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PURPOSE: Although multigene panel testing (MGPT) is increasingly utilized in clinical practice, there remain limited data on patient-reported outcomes. METHODS: BRCA 1/2 negative patients were contacted and offered MGPT. Patients completed pre- and post-test counseling, and surveys assessing cognitive, affective and behavioral outcomes at baseline, post-disclosure and 6 and 12 months. RESULTS: Of 317 eligible BRCA1/2 negative patients who discussed the study with research staff, 249 (79%) enrolled. Decliners were more likely to be older, non-white, and recruited by mail or email. Ninety-five percent of enrolled patients proceeded with MGPT. There were no significant changes in anxiety, depression, cancer specific distress or uncertainty post-disclosure. There were significant but small increases in knowledge, cancer-specific distress and depression at 6–12 months. Uncertainty declined over time. Those with a VUS had significant decreases in uncertainty but also small increases in cancer specific distress at 6 and 12 months. Among those with a positive result, medical management recommendations changed in 26% of cases and 2.6% of all tested. CONCLUSION: Most BRCA1/2 negative patients have favorable psychosocial outcomes after receipt of MGPT results, although small increases in depression and cancer-specific worry may exist and may vary by result. Medical management changed in few patients.

Purpose Multigene panels (MGPs) are increasingly being used despite questions regarding their clinical utility and no standard approach to genetic counseling. How frequently genetic providers use MGP testing and how patient-reported outcomes (PROs) differ from targeted testing (eg, BRCA1/2 only) are unknown. Methods We evaluated use of MGP testing and PROs in participants undergoing cancer genetic testing in the multicenter Communication of Genetic Test Results by Telephone study (ClinicalTrials.gov identifier: NCT01736345), a randomized study of telephone versus in-person disclosure of genetic test results. PROs included genetic knowledge, general and state anxiety, depression, cancer-specific distress, uncertainty, and satisfaction. Genetic providers offered targeted or MGP testing based on clinical assessment. Results Since the inclusion of MGP testing in 2014, 395 patients (66%) were offered MGP testing. MGP testing increased over time from 57% in 2014 to 66% in 2015 ( P = .02) and varied by site (46% to 78%; P < .01). Being offered MGP testing was significantly associated with not having Ashkenazi Jewish ancestry, having a history of cancer, not having a mutation in the family, not having made a treatment decision, and study site. After demographic adjustment, patients offered MGP testing had lower general anxiety ( P = .04), state anxiety ( P = .03), depression ( P = .04), and uncertainty ( P = .05) pre-disclosure compared with patients offered targeted testing. State anxiety ( P = .05) and cancer-specific distress ( P = .05) were lower at disclosure in the MGP group. There was a greater increase in change in uncertainty ( P = .04) among patients who underwent MGP testing. Conclusion MGP testing was more frequently offered to patients with lower anxiety, depression, and uncertainty and was associated with favorable outcomes, with the exception of a greater increase in uncertainty compared with patients who had targeted testing. Addressing uncertainty may be important as MGP testing is increasingly adopted.

Purpose To better understand the longitudinal risks and benefits of telephone disclosure of genetic test results in the era of multi-gene panel testing. Patients and Methods Adults who were proceeding with germline cancer genetic testing were randomized to telephone disclosure (TD) with a genetic counselor or in-person disclosure (IPD) of test results (i.e., usual care). All participants who received TD were recommended to return to meet with a physician to discuss medical management recommendations. Results 473 participants were randomized to TD and 497 to IPD. There were no differences between arms for any cognitive, affective or behavioral outcomes at 6 and 12 months. Only 50% of participants in the TD arm returned for the medical follow-up appointment. Returning was associated with site (p

Background While there is increasing interest in sharing genetic research results with participants, how best to communicate the risks, benefits and limitations of research results remains unclear. Methods Participants who received genetic research results answered open and closed‐ended questions about their experiences receiving results and interest in and advantages and disadvantages of a web‐based alternative to genetic counseling. Results 107 BRCA1/2 negative women with a personal or family history of breast cancer consented to receive genetic research results and 82% completed survey items about their experience. Most participants reported there was nothing they disliked (74%) or would change (85%) about their predisclosure or disclosure session (78% and 89%). They most frequently reported liking the genetic counselor and learning new information. Only 24% and 26% would not be willing to complete predisclosure counseling or disclosure of results by a web‐based alternative, respectively. The most frequently reported advantages included convenience and reduced time. Disadvantages included not being able to ask questions, the risk of misunderstanding and the impersonal nature of the encounter. Conclusion Most participants receiving genetic research results report high satisfaction with telephone genetic counseling, but some may be willing to consider self‐directed web alternatives for both predisclosure genetic education and return of results.

The risks, benefits, and utilities of multiplex panels for breast cancer susceptibility are unknown, and new counseling and informed consent models are needed. We sought to obtain patient feedback and early outcome data with a novel tiered-binned model for multiplex testing.BRCA1/2-negative and untested patients completed pre- and posttest counseling and surveys evaluating testing experiences and cognitive and affective responses to multiplex testing.Of 73 patients, 49 (67%) completed pretest counseling. BRCA1/2-negative patients were more likely to proceed with multiplex testing (86%) than those untested for BRCA1/2 (43%; P0.01). Many patients declining testing reported concern for uncertainty and distress. Most patients would not change anything about their pre- (76%) or posttest (89%) counseling sessions. Thirty-three patients (72%) were classified as making an informed choice, including 81% of those who proceeded with multiplex testing. Knowledge increased significantly. Anxiety, depression, uncertainty, and cancer worry did not significantly increase with multiplex testing.Some patients, particularly those without prior BRCA1/2 testing, decline multiplex testing. Most patients who proceeded with testing did not experience negative psychological responses, but larger studies are needed. The tiered-binned approach is an innovative genetic counseling and informed consent model for further study in the era of multiplex testing.Genet Med 18 1, 25-33.

Telephone disclosure of cancer genetic test results is noninferior to in-person disclosure. However, how patients who prefer in-person communication of results differ from those who agree to telephone disclosure is unclear but important when considering delivery models for genetic medicine. Patients undergoing cancer genetic testing were recruited to a multicenter, randomized, noninferiority trial (NCT01736345) comparing telephone to in-person disclosure of genetic test results. We evaluated preferences for in-person disclosure, factors associated with this preference and outcomes compared to those who agreed to randomization. Among 1178 enrolled patients, 208 (18%) declined randomization, largely given a preference for in-person disclosure. These patients were more likely to be older (P = 0.007) and to have had multigene panel testing (P < 0.001). General anxiety (P = 0.007), state anxiety (P = 0.008), depression (P = 0.011), cancer-specific distress (P = 0.021) and uncertainty (P = 0.03) were higher after pretest counseling. After disclosure of results, they also had higher general anxiety (P = 0.003), depression (P = 0.002) and cancer-specific distress (P = 0.043). While telephone disclosure is a reasonable alternative to in-person disclosure in most patients, some patients have a strong preference for in-person communication. Patient age, distress and complexity of testing are important factors to consider and requests for in-person disclosure should be honored when possible.

This study examines the analytic validity of a software tool designed to provide individuals with risk assessments for colorectal cancer based on personal health and family history information. The software is compatible with the US Surgeon General's My Family Health Portrait (MFHP).An algorithm for risk assessment was created using accepted colorectal risk assessment guidelines and programmed into a software tool (MFHP). Risk assessments derived from 150 pedigrees using the MFHP tool were compared with "gold standard" risk assessments developed by three expert cancer genetic counselors.Genetic counselor risk assessments showed substantial, but not perfect, agreement. MFHP risk assessments for colorectal cancer yielded a sensitivity for colorectal cancer risk of 81% (95% confidence interval: 54-96%) and specificity of 90% (95% confidence interval: 83-94%), as compared with genetic counselor pedigree review. The positive predictive value for risk for MFHP was 48% (95% confidence interval: 29-68%), whereas the negative predictive value was 98% (95% confidence interval: 93-99%). Agreement between MFHP and genetic counselor pedigree review was moderate (κ = 0.54).The analytic validity of the MFHP colorectal cancer risk assessment software is similar to those of other types of screening tools used in primary care. Future investigations should explore the clinical validity and utility of the software in diverse population groups.Genet Med 17 9, 753-756.

Multiplex genetic testing, including both moderate- and high-penetrance genes for cancer susceptibility, is associated with greater uncertainty than traditional testing, presenting challenges to informed consent and genetic counseling. We sought to develop a new model for informed consent and genetic counseling for four ongoing studies.Drawing from professional guidelines, literature, conceptual frameworks, and clinical experience, a multidisciplinary group developed a tiered-binned genetic counseling approach proposed to facilitate informed consent and improve outcomes of cancer susceptibility multiplex testing.In this model, tier 1 "indispensable" information is presented to all patients. More specific tier 2 information is provided to support variable informational needs among diverse patient populations. Clinically relevant information is "binned" into groups to minimize information overload, support informed decision making, and facilitate adaptive responses to testing. Seven essential elements of informed consent are provided to address the unique limitations, risks, and uncertainties of multiplex testing.A tiered-binned model for informed consent and genetic counseling has the potential to address the challenges of multiplex testing for cancer susceptibility and to support informed decision making and adaptive responses to testing. Future prospective studies including patient-reported outcomes are needed to inform how to best incorporate multiplex testing for cancer susceptibility into clinical practice.Genet Med 17 6, 485-492.

Background: Given the increasing demand for genetic services and limited genetic workforce, many patients do not receive recommended pre- and post-test genetic counseling. Telemedicine has been used to expand specialized medical services to low access populations. The feasibility and outcomes of telemedicine in clinical genetics are not well described. Methods: Patients at 3 community sites without genetic counseling services received real-time pre-test (V1) and post-test (V2) counseling for cancer susceptibility with a genetic counselor (GC) at a center of expertise via community sites’ and host institution’s computers equipped with web cameras and videoconferencing software. Mixed-methods surveys assessed patient knowledge, satisfaction, psychosocial responses and experiences at baseline (BL), post-V1 and post-V2. We used paired T-tests to assess change between time points and linear regressions. Results: Of 100 patients approached, 83% consented to telegenetic services. To date, 57 have completed BL and V1, and 70% proceeded with genetic testing, 31 patients have received results, including 3 carriers (BRCA2, MSH2, PMS2). Patient characteristics did not differ between those who agreed to and declined telegenetics. 4% of sessions were aborted due to technology failures. 30% experienced disconnections but were completed. Nearly all (94%) were satisfied with their telegenetic experience. Knowledge and satisfaction with telegenetic services significantly increased and general anxiety and depression significantly decreased. Event related (state) anxiety did not change significantly. Table 1.OutcomeBL Mean (sd)Post-V1 Mean(sd)Post-V2 Mean(sd)pKnowledge (6-28)20.9(2.8)22.0 (3.0) 0.007 20.8 (3.3)21.8(3.2)21.5(3.1)NSSGeneral Anxiety (0-21)7.4(4.1)6.6(4.1) 0,02 6.6 ((4.0)5.7 (3.8)5.7 (3.5)0.06Genarla Depression(0-21)3.9 (3.9)3.5 (3.4) 0,05 3.6 (3.7)3.4(3.5)2.9 (3.5)0.07State Anxiety(20-80)36.0(15.2)35.7(13.7) NSS 34.6(15.0)34.5(13.1)32.1(12.5)NSSSatisfaction with Genetic Services 39.5(3.( 39.8(4.0)42.2(3.6)0.002Satisfaction with Telemedicine 51.3(5.6) 51.5(5.7)53.0(5.3)0.008 Patients reported several advantages to telegenetics (e.g. decreased travel burden) and few disadvantages (e.g. audio challenges and technical glitches).Conclusions: Telemedicine delivery of cancer genetic services is feasible, identifies genetic mutation carriers, increases knowledge, decreases anxiety and depression and is associated with high satisfaction, suggesting an innovative model for delivery of genetic services for patients and community practices without access to local genetic providers. Citation Format: Linda Patrick-Miller, Diana Harris, Evelyn Stevens, Brian Egleston, Linda Fleisher, Rebbeca Mueller, Amanda Brandt, Jill Stopfer, Susan Domchek, Angela Bradbury. Telemedicine: Expanding access to cancer genetic services to underserved populations [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-11-02.

Background: New counseling models for multiplex genetic testing for breast cancer susceptibility are needed. Further, the risks, benefits and utilities of multiplex genetic panels are unknown. Purpose: To obtain stakeholder feedback on an innovative tiered-binned model for pretest counseling and informed consent for multiplex testing and to evaluate the uptake of, cognitive and affective responses to and perceived utility of panel testing. Methods: Patients previously BRCA1/2- or BRCA1/2 untested completed in-person pre-test (V1) and post-test counseling (V2) and surveys regarding the novel counseling model and evaluating cognitive and affective responses to, and perceived utility of the 26 gene Myriad MyRisk panel for cancer susceptibility. Results: 49 patients (62% of eligible) enrolled and completed V1. 38% of decliners were not interested in panel testing. BRCA1/2- were more likely to proceed with MyRisk (89%) than BRCA1/2 untested (48%, p Table 1 BaselinePost V1Post V2 Mean (SD)Mean (SD)Mean (SD)General Anxiety6.8 (3.9)*6.1 (4.0)* 7.2 (3.5)*6.1 (3.6)*5.8 (4.2)*General Depression2.6 (3.0)2.3 (2.6) 2.6 (2.9)2.3 (2.6)2.9 (3.6)Event Anxiety37.1 (9.6)37.7 (9.5) 37.0 (8.9)37.3 (8.5)37.3 (9.4)Cancer Worry18.3 (15.7)16.9 (14.1) 18.4 (15.4)15.7 (14.1)6.6 (14.7)Knowledge (K) Total61.8 (6.1)**63.9 (6.4)** 62.1 (6.7)**64.1 (6.8)**66.3 (6.9)**K-Inheritance29.5 (3.2)30.0 (3.2) 29.7 (3.5)29.8 (3.3)30.3 (3.7)K-Benefits12.0 (1.4)12.3 (1.8) 12.0 (1.4)12.4 (1.7)12.4 (1.9)K-Limitations20.3 (3.2)**21.6 (2.8)** 20.4 (3.4)**21.9 (3.0)**23.6 (2.6)**Satisfaction 42.8 (3.8) 42.9 (3.6)*41.4 (2.6)*Uncertainty7.5 (4.3)6.9 (4.6) 7.7 (4.0)6.5 (4.5)6.7 (4.6)Perceived Utility 37.2 (7.9) 37.7 (7.0)*33.8 (8.6)**p,0.05, **p Conclusion: With a tiered-binned counseling model, patients experience increased knowledge. Uptake of panel testing varies by prior testing and potentially by patient affective factors. Most patients do not experience negative psychological responses, although this may vary by test result. Declines in satisfaction and perceived utility may also vary by test result and may reflect the current unclear utility and uncertainty of multiplex testing. Citation Format: Angela R Bradbury, Linda Patrick-Miller, Brian L Egleston, Amanda Brandt, Jessica Long, Jacquelyn Powers, Jill Stopfer, Laura DiGiovanni, Jamie Brower, Susan M Domchek. Uptake and outcomes of multiplex testing for breast cancer susceptibility [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-12-10.

Women at elevated risk for breast cancer are motivated to reduce their risk. Current approaches rely primarily on hormonal intervention. A preventive exercise intervention might address the same hormonal issues, yet have fewer serious side effects and less negative impact on quality of life as compared to prophylactic mastectomy. WISER Sister was a randomized controlled trial which examined effects of two doses of exercise training on endogenous sex hormone exposure, hormonally active breast tissue, and other breast cancer risk factors.Subjects for this single site trial were recruited from across the U.S., in collaboration with organizations that serve women at elevated risk, via emails, flyers, and letters. Eligibility criteria included age ≥ 18, eumenorrheic, and at elevated risk for breast cancer (e.g. BRCA1 or BRCA2 mutation and/or ≥ 18% lifetime risk according to prediction models). A 1:1:1 randomization scheme was used to allocate participants into: control, low dose (150 min/week), or high dose (300 min/week) home based treadmill exercise. Participants provided first morning urine samples daily for two menstrual cycles at study beginning and end for calculation of endogenous hormone exposure. In addition, women completed breast dynamic contrast enhanced magnetic resonance imaging, a fasting blood draw, a treadmill exercise test, and surveys at baseline and follow-up.WISER Sister randomized 139 women, 122 of whom completed the study. The overall drop-out rate was 12%. Findings will be useful in understanding the potential for exercise to assist with reducing risk for breast cancer among women at elevated risk.

Background Germline genetic testing is standard practice in oncology. Outcomes of telephone disclosure of a wide range of cancer genetic test results, including multigene panel testing (MGPT) are unknown. Methods Patients undergoing cancer genetic testing were recruited to a multicenter, randomized, noninferiority trial (NCT01736345) comparing telephone disclosure (TD) of genetic test results with usual care, in-person disclosure (IPD) after tiered-binned in-person pretest counseling. Primary noninferiority outcomes included change in knowledge, state anxiety, and general anxiety. Secondary outcomes included cancer-specific distress, depression, uncertainty, satisfaction, and screening and risk-reducing surgery intentions. To declare noninferiority, we calculated the 98.3% one-sided confidence interval of the standardized effect; t tests were used for secondary subgroup analyses. Only noninferiority tests were one-sided, others were two-sided. Results A total of 1178 patients enrolled in the study. Two hundred eight (17.7%) participants declined random assignment due to a preference for in-person disclosure; 473 participants were randomly assigned to TD and 497 to IPD; 291 (30.0%) had MGPT. TD was noninferior to IPD for general and state anxiety and all secondary outcomes immediately postdisclosure. TD did not meet the noninferiority threshold for knowledge in the primary analysis, but it did meet the threshold in the multiple imputation analysis. In secondary analyses, there were no statistically significant differences between arms in screening and risk-reducing surgery intentions, and no statistically significant differences in outcomes by arm among those who had MGPT. In subgroup analyses, patients with a positive result had statistically significantly greater decreases in general anxiety with telephone disclosure (TD -0.37 vs IPD +0.87, P = .02). Conclusions Even in the era of multigene panel testing, these data suggest that telephone disclosure of cancer genetic test results is as an alternative to in-person disclosure for interested patients after in-person pretest counseling with a genetic counselor.

During the last 30 years, key advances in the field of cancer genetics have improved identification of high-risk families in which cancer risk can be linked to mutations in cancer susceptible genes. Identification of individuals with heritable cancer risk may influence short- and long-term medical management issues. Heightened screening and risk reducing options can offer lifesaving interventions for the woman and family members who are at risk.

A1 Introduction to the 8th Annual Conference on the Science of Dissemination and Implementation: Optimizing Personal and Population Health David Chambers1, Lisa Simpson2 1Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Rockville, MD, 20850, USA; 2AcademyHealth, Washington, DC, 20036, USA For the second year in a row, we are pleased to be able to share the proceedings of the Annual Conference on the Science of Dissemination and Implementation in Health, a large meeting reflecting the expanding and evolving research field that seeks to optimize the use of evidence, interventions, and tools from health research within the myriad of settings where people receive health care, make health-related decisions, and increase knowledge of influences on the health of the population. We once again benefitted from a strong partnership, co-led by AcademyHealth and the National Institutes of Health (NIH), with co-sponsorship from the Agency for Healthcare Research and Quality (AHRQ), the Patient Centered Outcomes Research Institute (PCORI), the Robert Wood Johnson Foundation (RWJF), the US Department of Veterans Affairs (VA), and the WT Grant Foundation. In addition, we benefitted from the collaboration of staff from the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO). NIH and AcademyHealth again co-led the program planning committee, which focused on the development of the plenary sessions, and convened a scientific advisory panel to suggest speakers and advise on the overall conference development. The planning committee identified four key areas around which to focus the plenary panels and keynote address. Dr. America Bracho, M.D., M.P.H., Executive Director of Latino Health Access in Orange County, California, spoke about the opportunities for implementation science to inform efforts to improve community health and engage underserved populations. The three plenary panels each focused on a significant future direction for dissemination and implementation (D & I) research: the interface between D&I science and population health, emerging opportunities for global implementation science, and the challenges around implementation of precision medicine. The plenary sessions were complemented by facilitated lunchtime discussions on the same three topics, which offered participants an opportunity to identify key research questions for each and brainstorm next steps. Synopses of the lunchtime discussions are included in this supplement. Given the overwhelming success of the 2014 conference and the large number of abstracts received in 2014 (660), the program planning committee identified eight program tracks for abstract submitters to respond to, and through which the concurrent sessions of the conference would be organized. These tracks—Behavioral Health, Big Data and Technology for Dissemination and Implementation Research, Clinical Care Settings, Global Dissemination and Implementation, Promoting Health Equity and Eliminating Disparities, Health Policy Dissemination and Implementation, Prevention and Public Health, and Models, Measures and Methods— were designed to enable conference participants to follow a consistent theme across the multiple sessions of the conference and form the structure of this supplement. The call for abstracts, including individual paper presentations, individual posters and panel presentations, resulted in 515 submissions, spread across the eight thematic tracks. Over one hundred reviewers devoted their time to ensuring a comprehensive and expert review, and reviews were conducted within each track and coordinated by the track leads. For the final program, 64 oral presentations, 12 panels, and 263 posters were presented over the two-day meeting. Slides for the oral presentations and panels (with the agreement of the authors) were posted on the conference website (http://diconference.academyhealth.org/archives/2015archives) and all abstracts were included on the conference webapp (https://academyhealth.confex.com/academyhealth/2015di/meetingapp.cgi). This supplement has compiled the abstracts for presented papers, panel sessions, and lunchtime discussions from the 8th Annual Meeting on the Science of Dissemination and Implementation in Health: Optimizing Personal and Population Health. We are pleased to have the abstracts from the conference together in one volume once again, and look forward to the 9th Annual meeting, scheduled for December in Washington, D.C.

Experimental and clinical data support a role for estrogens in the development and growth of breast cancer, and lowered estrogen exposure reduces breast cancer recurrence and new diagnoses in high-risk women. There is varied evidence that increased physical activity is associated with breast cancer risk reduction in both pre- and postmenopausal women, perhaps via lowered estrogen levels. The purpose of this study was to assess whether exercise intervention in premenopausal women at increased breast cancer risk reduces estrogen or progesterone levels. Seven healthy premenopausal women at high risk for breast cancer completed a seven-menstrual-cycle study. The study began with two preintervention cycles of baseline measurement of hormone levels via daily first-morning urine collection, allowing calculation of average area under the curve (AUC) hormone exposure across the menstrual cycle. Participants then began five cycles of exercise training to a maintenance level of 300 min per week at 80–85% of maximal aerobic capacity. During the last two exercise cycles, urinary estradiol and progesterone levels were again measured daily. Total estrogen exposure declined by 18.9% and total progesterone exposure by 23.7%. The declines were mostly due to decreased luteal phase levels, although menstrual cycle and luteal phase lengths were unchanged. The study demonstrated the feasibility of daily urine samples and AUC measurement to assess hormone exposure in experimental studies of the impact of interventions on ovarian hormones. The results suggest value in exercise interventions to reduce hormone levels in high-risk women with few side effects and the potential for incremental benefits to surgical or pharmacologic interventions.

Purpose Short-term reactions to BRCA1 and BRCA2 (BRCA1/2) genetic test results have been described in several reports, but the long-terms effects of testing have not been examined extensively. Methods We conducted an observational study to characterize the long-term impact of genetic testing for BRCA1/2 mutations in 167 women who had received genetic test results at least 4 years ago. We also evaluated the relationship between genetic testing–specific reactions and breast and ovarian cancer screening to determine the behavioral significance of adverse reactions. Results Seventy-four percent of women were not experiencing any distress regarding their test result, 41% were not experiencing any uncertainty, and 51% had a score for positive experiences that was suggestive of low levels of adverse reactions in terms of family support and communication. Mutation carriers (odds ratio, 3.96; 95% CI, 1.44 to 10.89; P = .01) were most likely to experience distress. Only less time since disclosure was related significantly to experiencing uncertainty (odds ratio, 0.62; 95% CI, 0.44 to 0.88; P = .008). In terms of cancer screening, 81% of women had a mammogram during the year before study enrollment, 25% had magnetic resonance imaging (MRI), 20% had a transvaginal ultrasound, and 20% had a CA-125. Experiencing distress was associated significantly with having a CA-125 (χ2 = 3.89, P = .05), and uncertainty was associated with having an MRI (χ2 = 8.90, P = .003). Conclusion Our findings show that women are not likely to experience genetic testing concerns several years after receiving BRCA1/2 test results; distress and uncertainty are not likely to have adverse effects on screening among women at risk for hereditary disease.

Risk-reducing salpingo-oophorectomy (RRSO) significantly reduces the risk of ovarian cancer and breast cancer in pre-menopausal women with BRCA1 and BRCA2 (B1/2) mutations. Despite its clear benefits, little is known about non-cancer endpoints in this population. Medical records were examined in 226 B1/2 mutation carriers, who had previously undergone RRSO with a focus on bone health as well as the frequency of hypertension, hyperlipidemia, coronary artery disease (CAD), myocardial infarction (MI), diabetes, hypothyroidism and depression. From the medical records, DEXA scans, medications and medical conditions were recorded. Of the 226 patient records examined, 16% (36/226) had hypertension, 17% (39/226) hyperlipidemia, 2% (5/226) CAD or MI, 2% (4/226) diabetes, 13% (29/226) hypothyroidism and 14% (31/226) depression. DEXA results were available in 152 women. Of those DEXA scans, 71% (108/152) were abnormal (57% osteopenia and 14% osteoporosis). Among women who underwent RRSO prior to age 50, 71% (62/88) had osteopenia/osteoporosis. Although there was no difference in osteopenia/osteoporosis in women with RRSO prior to age 50 compared to those RRSO > 50, the age at follow up in these two groups differs greatly (mean age 44.7 vs. 60.6), suggesting that both current age and age at RRSO contribute to bone health assessment. In summary, here, we report the prevalence of non-cancer endpoints in a cohort of B1/2 mutation carriers and note a particularly high rate of osteopenia and osteoporosis in B1/2 with breast cancer undergoing RRSO prior to 50. Despite the risk reduction RRSO offers, attention should be paid to non-cancer endpoints, particularly bone health, in this population.

1531Background: How frequently research participants are interested in receiving genetic individual research results (IRR) and the best method for returning IRR remains unknown. Methods: Woman at t...

e18705Background: Germline testing guidelines are centered on BRCA1 and BRCA2 despite clear medical management recommendations in several other high and moderate penetrance genes. Clinician utiliza...

Annual MRI screening is recommended as an adjunct to mammography for BRCA1 and BRCA2 mutation carriers. Prophylactic oophorectomy has been shown to decrease breast cancer risk in BRCA1/2 mutation carriers. Here, we aimed to examine the combined effects of MRI and oophorectomy. For this purpose, 93 BRCA1/2 mutation carriers were screened with yearly mammograms and yearly MRI scans. Study endpoints were defined as date of breast cancer diagnosis, date of prophylactic mastectomy, or date of most recent contact. Of 93 women, with a median age of 47, 80 (86%) had prophylactic oophorectomy. Fifty-one women (55%) had BRCA1 mutations. A total of 283 MRI scans were performed. Eleven breast cancers (9 invasive, 2 ductal carcinoma in situ) were detected in 93 women (12%) with a median follow-up of 3.2 years (incidence 40 per 1,000 person-years). Six cancers were first detected on MRI, three were first detected by mammogram, and two were “interval cancers.” All breast cancers occurred in BRCA1 mutation carriers (incidence 67 per 1,000 person-years). Apart from BRCA1 vs. BRCA2 mutation status, there were no other significant predictors of breast cancer incidence. Most invasive breast cancers were estrogen receptor negative (7 of 9) and lymph node negative (7 of 9). There have been no systemic recurrences with a median follow-up of 19 months after cancer diagnosis. Finally, it was concluded that all breast cancers occurred in BRCA1 mutation carriers, in most cases despite oophorectomy. These data suggest that surveillance and prevention strategies may have different outcomes in BRCA1 and BRCA2 mutation carriers.

This observational study evaluated utilization of religious coping strategies among 95 African American women who were at increased risk for having a BRCA1/BRCA2 (BRCA1/2) mutation. Overall, women reported high levels of collaborative coping; however, women with fewer than 2 affected relatives (beta = -1.97, P = 0.04) and those who had a lower perceived risk of having a BRCA1/2 mutation (beta = -2.72, P = 0.01) reported significantly greater collaborative coping. These results suggest that African American women may be likely to use collaborative strategies to cope with cancer-related stressors. It may be important to discuss utilization of religious coping efforts during genetic counseling with African American women.

Introduction Risk-reducing salpingo-oophorectomy (RRSO) reduces the risk of developing ovarian and breast cancer in BRCA 1 and BRCA 2 (BRCA1/2) mutation carriers. The short-term use of hormone replacement therapy (HRT) after RRSO may relieve menopausal symptoms and does not appear to affect the breast cancer risk reduction gained by RRSO. Multiple factors may influence decisions regarding whether or not total abdominal hysterectomy (TAH) is done at the time of RRSO, whether HRT is elected after surgery, and if so, which type of HRT is selected. Our investigation has been to examine factors associated with TAH and HRT use and to determine if the choice of TAH at the time of RRSO and the type of HRT that was chosen has changed since the report of data from the Women’s Health Initiative (WHI) in 2002, which showed that the relative risk for breast cancer is higher in subjects who used combined estrogen–progestin HRT compared with those who used estrogen alone. Methods We identified 73 female BRCA1/2 mutation carriers who were known to have undergone RRSO between 1/1972 and 11/2005 who had no history of breast or ovarian cancer at the time of the surgery. Information regarding whether or not TAH was done in addition to RRSO, the type of HRT, and the subsequent diagnosis of breast cancer was collected. Results Of 73 unaffected BRCA1/2 carriers known to have had RRSO, 40 (40/73, 55%) also underwent TAH. Thirty-three of 73 (33/73, 45%) began HRT following RRSO. Of 33 HRT users, 17 (17/33, 52%) used estrogen only and 14 (14/33, 42%) used combined hormonal therapy. There was no difference in use of HRT in women with TAH (17/40, 43%) vs. those without (16/33, 48%) (P = 0.6). There was no difference in the proportion of women who underwent TAH before and after the WHI report in 2002. Use of HRT, most notably combined estrogen–progestin HRT, appears to have declined since 2002, although this result did not reach statistical significance. Conclusion In this single institution study, the majority of BRCA1/2 mutation carriers undergoing RRSO also underwent TAH, and a substantial number took HRT. TAH did not increase the likelihood of taking HRT compared to RRSO alone.

Uptake of genetic testing remains low, even in families with known BRCA1 and BRCA2 (BRCA1/2) mutations, despite effective interventions to reduce risk. We report disclosure and uptake patterns by BRCA1/2-positive individuals to at-risk relatives, in the setting of no-cost genetic counseling and testing.Relatives of BRCA1/2-positive individuals were offered cost-free and confidential genetic counseling and testing. If positive for a BRCA1/2 mutation, participants were eligible to complete a survey about their disclosure of mutation status and the subsequent uptake of genetic testing by at-risk family members.One hundred and fifteen of 142 eligible individuals responded to the survey (81%). Eighty-eight (77%) of those surveyed disclosed results to all at-risk relatives. Disclosure to first-degree relatives (FDRs) was higher than to second-degree relatives (SDRs) and third-degree relatives (TDR) (95% vs. 78%; p0.01). Disclosure rates to male versus female relatives were similar, but reported completion of genetic testing was higher among female versus male FDRs (73% vs. 49%; p0.01) and SDRs (68% vs. 43%; p0.01), and among members of maternal versus paternal lineages (63% vs. 0%; p0.01). Men were more likely than women to express general difficulty discussing positive BCRA1/2 results with at-risk family members (90% vs. 70%; p = 0.03), while women reported more emotional distress associated with disclosure than men (48% vs. 13%; p0.01).We report a very high rate of disclosure of genetic testing information to at-risk relatives. However, uptake of genetic testing among at-risk individuals was low despite cost-free testing services, particularly in men, SDRs, and members of paternal lineages. The complete lack of testing among paternally related at-risk individuals and the lower testing uptake among men signify a significant barrier to testing and a challenge for genetic counselors and physicians working with high-risk groups. Further research is necessary to ensure that family members understand their risk and the potential benefits of genetic counseling.

Objectives: To describe BRCA1 or BRCA2 (BRCA1/2) risk perceptions among African American women at increased risk for hereditary breast-ovarian cancer and to identify factors having independent associations with these perceptions. Methods: Risk perceptions were evaluated by self-report during a structured telephone interview among African American women (n = 162) at increased risk for hereditary cancer who were recruited from oncology clinics, general medical practices, and community oncology resources. Results: The majority of women (75%) believed that it was likely that they had a BRCA1/2 mutation. Women ages 50 and younger and those with greater cancer-specific worry were most likely to believe that they had a BRCA1/2 mutation. Conclusions: Although BRCA1/2 risk perceptions may be consistent with objective risk levels among African American women, discussion about the basis of risk perceptions may enhance provision of genetic counseling and testing in this population.

Although African American breast cancer survivors are at increased risk for developing breast cancer again, empirical data are not available on breast cancer risk perceptions in these women. This study characterized perceived risk of developing breast cancer in African American breast cancer survivors at risk for having a BRCA1 or BRCA1 (BRCA1/2) mutation and identified factors having significant independent associations with risk perceptions. Participants were 95 African American breast cancer survivors at an increased risk for having a BRCA1/2 mutation. Risk perceptions and sociodemographic, clinical, treatment, and sociocultural factors were collected during a structured telephone interview. Most women reported that they had the same or lower risk of developing breast cancer again compared with other women (53%); however, a substantial minority of women (47%) reported that they had a higher or much higher risk. Factors having significant independent associations with heightened risk perceptions included having a ≥10% prior probability of having a BRCA1/2 mutation [odds ratio (OR), 2.91; 95% confidence interval (95% CI), 1.09-7.72; P = 0.03] and more years of formal education (OR, 2.74; 95% CI, 1.02-7.36; P = 0.05). In addition, women who thought about the past a lot were three times more likely to report heightened risk perceptions compared with those who did not think about the past a lot (OR, 3.72; 95% CI, 1.45-9.57; P = 0.01). These results suggest that it may be important to ensure adequate risk comprehension among African American women as part of genetic counseling for inherited breast-ovarian cancer risk. Discussion of risk perceptions within the context of existing beliefs and values may facilitate this process. (Cancer Epidemiol Biomarkers Prev 2007;16(2):244–8)

Background: Dysregulation of adipokines, such as adiponectin and leptin, is associated with a variety of chronic diseases, including cancer. Physical activity protects against breast cancer and one of the mechanisms which may underlie this association is exercise-induced changes in adipokine levels. The WISER Sister Trial was a three-armed randomized controlled trial in premenopausal women (n = 137) with an elevated risk for breast cancer. Methods: A 5-menstrual-cycle-long dosed aerobic exercise intervention compared low-dose exercise (150 min/wk; n = 44) or high-dose exercise (300 min/wk; n = 48) with a control group asked to maintain usual activity levels (n = 45). Exercise intensity progressed to and was maintained at 70% to 80% of age predicted heart rate max. Body composition and adipokine levels were measured at baseline and follow-up. Results: We observed significant linear trends for increased fitness capacity (Δ%: −2.0% control, 10.1% low dose, 13.1% high dose), decreased fat tissue-to-total tissue mass (Δ%: 0.7% control, −2.9% low dose, −3.7% high dose), increased body fat adjusted adiponectin (Δ%: −0.6% control, 0.6% low dose, 0.9% high dose), and decreased body fat adjusted leptin (Δ%: 0.7% control, −8.2% low dose, −10.2% high dose). Conclusions: In this randomized clinical trial of premenopausal women at risk for breast cancer, we demonstrate a dose–response effect of exercise on adiponectin and leptin and that dose response is dependent on changes in body fat. Impact: Improved adipokine levels, achieved by aerobic exercise training-induced decreases in body fat, may decrease breast cancer risk for high-risk premenopausal women. Cancer Epidemiol Biomarkers Prev; 25(8); 1195–200. ©2016 AACR.

Medical and surgical interventions for elevated breast cancer risk (e.g., BRCA1/2 mutation, family history) focus on reducing estrogen exposure. Women at elevated risk may be interested in less aggressive approaches to risk reduction. For example, exercise might reduce estrogen, yet has fewer serious side effects and less negative impact than surgery or hormonal medications. Randomized controlled trial. Increased risk defined by risk prediction models or BRCA mutation status. Eligibility: Age 18–50, eumenorrheic, non-smokers, and body mass index (BMI) between 21 and 50 kg/m2. 139 were randomized. Treadmill exercise: 150 or 300 min/week, five menstrual cycles. Control group maintained exercise

Complexities abound in the identification and management of families at increased risk for inherited forms of cancer. One of the ways to learn as a profession how best to provide cancer risk counseling (CRC) is to share counseling experiences. Such cases can provide insight into the issues raised by families and ways in which genetic counselors have handled complex situations. Here we describe three CRC cases initially presented at the 1995 American College of Medical Genetics meeting. The first case involves balancing the importance of informing a family of the presence of an inherited cancer syndrome with the family's right “not to know.” The second case illustrates the difficulties in assisting an individual to make medical management decisions in the face of uncertain risk information. The third case describes the complex interactions with a woman before and after her decision to have prophylactic surgery.

Despite the importance of breast cancer screening to reduce morbidity and mortality, limited information is available on screening practices among African American women with a family history that is suggestive of hereditary breast cancer.To describe adherence to breast cancer screening recommendations among African American women with a family history that is suggestive of hereditary disease.Participants were unaffected African American women (n=65) who had a family history of cancer that was suggestive of hereditary breast cancer. Breast cancer screening practices were evaluated by self-report. The study was conducted at the University of Pennsylvania in Philadelphia, PA. Women were recruited to participate in the study from February 2003-December 2005.Most women were adherent to recommendations for mammography (75%) and CBE (93%). A sizeable minority of women (41%) also performed excessive BSE. Being older than age 50 was associated significantly with mammography adherence (FET0.05). Employment had a significant independent association with BSE; unemployed women were most likely to perform excessive BSE (OR=3.28, 95% CI: 1.05, 10.21, p0.05).The results of this study suggest a complex pattern of breast cancer screening practices among African American women at increased risk for hereditary breast cancer.

The objective of this study was to evaluate satisfaction with genetic counseling for BRCA1 and BRCA2 (BRCA1/2) mutations among African American women.Participants were 54 African American women at moderate and high risk for BRCA1/2 mutations who were offered genetic testing as part of a randomized clinical trial designed to compare the effects of culturally tailored genetic counseling (CTGC) and standard genetic counseling (SGC). Satisfaction with genetic counseling was evaluated using a self-administered questionnaire following culturally tailored or standard pre-test education and counseling.Overall, the majority of women (96%) were very satisfied with genetic counseling; however, only 26% reported that their worries were lessened and 22% reported that they were able to cope better. Women who received CTGC were significantly more likely than women who received SGC to report that their worries were lessened (p0.05). In addition, women with household incomes less than US$ 35,000 were significantly more likely to report that the counselor lessened their worries compared to women with higher incomes (p0.05).Most African American women were satisfied with genetic counseling; however, women who received culturally tailored genetic counseling were significantly more likely to strongly agree that their worries were lessened compared to women who received standard genetic counseling.Discussion of cultural beliefs and values during genetic counseling may be beneficial to African American women, especially those with low incomes.

Purpose: This study evaluated rates of BRCA1 and BRCA2 (BRCA1/2) test result acceptance among African American women and identified determinants of test result acceptance. Methods: Acceptance of BRCA1/2 test results was evaluated among 157 African American women at high and moderate risk for having a BRCA1/2 mutation who were offered genetic testing as part of a clinical genetic counseling research program. Results: Twenty-two percent of women received BRCA1/2 test results. Test result acceptance differed between women with ≥10% prior probability of having a BRCA1/2 mutation (34%) and those who had a 5% prior probability (8%). Among women with ≥10% prior probability, test result acceptors were most likely to be married (OR = 5.29, 95% CI = 1.82, 15.38, P = 0.002) and be less certain about their risk of developing cancer (OR = 3.18, 95% CI = 1.04, 9.80, P = 0.04). Conclusion: These results demonstrate that acceptance of BRCA1/2 test results may be limited among African American women. Being married and having less certainty about one's cancer risk may motivate acceptance of BRCA1/2 test results among African American women. It may be important to emphasize the possibility that BRCA1/2 test results may not clarify cancer risks during pre-test counseling with African American women to ensure informed decision-making about testing.

PurposeThis study evaluated the process of recruiting African American women to participate in genetic counseling research for BRCA1 and BRCA2 (BRCA1/2) mutations with respect to referral, study enrollment, and participation in genetic counseling.Patients and MethodsAfrican American women (n = 783) were referred for study enrollment.ResultsOf 783 referrals, 164 (21%) women were eligible for enrollment. Eligible women were most likely to be referred from oncology clinics (44%) and were least likely to be referred from general medical practices (11%; χ2= 96.80; P = .0001). Overall, 62% of eligible women enrolled onto the study and 50% of enrollees completed genetic counseling. Women with a stronger family history of cancer (odds ratio [OR] = 3.18; 95% CI, 1.36 to 7.44; P = .01) and those referred from oncology clinics and community oncology resources (OR = 2.97; 95% CI, 1.34 to 6.58; P = .01) were most likely to enroll onto the study. Referral from oncology clinics was associated significantly with participation in genetic counseling (OR = 5.46; 95% CI, 1.44 to 20.60; P = .01).ConclusionDespite receiving a large number of referrals, only a small subset of women were eligible for enrollment. Oncology settings were the most effective at identifying eligible African American women and general medical practices were the least effective. Factors associated with enrollment included having a stronger family history of cancer and being referred from oncology clinics and community oncology resources. Referral from oncology clinics was the only factor associated significantly with participation in genetic counseling. Education about hereditary breast cancer may be needed among primary care providers to enhance appropriate referral of African American women to genetic counseling for BRCA1/2 mutations.

These cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in this document is derived from extensive review of the current literature on cancer genetic risk assessment and counseling as well as the personal expertise of genetic counselors specializing in cancer genetics. The recommendations are intended to provide information about the process of genetic counseling and risk assessment for hereditary cancer disorders rather than specific information about individual syndromes. Key components include the intake (medical and family histories), psychosocial assessment (assessment of risk perception), cancer risk assessment (determination and communication of risk), molecular testing for hereditary cancer syndromes (regulations, informed consent, and counseling process), and follow-up considerations. These recommendations should not be construed as dictating an exclusive course of management, nor does use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care provider's professional judgment based on the clinical circumstances of a client.

When BRCA1/2 testing became commercially available in 1996, many U.S. experts voiced concern about the potential for indiscriminate use of testing among low-risk women. Supporting this concern, several early surveys of interest in genetic testing suggested that genetic testing for cancer susceptibility might appeal most to individuals at low risk of carrying a mutation. To identify factors associated with early use of clinical BRCA1/2 testing, a case-control study was conducted at a large academic health system in the metropolitan Philadelphia region. A total of 167 women underwent genetic counseling for clinical BRCA1/2 testing between 1996 and 1997 (cases) compared with 138 women who were seen in faculty general internal medicine practices over the same period (controls). In this study we measured the risk factors for breast cancer, the risk factors for carrying a BRCA1/2 mutation, and sociodemographic characteristics. Use of BRCA1/2 counseling between 1996 and 1997 was positively associated with family but no personal history of breast cancer (odds ratio (OR), 22.4; 95% confidence interval (CI), 9.3-54.3); family and personal history of breast cancer (OR, 150.3; 95% CI, 24.1-939.6); being Caucasian and non-Jewish (OR, 4.1; 95% CI, 1.3-13.5); being Caucasian and Jewish (OR, 8.8; 95% CI, 2.2-35.5); and being married (OR, 3.2; 95% CI, 1.6-6.3). Use of BRCA1/2 counseling was inversely associated with increasing age (OR, 0.07; 95% CI, 0.02-0.28 for >60 compared to

Background: Increasing numbers of BRCA1 mutation carriers are being identified in cancer risk evaluation programs. However, no estimates of cancer risk specific to a clinic-based population of mutation carriers are available. These data are clinically relevant, because estimates based on families ascertained for linkage studies may overestimate cancer risk in mutation carriers, and population-based series may underestimate it. Wide variation in risk estimates from these disparate ascertainment groups makes counseling in risk evaluation programs difficult. The purpose of this study was to estimate BRCA1-related cancer risks for individuals ascertained in a breast cancer risk evaluation clinic. Methods: Cumulative observed and age-adjusted cancer risk estimates were determined by analyzing 483 BRCA1 mutation carriers in 147 families identified in two academic breast and ovarian cancer risk evaluation clinics. Cancer risks were computed from the proportion of individuals diagnosed with cancer during a 10-year age interval from among the total number of individuals alive and cancer-free at the beginning of that interval. Age-of-diagnosis comparisons were made using two-sided Student's t tests. Results: By age 70, female breast cancer risk was 72.8% (95% confidence interval [CI] = 67.9% to 77.7%) and ovarian cancer risk was 40.7% (95% CI = 35.7% to 45.6%). The risk for a second primary breast cancer by age 70 was 40.5% (95% CI = 34.1% to 47.0%). We also identified an increased risk of cancer of the colon (twofold), pancreas (threefold), stomach (fourfold), and fallopian tube (120-fold) in BRCA1 mutation carriers as compared with Surveillance, Epidemiology, and End Results (SEER) Program population-based estimates. Conclusion: The estimates for breast and ovarian cancer risk in BRCA1 mutation carriers is higher than population-based estimates but lower than estimates based on families ascertained for linkage studies. These cancer risk estimates may most closely approximate those faced by BRCA1 mutation carriers identified in risk evaluation clinics.

The traditional emphasis on nondirectiveness in genetic counseling has become increasingly controversial with the rapid expansion of genetic testing in clinical medicine. This study was done to determine whether women considering clinical testing for BRCA1/2 mutations want to know their health care providers' opinions about whether or not they should undergo testing. Participating in the study was a retrospective cohort of 335 women who participated in a university-based clinic offering breast cancer risk assessment, genetic counseling, and BRCA1/2 testing between January, 1996, and April, 1998. A total of 242 women (77%) wanted to know if the doctors at the Breast and Ovarian Cancer Risk Evaluation Program (BCREP) thought they should be tested, 28 women (9%) were unsure, and 46 women (14%) did not want a BCREP doctor's opinion on testing. A total of 158 women (49%) wanted to know if their primary doctor thought they should be tested, 31 women (10%) were unsure, and 130 women (41%) did not want to know. Desire to know the opinion of the BCREP doctors was inversely associated with having undergone BRCA1/2 testing (RR 0.83, 95% CI 0.73-0.95) and having a breast cancer diagnosis (RR 0.86, 95% CI 0.75-0.99). Desire to know their primary doctor's opinion was inversely associated with having undergone BRCA1/2 testing (RR 0.72, 95% CI 0.56-0.92). Our study suggests that over three-quarters of women who considered clinical testing for BRCA1/2 mutations wanted to know the opinions of the cancer genetics doctors and almost half wanted to know their primary doctor's opinion about whether or not they should undergo testing. These results support the use of models of genetic counseling that allow for sharing the health care providers' opinions when desired by the patient.

Cancer genetic services, typically provided by clinicians with expertise in both oncology and genetics, include cancer risk assessment and education, facilitation of genetic testing, pre-and post-test counseling, provision of personally tailored cancer risk management options and recommendations, and psychosocial counseling and support services. All oncology providers should obtain basic information on the family cancer history of their patients to determine the likelihood of hereditary cancer risk as well as possible indications for providing brief or comprehensive cancer genetic counseling. Those who choose to provide these services themselves must be familiar with the complex issues of genetic counseling and testing, and be aware of the time and expertise required to adequately deliver these services. Genetic nurses and genetic counselors with master's degrees function as valuable members of a comprehensive cancer genetic service; they are trained to independently collect and confirm medical and family history information, perform risk assessments, offer patient education regarding cancer and genetics, and provide supportive counseling services for patients and families. It is hoped that specific risk interventions will significantly reduce morbidity and mortality from familial forms of cancer. This review outlines the process of cancer genetic counseling and defines the roles of the cancer genetic counselor and the function of the cancer genetics specialty clinic. The possible medical and legal implications for failing to obtain adequate family history information are reviewed, and the issues of genetic discrimination are discussed. Semin. Surg. Oncol. 18:347–357, 2000. © 2000 Wiley-Liss, Inc.

Background To define the incidence of BRCA1 mutations among patients seen in clinics that evaluate the risk of breast cancer, we analyzed DNA samples from women seen in this setting and constructed probability tables to provide estimates of the likelihood of finding a BRCA1 mutation in individual families. Methods Clinical information, family histories, and blood for DNA analysis were obtained from 263 women with breast cancer. Conformation-sensitive gel electrophoresis and DNA sequencing were used to identify BRCA1 mutations. Results BRCA1 mutations were identified in 16 percent of women with a family history of breast cancer. Only 7 percent of women from families with a history of breast cancer but not ovarian cancer had BRCA1 mutations. The rates were higher among women from families with a history of both breast and ovarian cancer. Among family members, an average age of less than 55 years at the diagnosis of breast cancer, the presence of ovarian cancer, the presence of breast and ovarian cancer in t...

Low rates of genetic counseling among African American women have generated concerns about disparities; however, to the extent that women's decisions to accept or decline counseling are consistent with their values, then lower participation may reflect preferences and not disparities. We evaluated the extent to which women were satisfied with their decision about participating in genetic counseling for BRCA1/2 mutations and identified variables that were associated significantly with satisfaction. Prospective study of decision satisfaction with 135 African American women who had a minimum 5% prior probability of having a BRCA1/2 mutation. Decision satisfaction was evaluated one month after women were offered participation in genetic counseling using a structured questionnaire. Women were satisfied with their participation decision; more than 80% reported that their decision was consistent with their family values. However, women who declined pre-test counseling had significantly lower satisfaction scores. Our findings highlight the importance ensuring that racial differences that are due to preferences and values are not misclassified as disparities in order to identify and address the root causes of disparate treatment.

BACKGROUND: This study sought to estimate the risk of breast cancer (BC) after a diagnosis of ovarian cancer (OC) associated with mutation of the BRCA1/2 (breast cancer, early onset) genes (BRCA-OC). METHODS: The Memorial Sloan-Kettering Cancer Center and the University of Pennsylvania, clinical genetics databases were searched to identify women with BRCA-OC who participated in genetic testing and follow-up studies from 1995 to 2009. The primary objective was to determine the risk of developing BC after BRCA-OC. Overall survival (OS) and BC-free survival (BCFS) were determined by the Kaplan-Meier method; patients were censored at the time of last follow-up. RESULTS: A total of 164 patients had BRCA-OC (115 with BRCA1; 49 with BRCA2). Of these 164 patients, 152 developed OC prior to BRCA testing (median time to testing, 2.4 years [0.01-55 years]). Median follow-up from OC for those not developing BC was 5.8 years (0.25-55.6 years). There were 46 deaths, but none were due to BC. The 5- and 10-year OS were 85% (95% confidence interval [CI] = 0.78, 0.90) and 68% (95% CI = 0.59, 0.76), respectively. There were 18 metachronous BC diagnoses. The 5- and 10-year BCFS were 97% (95% CI = 0.92, 0.99) and 91% (95% CI = 0.82, 0.95), respectively. A subset of 64 women were tested either before or within 12 months of BRCA-OC. In this pseudo-incident subset, 5- and 10- year OS was 71% (95% CI = 0.53, 0.83) and 62% (95% CI = 0.44, 0.75), respectively, and 5- and 10-year BCFS were 100% and 87% (95% CI = 0.56, 0.96), respectively. CONCLUSIONS: OS was dominated by OC deaths. Metachronous BC risk was lower than reported for unaffected BRCA mutation carriers. These results support nonsurgical management of BC risk in women with BRCA-OC. Cancer 2013. © 2012 American Cancer Society.

Background In developed countries, the lifetime risk of developing colorectal cancer (CRC) is 5%, and it is the second leading cause of death from cancer. The presence of family history is a well established risk factor with 25-35% of CRCs attributable to inherited and/or familial factors. The highly penetrant inherited colon cancer syndromes account for approximately 5%, leaving greater than 20% without clear genetic definition. Familial colorectal cancer has been linked to chromosome 7q31 by multiple affected relative pair studies. The MET proto-oncogene which resides in this chromosomal region is considered a candidate for genetic susceptibility. Methods MET exons were amplified by PCR from germline DNA of 148 affected sibling pairs with colorectal cancer. Amplicons with altered sequence were detected with high-resolution melt-curve analysis using a LightScanner (Idaho Technologies). Samples demonstrating alternative melt curves were sequenced. A TaqMan assay for the specific c.2975C >T change was used to confirm this mutation in a cohort of 299 colorectal cancer cases and to look for allelic amplification in tumors. Results Here we report a germline non-synonymous change in the MET proto-oncogene at amino acid position T992I (also reported as MET p.T1010I) in 5.2% of a cohort of sibling pairs affected with CRC. This genetic variant was then confirmed in a second cohort of individuals diagnosed with CRC and having a first degree relative with CRC at prevalence of 4.1%. This mutation has been reported in cancer cells of multiple origins, including 2.5% of colon cancers, and in Conclusions Although the MET p.T992I genetic mutation is commonly found in somatic colorectal cancer tissues, this is the first report also implicating this MET genetic mutation as a germline inherited risk factor for familial colorectal cancer. Future studies on the cancer risks associated with this mutation and the prevalence in different at-risk populations will be an important extension of this work to define the clinical significance.

Genetic testing for BRCA1 and BRCA2 mutations in family members of individuals with known deleterious mutations can distinguish between patients at high risk of disease and those who are not. Some studies have suggested that individuals testing negative for known familial mutations (true negatives), may still have a higher risk of breast cancer (BC) than the general population. We have examined a prospectively followed cohort of true negative women in the US. Subjects were close relatives of known BRCA1 and BRCA2 mutation carriers who had undergone genetic testing, were negative for the known familial mutation, and were unaffected at the time of genetic testing. Standardized incidence ratios (SIR) and 95% confidence intervals (CI) were calculated using SEER incidence rates. Among 375 true negatives, two invasive and two in situ BC and no ovarian cancers were diagnosed with mean follow up of 4.9 years (total of 1,962 person-years). Four invasive BC were expected, whereas two were observed, for an age-adjusted SIR of 0.52 (95% CI 0.13–2.09). We observed more cases of in situ BC (n = 2) than were expected (n = 0.9; SIR = 2.30; 95% CI 0.57–9.19). There were no cases of ovarian cancer observed; 0.4 case was expected. In this prospective study of women who were unaffected at the time of genetic testing and who were negative for the known familial mutation in BRCA1/2, no excess risk of invasive BC was observed. Our data suggest that such women in the US should adhere to population-based guidelines for breast cancer screening.

Although retention is a critical component of longitudinal cancer genetics research, limited empirical data are available on predictors of study retention among populations that are difficult to enroll. We evaluated predictors of retention in cancer genetics research among African American women at increased risk for having a BRCA1 and BRCA2 (BRCA1/2) mutation. Participants were African American women (n = 192) at increased risk for hereditary breast-ovarian cancer who were enrolled in a longitudinal genetic counseling research study. Retention was evaluated separately for the 1- and 6-month follow-ups and in terms of overall retention (e.g., completion of both telephone interviews). Seventy-three percent of women and 65% of women were retained at the 1- and 6-month follow-ups respectively; in terms of overall retention, 60% of women were retained in both follow-up telephone interviews. Predictors of retention at 1-month included being employed (OR = 2.47, 95% CI = 1.24, 4.93, P = 0.01) whereas predictors of overall retention included having a personal history of breast and/or ovarian cancer (OR = 2.06, 95% CI = 1.07, 3.95, P = 0.03) and having completed genetic counseling (OR = 2.63, 95% CI = 1.39, 4.98, P = 0.003). These data suggest that once enrolled in genetic counseling research, the majority of African American women will continue to participate, especially if concrete clinical services are provided. © 2007 Wiley-Liss, Inc.

The occurrence of multiple primary (MP) cancers in a patient suggests a genetic predisposition to tumor formation. Multiplex panel testing may be an efficient way of evaluating MP patients for the presence of germline mutations in cancer susceptibility genes. However the spectrum of mutations in many cancer susceptibility genes in the MP patient population is largely unknown. We performed massively parallel sequencing using targeted capture of 15 genes with well-established risks of breast and/or other cancers, specifically TP53, CDH1, PTEN, STK11, ATM, CHEK2, MRE11A, NBN, RAD50, PALB2, MLH1, MSH2, MSH6, PMS2, and MUTYH. Our patient cohort consisted of 221 BRCA1/2 negative patients diagnosed with breast cancer and at least one other primary cancer, excluding non-melanoma skin cancer. Patients diagnosed with contralateral breast cancer were included. Thirty patients (14%) were found to have at least one deleterious variant in these 15 genes. Deleterious variants were found in CHEK2 (16 patients, 7.2%), TP53 (4, 1.8%), MSH6 (3, 1.4%), ATM (2, 0.9%) and one patient each had deleterious variants in CDKN2A, PTEN, PMS2, PALB2, BRIP1 and NBN. In addition, six patients (2.7%) were found to be heterozygous carriers of a MUTYH mutation. In comparison, deleterious variants were identified in 9% of 341 patients with breast cancer only, indicating a small but nonsignificant increase in the rate of deleterious variants in MP patients. The rate of MUTYH heterozygous mutations was also non-significantly different in patients with breast cancer only (1.2%). There was a significant increase in the rate of CHEK2 and MSH6 mutations in the MP versus breast-only patients (7.2% vs 3.5%, p = 0.04 for CHEK2 and 1.4% vs 0%, p = 0.05 for MSH6). As a corollary study, a subset of MP patients (n = 165) were assayed on a panel including TET2. Deleterious TET2 mutations were identified in 2 of 165 patients (1.2%) at allele frequencies of 0.17 and 0.36. These patients blood samples were ascertained at ages 77 and 72, respectively. These preliminary data show that in our cohort of patients with multiple primary cancers, over 16% of patients were found to have deleterious variants in 15 cancer susceptibility genes. In addition, approximately 1% of MP patients have deleterious variants in TET2 that may be due to age-related clonal hematopoiesis, although it is unknown if these mutations are related to the development of the tumors in these individuals. Further analysis of variants in less well-characterized cancer susceptibility genes and unclassified variants is ongoing. Discovery of clinically relevant mutations can potentially guide future treatment practices for those with similar diagnoses to our patients. Citation Format: Brandon Wenz, Kara N. Maxwell, Bradley Wubbenhorst, Kurt D'Andrea, Bradley Garman, Jessica M. Long, Jacquelyn Powers, Jill E. Stopfer, Angela R. Bradbury, Angela DeMichele, Susan M. Domchek, Katherine L. Nathanson. Identification of germline variants in cancer susceptibility genes in patients with multiple primary cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4663. doi:10.1158/1538-7445.AM2015-4663

1562 Background: BRCA1/2 mutation carriers have an elevated lifetime risk of developing breast cancer. Knowledge of one’s BRCA1/2 mutation status may aid earlier detection of breast cancers due to ...

1511 Background: Multiplex panel testing studies evaluating cancer susceptibility in breast cancer (BC) patients suggest that between 4-11% of BRCA1/2 negative individuals have a deleterious mutati...

e12503 Background: There is ongoing debate over the obligation, risks, benefits and utilities of returning individual genetic research results (IRR) identified in gene discovery or translational re...

541 Background: The Oncotype DX score is widely used to evaluate recurrence risk and potential benefit of chemotherapy in stage 1, estrogen receptor (ER) positive, Her2 negative tumors. Oncotype DX...

Germline mutations in the BRCA1 and BRCA2 genes are associated with breast cancer, ovarian cancer and other malignancies. Biallelic mutations of BRCA2 are a cause of Fanconi anemia and characteristic childhood cancers. We undertook this study to evaluate the contribution of familial BRCA mutations to childhood cancer in hereditary breast cancer families.We compared the prevalence of childhood cancers in 379 families with BRCA1 or BRCA2 mutations and 426 families without mutations. All families were ascertained at a high-risk breast cancer clinic. Our study included first- through fourth-degree relatives of BRCA mutation carriers and cancer-affected individuals with negative testing for BRCA mutations. The primary endpoint was any case of childhood cancer (diagnosedage 21).20 cases of childhood cancer occurred in 379 families with BRCA1 or BRCA2 mutations and 35 cases of childhood cancer occurred in 426 families with negative mutation testing (p = 0.12). Nine childhood cancers occurred in 240 families with BRCA1 mutations, and 11 childhood cancers occurred in 141 families with BRCA2 mutations (p = 0.1). 13 of 18 families with childhood cancer and BRCA1 or BRCA2 mutations (72%) and 13 of 31 families with childhood cancer and negative mutation testing (42%) met the Birch criteria for Li-Fraumeni like syndrome (LFL).In this retrospective analysis, heterozygous BRCA1 and BRCA2 mutations were not a risk factor for childhood cancer in hereditary breast cancer families. These data support the current practice of delaying BRCA mutation testing until adulthood.

Bilateral risk-reducing oophorectomy (BRRO) is widely used for cancer risk reduction in women with BRCA1 and BRCA2 (BRCA1/2) mutations. BRRO significantly reduces breast cancer risk by approximately 50% and ovarian cancer risk by 85% to 95%, but it may be accompanied by menopausal symptoms, impaired quality of life, and accelerated bone loss. Therefore, decisions regarding the timing of BRRO, the risks and benefits of a simultaneous hysterectomy, and the use of hormone replacement therapy (HRT) must be made in concert with the patient and individualized to their circumstances. However, recent data demonstrate that HRT after BRRO in unaffected premenopausal women does not negate the breast cancer risk reduction that BRRO provides. This article reviews the studies regarding BRRO in BRCA1/2 mutation carriers, with particular focus on the use of HRT.