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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.

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.

Clinical testing for germ-line variation in multiple cancer susceptibility genes is available using massively parallel sequencing. Limited information is available for pretest genetic counseling regarding the spectrum of mutations and variants of uncertain significance in defined patient populations.We performed massively parallel sequencing using targeted capture of 22 cancer susceptibility genes in 278 BRCA1/2-negative patients with early-onset breast cancer (diagnosed at younger than 40 years of age).Thirty-one patients (11%) were found to have at least one deleterious or likely deleterious variant. Seven patients (2.5% overall) were found to have deleterious or likely deleterious variants in genes for which clinical guidelines exist for management, namely TP53 (4), CDKN2A (1), MSH2 (1), and MUTYH (double heterozygote). Twenty-four patients (8.6%) had deleterious or likely deleterious variants in a cancer susceptibility gene for which clinical guidelines are lacking, such as CHEK2 and ATM. Fifty-four patients (19%) had at least one variant of uncertain significance, and six patients were heterozygous for a variant in MUTYH.These data demonstrate that massively parallel sequencing identifies reportable variants in known cancer susceptibility genes in more than 30% of patients with early-onset breast cancer. However, only few patients (2.5%) have definitively actionable mutations given current clinical management guidelines.Genet Med 17 8, 630-638.

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.

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.

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.

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.