap procedures were associated with significantly more OVs than implant procedures during the 3 years (median of 16 vs.14 visits, p < 0.001). Conclusions: Outpatient visits represent a significant resource requirement associated with breast cancer care. These data are an important baseline as we design improved models of care and bundled payment models, and can be used to set expectations among breast cancer patients and care teams. [Table: see text]

e21586 Background: With significant advances in breast cancer (BC) treatment and improvements in long-term survival, high-quality, coordinated survivorship care is important. Methods: In this retrospective study of patients who were diagnosed with BC (Stages 0 to 3) in 2012 and had > 1 year of follow-up within our network (mean follow-up 3.2 yrs), we analyzed BMI trends and compliance with age appropriate health measures. One-sample t-test was used to compare average BMI at diagnosis and year 3. p < 0.05 was considered as statistically significant. Results: Of 643 patients studied, 99.5% were female, 83% were Caucasian, and 27% were ≤ 50 years of age at diagnosis (mean age 59 yrs). 17% had DCIS and 83% had invasive cancer (Stage I – 40%, II – 33%, III- 10%). 40% had a BMI > 30 Kg/m2. BC Surveillance: 89.4% of patients with residual breast tissue or tissue flaps had surveillance mammograms during 3 years of follow-up (Year 1 - 90.0%, 2 - 89.8%, 3 - 88.3%), in compliance with current guidelines. Weight management: There was a statistically significant increase in BMI from diagnosis to year-3. This trend was consistent across different age, race, and baseline BMI groups (See Table). Colon cancer screening: 49% of eligible patients had completed age appropriate screening colonoscopies either prior to diagnosis or during the course of follow-up. Bone health: Among patients who were on aromatase inhibitors, 76% had a documented DEXA scan. Vaccination: Vaccine coverage for eligible patients was low – 63% for pneumococcal, 38% for herpes zoster, and 30% for annual influenza vaccines. Conclusions: While compliance with BC surveillance is high among patients following treatment for BC, adherence to many other important health maintenance practices is low. Renewed focus on these measures, such as weight management, bone health, vaccination and screening for other cancers, represents an important opportunity to improve not only cancer-related outcomes but also the overall health and well-being of BC survivors. [Table: see text]

Purpose Breast magnetic resonance imaging (MRI) is accepted as a useful adjunct to screening mammography for women at high risk for breast cancer. Nevertheless, concerns about false-positive findings remain, and data about MRI harms and yields are limited. The aim of this study was to quantify harms and yields of breast MRI over time in a large series of patients. Methods A retrospective review was performed of patients at increased risk for breast cancer who underwent annual screening digital mammography and MRI from 2007 to 2013. Harms were defined as events not producing a breast cancer diagnosis (ultrasonography [US], imaging-guided core or surgical biopsy procedure, recommendation for short-term follow-up, or a combination). Results Of 350 high-risk patients offered MRI screening, 320 underwent 757 screening MRI procedures over time. The median age at the first MRI was 48 years. All patients met American Cancer Society criteria for annual screening breast MRI. Total harms were highest with the first MRI procedure and decreased with subsequent MRI screening. Of 75 biopsy procedures performed, including 58 US- or MRI-guided core biopsy procedures and 17 surgical biopsy procedures, 6 specimens were found to be malignant, including 2 resulting from biopsy procedures performed based on findings from the first MRI scan, 0 from the second MRI scan, 3 from the third MRI scan, and 1 from the fourth MRI scan. Conclusion Among women followed with screening MRI, the number of harms was shown to decrease over time. Breast cancer continued to be detected in MRI studies performed over time. This study demonstrates the utility of MRI screening performed over time in high-risk women.

Though they claim to, direct-to-consumer genetic tests may not correctly identify an individual's ancestral background, and thus may overstate or understate one's risk for heritable disease.

Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome are allelic, defined by germline PTEN mutations, and collectively referred to as PTEN hamartoma tumor syndrome. To date, there are no existing criteria based on large prospective patient cohorts to select patients for PTEN mutation testing. To address these issues, we conducted a multicenter prospective study in which 3042 probands satisfying relaxed CS clinical criteria were accrued. PTEN mutation scanning, including promoter and large deletion analysis, was performed for all subjects. Pathogenic mutations were identified in 290 individuals (9.5%). To evaluate clinical phenotype and PTEN genotype against protein expression, we performed immunoblotting (PTEN, P-AKT1, P-MAPK1/2) for a patient subset (n = 423). In order to obtain an individualized estimation of pretest probability of germline PTEN mutation, we developed an optimized clinical practice model to identify adult and pediatric patients. For adults, a semiquantitative score—the Cleveland Clinic (CC) score—resulted in a well-calibrated estimation of pretest probability of PTEN status. Overall, decreased PTEN protein expression correlated with PTEN mutation status; decreasing PTEN protein expression correlated with increasing CC score (p < 0.001), but not with the National Comprehensive Cancer Network (NCCN) criteria (p = 0.11). For pediatric patients, we identified highly sensitive criteria to guide PTEN mutation testing, with phenotypic features distinct from the adult setting. Our model improved sensitivity and positive predictive value for germline PTEN mutation relative to the NCCN 2010 criteria in both cohorts. We present the first evidence-based clinical practice model to select patients for genetics referral and PTEN mutation testing, further supported biologically by protein correlation.

1508 Background: MRI has been accepted as a useful adjunct to screening mammography in high-risk women. Concerns remain over false positive findings, however, and little is known about harms and yield over time. Such information will help women decide about enhanced surveillance. Methods: Of 350 high risk patients offered MRI screening, 320 underwent 757 screens with a 1.5 Tesla magnet from 2008 to 2012 alternating (q 6 mo.) with digital mammography. Data collected included patient characteristics, mammographic density, estimated lifetime risk, and need for additional imaging and/or biopsy. Harms were defined as second look ultrasounds, US or MRI guided core biopsies, surgical biopsies or recommendation for short interval follow up. Estimates of harms over time were modeled by logistic regression. A significance level of 0.05 was used for all testing. Results: Compliance with MRI screening as recommended was 91% with the first MRI, and was not associated with age, race or level of risk. Harms were highest with the first MRI and decreased significantly with subsequent MRIs. Of 59 biopsies, 7 were malignant. Two were found in MRI 1, 3 in MRI 3 and 2 in MRI 4. Women with biopsies resulting from false positive findings were significantly younger (median age 44.5 as compared with 48; p=0.049) and were more likely to have extremely dense breast tissue (36% vs 17%; p=0.028.) Conclusions: This study of highly compliant high risk patients supports the use of MRI as an adjunct to mammography for early detection. The rate of harmful events decreased over time, yet cancer detection did not. This information is critical in counseling women who are considering annual screening breast MRI, particularly younger women and those with dense tissue. [Table: see text]