Breast Cancer Risk Management Research Articles

Factors associated with intentions for breast cancer risk management: Does risk group matter?

National guidelines provide breast cancer (BC) risk management recommendations based on estimated lifetime risk. Despite this specificity, it is unclear if women's risk management intentions are or are not guideline concordant. To address this knowledge gap, women at varying risk levels reported intentions for risk-reducing behaviors. Factors associated with intentions, informed by the Health Beliefs Model, were also studied. Women with elevated BC risk (N=103) were studied and categorized by risk level: moderate (15%-20%), high (greater than or equal to 20%), or very high (BRCA1/2 positive). Participants self-reported BC susceptibility, self-efficacy, and benefits, barriers, and intentions for risk-reducing mastectomy (RRM), risk-reducing salpingo-oophorectomy (RRSO), chemoprevention, improving diet or physical activity, and reducing alcohol use. Groups significantly differed in RRSO intentions (P<.01); BRCA1/2 positive women had greater intentions for RRSO. Groups did not differ in intentions for RRM, chemoprevention, or lifestyle changes (Ps>.28). In hierarchical linear regression models examining Health Belief Model (HBM) factors, perceived susceptibility was associated with intentions for RRM (β=.169, P=.08). Perceived benefits was associated with intentions for RRM (β=.237, P=.02) and chemoprevention (β=.388, P<.01). Self-efficacy was associated with intentions for physical activity (β=.286, P<.01). Consistent with guidelines, BRCA1/2 positive women reported greater intentions for RRSO, and risk groups did not differ in intentions for lifestyle changes. Notably, women's intentions for RRM and chemoprevention were guideline discordant; groups did not differ in intentions for these behaviors. Accounting for the effects of risk group, modifiable health beliefs were also associated with risk management intentions; these may represent targets for decision support interventions.

Abstract GS2-01: Age-related breast cancer risk estimates for the general population based on sequencing of cancer predisposition genes in 19,228 breast cancer patients and 20,211 matched unaffected controls from US based cohorts in the CARRIERS study

Abstract Background: Clinical germline genetic testing of cancer predisposition gene panels is used to identify women at increased risk for breast cancer. The identification of pathogenic mutations in established high and moderate predisposition genes may result in improved risk management of breast cancer for tested patients and their family members through tailored screening, prophylactic surgeries, or chemoprevention. However, the risks of breast cancer associated with mutations in these genes have likely been overestimated for many women in the general population because previous studies have focused on individuals with a family history of breast and/or ovarian cancer, early onset disease, or triple negative breast cancer. The goal of the “CAnceR RIsk Estimates Related to Susceptibility” (CARRIERS) study is to estimate breast cancer risks associated with mutations in hereditary cancer panel genes in the general population. Methods: Germline DNA samples from blood or saliva were obtained from 39,439 breast cancer patients and matched unaffected controls from six US-based cohorts (BWHS, CPSII, CTS, MEC, NHS1, NHS2, WHI). DNA was subjected to dual bar-coded QIAseq multiplex PCR-based amplification of 1733 target regions covering all coding regions of 37 cancer predisposition genes and sequenced. Mutation calling was conducted with Haplotype Caller and Vardict. Results: High quality sequence data was obtained for 38,990 of 39,439 samples (98.9%) and for 99.3% of target regions. Pathogenic mutations in 12 known breast cancer predisposition genes were identified 4.5% of all breast cancer cases and 2.1% of controls; and in 6.7% of African American breast cancer cases and 1.8% of controls. Differences in mutation frequencies were observed by age with mutations in 7.8% of cases diagnosed £50 years of age and 4.0% of cases diagnosed over age 50. Mutations in ATM, BRCA1, BRCA2, and PALB2 were enriched 2 to 3-fold in cases diagnosed under age 50 relative to older cases. No change in frequency of CHEK2 mutations by age was observed. In case-control analyses mutations in BRCA1, BRCA2 and PALB2 were significantly associated with a high risk of breast cancer (odds ratio (OR)&amp;gt;4.0). Of these, BRCA1 and BRCA2 displayed ORs of 13.5 and 16.6 in the £50 age group, but only 5.7 and 3.2 in the &amp;gt;50 age group. Only minor age-specific effects were observed for PALB2. Mutations in ATM and CHEK2 were associated with moderate risks of breast cancer (OR=2.0 to 4.0) in the younger age group, but not in the older age group. Conclusions: Results from the CARRIERS cohort-based study establish that mutations in known breast cancer predisposition genes are associated with only moderate risks of breast cancer in the general population. However, risks are substantially increased for BRCA1 and BRCA2 but not ATM, CHEK2 or PALB2 mutations in those £50 years of age. The age-related estimates of breast cancer risk for each of the hereditary cancer panel genes in this study may inform selection of individuals in the general population who may benefit from genetic testing and associated risk management strategies. Citation Format: Couch FJ, Hu C, Hart SN, Gnanaolivu RD, Lilyquist J, Lee KY, Gao C, Eckloff B, Samara R, Klebba J, Auer P, Bernstein L, Gaudet M, Haiman C, Palmer JR, Yao S, Domchek SM, Weitzel JN, Goldgar DE, Nathanson KL, Kraft P, Polley EC. Age-related breast cancer risk estimates for the general population based on sequencing of cancer predisposition genes in 19,228 breast cancer patients and 20,211 matched unaffected controls from US based cohorts in the CARRIERS study [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 GS2-01.

Double Trouble: Contralateral Breast Cancer Risk Management in the Modern Era.

Double Trouble: Contralateral Breast Cancer Risk Management in the Modern Era.

Layers of information: interacting constraints on breast cancer risk-management by high-risk African American women

ABSTRACT Objectives: To understand how various decision-making dynamics interact to shape the risk-management choices of African American women at high-risk of breast cancer, and to explore whether African American and White women have differential access to the information and interactions that promote proactive, confident risk-management behavior. Design: This paper draws on 50 original in-depth, semi-structured interviews with African American and White women at elevated risk of breast cancer. We used inductive grounded-theory methodology to explore the processes by which women make risk-management decisions and to compare those processes between racial groups. Moving backward from women’s decisions about whether or not to engage in specific risk-management behaviors, we explored the patterns that underlie behavioral decisions. Results: We find that decisions to engage in risk-management behavior rest on three accumulated layers of information. The layer most proximal to making risk-management decisions involves specific information about risk-management options; the middle layer involves general information about managing breast cancer risk; and the foundational layer involves personal perceptions of breast cancer risk and prevention. African American and White women experience distinct dynamics at each of these levels, and these differences may help explain racial differences in risk-management behavior. Compared to their White counterparts, African American women faced additional burdens at every step along the risk-management journey. Conclusion: These findings suggest that information gathering is more complex than has previously been addressed, that information access and provider access are closely related, and that African American women may be systematically disadvantaged with respect to information-generating experiences. Preventing cancer morbidity and mortality requires that all high-risk women have access to the layers of information necessary to engage in cancer screenings and preventive interventions. These results exemplify the ways that structural, social, and interpersonal inequalities combine to influence risk-management choices.

Breast cancer awareness among undergraduate medical students in a tertiary healthcare centre in Mangalore, India

Background: Breast cancer is currently one of the leading causes of cancer related deaths in India. Early detection of breast cancer can improve the survival rates. The aim of this study was to assess the breast cancer awareness among undergraduate medical students in a tertiary healthcare centre in Mangalore, India. This was an observational study conducted among 95 medical students from first to final year in a tertiary healthcare centre.Methods: Data was collected using a standard self-administered questionnaire. Participants were given printed copies of the questionnaire and were given time to fill their responses in a confidential setting. Participants were then asked to return these questionnaires anonymously. Statistical analysis used- Frequency distribution statistics.Results: All the participants had good knowledge about breast cancer and 78.94 % had good overall awareness about Breast self-examination (BSE). 88.42 % of the participants believed that breast cancer is curable. 75.78 % of the participants knew the technique of performing BSE and around 98.93% agreed that BSE is important. Almost all the participants (98.94%) stated that Breast self-examination, Clinical breast examination and Mammogram can detect breast cancer.Conclusions: To improve the breast cancer awareness in the community, more effective health education programmes will be required to enlighten healthcare professionals as well as the general public regarding the risk factors, early detection and management of breast cancer.

The iPrevent Online Breast Cancer Risk Assessment and Risk Management Tool: Usability and Acceptability Testing.

BackgroundiPrevent estimates breast cancer (BC) risk and provides tailored risk management information.ObjectiveThe objective of this study was to assess the usability and acceptability of the iPrevent prototype.MethodsClinicians were eligible for participation in the study if they worked in primary care, breast surgery, or genetics clinics. Female patients aged 18-70 years with no personal cancer history were eligible. Clinicians were first familiarized with iPrevent using hypothetical paper-based cases and then actor scenarios; subsequently, they used iPrevent with their patients. Clinicians and patients completed the System Usability Scale (SUS) and an Acceptability questionnaire 2 weeks after using iPrevent; patients also completed measures of BC worry, anxiety, risk perception, and knowledge pre- and 2 weeks post-iPrevent. Data were summarized using descriptive statistics.ResultsThe SUS and Acceptability questionnaires were completed by 19 of 20 clinicians and 37 of 43 patients. Usability was above average (SUS score >68) for 68% (13/19) clinicians and 76% (28/37) patients. The amount of information provided by iPrevent was reported as “about right” by 89% (17/19) clinicians and 89% (33/37) patients and 95% (18/19) and 97% (36/37), respectively, would recommend iPrevent to others, although 53% (10/19) clinicians and 27% (10/37) patients found it too long. Exploratory analyses suggested that iPrevent could improve risk perception, decrease frequency of BC worry, and enhance BC prevention knowledge without changing state anxiety.ConclusionsThe iPrevent prototype demonstrated good usability and acceptability. Because concerns about length could be an implementation barrier, data entry has been abbreviated in the publicly available version of iPrevent.

Consumer and clinician perspectives on personalising breast cancer prevention information

BackgroundPersonalised prevention of breast cancer has focused on women at very high risk, yet most breast cancers occur in women at average, or moderately increased risk (≤moderate risk). ObjectivesTo determine; 1) interest of women at ≤ moderate risk (consumers) in personalised information about breast cancer risk; 2) familial cancer clinicians' (FCCs) perspective on managing women at ≤ moderate risk, and; 3) both consumers' and FCCs reactions to iPrevent, a personalised breast cancer risk assessment and risk management decision support tool. MethodsSeven focus groups on breast cancer risk were conducted with 49 participants; 27 consumers and 22 FCCs. Data were analysed thematically. ResultsConsumers reported some misconceptions, low trust in primary care practitioners for breast cancer prevention advice and frustration that they often lacked tailored advice about breast cancer risk. They expressed interest in receiving personalised risk information using iPrevent. FCCs reported an inadequate workforce to advise women at ≤ moderate risk and reacted positively to the potential of iPrevent to assist. ConclusionsWhile highlighting a potential role for iPrevent, several outstanding issues remain. For personalised prevention of breast cancer to extend beyond women at high risk, we must harness women's interest in receiving tailored information about breast cancer prevention and identify a workforce willing to advise women.

Genetic Testing and Clinical Management Practices for Variants in Non-BRCA1/2 Breast (and Breast/Ovarian) Cancer Susceptibility Genes: An International Survey by the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Clinical Working Group.

To describe a snapshot of international genetic testing practices, specifically regarding the use of multigene panels, for hereditary breast/ovarian cancers. We conducted a survey through the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium, covering questions about 16 non-BRCA1/2 genes. Data were collected via in-person and paper/electronic surveys. ENIGMA members from around the world were invited to participate. Additional information was collected via country networks in the United Kingdom and in Italy. Responses from 61 cancer genetics practices across 20 countries showed that 16 genes were tested by > 50% of the centers, but only six (PALB2, TP53, PTEN, CHEK2, ATM, and BRIP1) were tested regularly. US centers tested the genes most often, whereas United Kingdom and Italian centers with no direct ENIGMA affiliation at the time of the survey were the least likely to regularly test them. Most centers tested the 16 genes through multigene panels; some centers tested TP53, PTEN, and other cancer syndrome-associated genes individually. Most centers reported (likely) pathogenic variants to patients and would test family members for such variants. Gene-specific guidelines for breast and ovarian cancer risk management were limited and differed among countries, especially with regard to starting age and type of imaging and risk-reducing surgery recommendations. Currently, a small number of genes beyond BRCA1/2 are routinely analyzed worldwide, and management guidelines are limited and largely based on expert opinion. To attain clinical implementation of multigene panel testing through evidence-based management practices, it is paramount that clinicians (and patients) participate in international initiatives that share panel testing data, interpret sequence variants, and collect prospective data to underpin risk estimates and evaluate the outcome of risk intervention strategies.

Understanding and Practices of Gynaecologists Related to Breast Cancer Screening, Detection, Treatment and Common Breast Diseases: A Study from India.

The knowledge of breast cancer risk factors and screening practices in a community is largely influenced by the practising gynaecologist in that area. We assessed the understanding and knowledge of gynaecologists about breast cancer: screening, risk factors, clinical signs, management and common benign breast diseases. This cross-sectional study was carried out in Uttar Pradesh, India, from April to September 2017. One hundred and fifty-two gynaecologists were assessed using a self-designed and validated questionnaire to assess the knowledge of risk factors, clinical signs, screening practices and management of breast cancer as well as common benign breast diseases. Further, the results were compared based on their education: undergraduates (UGs; no residency experience in obstetrics and gynaecology) versus postgraduates (PGs; residency experience in obstetrics and gynaecology). 67 and 82.2% of gynaecologists possess excellent to very good knowledge of risk factors and clinical signs of breast cancer, respectively. The knowledge of PGs seems to be better than UGs (p < 0.01). 84.9% participants were aware that breast cancer screening decreases breast cancer-related mortality, and 61.2% considered CBE as most relevant screening investigation (66.1% PGs and 41.9% UGs; p = 0.04). 30.2% regularly offer breast cancer screening at their centre. 58.5% did not consider screening mammography as cost-effective for their patients (57.9% PGs and 61.3% UGs; p = 0.72), and 41.4% considered it to be a time-consuming process (39.7% PGs and 48.4% UGs; p = 0.38). 99.3% like to follow up a patient with familial breast cancer by themselves, and 0.7% like to refer them to specialist. 51.9% gynaecologists were convinced of breast conservation surgery (BCS) as a surgical option, however 51.3% feared leaving diseased breast behind. Despite the knowledge regarding risk factors, clinical signs and treatment of breast cancer and benign breast diseaseswas found adequate amongst the gynaecologists, this did not apply to their clinical practice. Structured and continuous training of gynaecologists is needed to improve the outcome of patients with breast diseases in terms of better management and reference.

Management of Lobular Neoplasia

Purpose of Review Lobular neoplasia (LN) is a well-established risk factor and non-obligate precursor for breast cancer. The clinical breast cancer risk assessment and management for these patients can be challenging.

Abstract P4-11-02: Acceptability and usability of iPrevent, a web-based decision support tool for assessment and management of breast cancer risk

Abstract Background: iPrevent estimates an individual's personal BC risk, using either the IBIS or BOADICEA algorithms, and provides tailored risk management information on screening, lifestyle modifications, risk-reducing surgery and risk-reducing medication. It is designed to be used collaboratively by women and their clinicians. The purpose of this pre-implementation pilot study was to assess the clinical usability and acceptability of the iPrevent prototype, and to identify barriers to clinical implementation. Exploratory aims investigated patients' BC worry, anxiety, risk perception and knowledge before and after using iPrevent. Methods: Eligible clinicians worked in primary care (PC), breast surgical (BS) or genetics clinics (GC). Their female patients were eligible if aged 18-70 years with no personal cancer history. Clinicians were familiarized with iPrevent using hypothetical cases, then actor scenarios, and lastly iPrevent was trialed with patients. All participants completed the System Usability Scale (SUS) and an acceptability questionnaire 2 weeks after using iPrevent. Patients also completed the Lerman BC Worry Scale, Spielberger State-Trait Anxiety Inventory, and BC risk perception and prevention knowledge questionnaires before and 2 weeks after using the tool. Data were summarized using descriptive statistics. Results: 63 participants comprising 20 clinicians (median age 47 years, 8 PC, 6 BS, 6 GC) and 43 patients (median age 38 years, 16% high risk, 51% moderate risk, 33% average risk) were recruited. Usability was rated above average (SUS score &amp;gt;68) by most clinicians (68%) and patients (76%). Most (79% of clinicians, 81% of patients) agreed iPrevent was 'easy to use', although 10 (53%) clinicians and 10 (27%) patients reported that it was too long. Most clinicians (84%) and patients (86%) found iPrevent 'very' or 'somewhat' helpful. 89% of participants reported that iPrevent provided the right amount of information. 5% reported to 'rarely' or 'not at all' worry about BC before iPrevent, and 29% after use. 25% of patients reported less impact of worrying about BC after iPrevent, 47% were unchanged and 28% reported more impact of worrying about BC after iPrevent use. State anxiety remained the same. 87% of patients correctly reported their risk category after using iPrevent® compared with 40% before. BC prevention knowledge improved for most questions. Conclusions: iPrevent has high usability and acceptability. Exploratory analyses suggest that iPrevent may also improve patients' BC risk perception and knowledge without adversely affecting anxiety or BC worry. Because concerns about length could be a barrier to implementation, data entry has been abbreviated in the modified version of iPrevent that will be publically available. Citation Format: Phillips K-A, Lo L, Bressel M, Collins IM, Emery J, Weideman P, Keogh L, Steel E, Bickerstaffe A, Mann GB, Trainer A, Hopper JL, Antoniou AC, Cuzick J, Butow P. Acceptability and usability of iPrevent, a web-based decision support tool for assessment and management of breast cancer risk [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 P4-11-02.

Abstract PD1-01: Triple negative breast cancer predisposition genes

Abstract Background: Germline cancer testing panels provide an effective method for identifying individuals at increased risk for breast cancer. However, estimates of risk for triple negative breast cancer (TNBC) (estrogen receptor-negative, progesterone receptor-negative, HER2-negative) associated with pathogenic mutations in panel genes have not been established. We sought to define the genes that contribute to TNBC. Methods:Germline hereditary cancer multigene panel testing results were obtained for 8,753 TNBCs evaluated by a clinical testing laboratory. Associations between pathogenic mutations in individual genes and TNBC were assessed by comparing mutation frequencies in TNBCs and in the Exome Aggregation Consortium, non-Finn European, non-Cancer Genome Atlas reference controls. Results: Inactivating mutations in 21 known cancer predisposition genes were identified in 14.6% of TNBCs. BRCA1, BRCA2, PALB2, BARD1, and RAD51D alterations were associated with high risks (odds ratio(OR)&amp;gt;5.0) of TNBC and variants in BRIP1, RAD51C, MSH6, and TP53 were associated with moderate risks (OR&amp;gt;2). In contrast, ATM, CHEK2, NBN, and RAD50 yielded no clinically relevant risks of TNBC. Pathogenic mutations in these established non-BRCA1/2 TNBC susceptibility genes were detected in 6.3% of TNBCs. Similar trends were observed among African American TNBCs. Overall, 5.5% of TNBCs with pathogenic mutations did not meet NCCN clinical testing criteria for BRCA1/2 due to a lack of significant family history and diagnosis over the age of 60. Conclusions: The identification of genes associated with elevated risk of TNBC will improve understanding of the etiology of this aggressive form of breast cancer and inform risk management of individuals receiving panel testing. The high frequency of pathogenic variants suggests that all patients with TNBC, regardless of age of diagnosis or family history of cancer, should be considered for multigene panel testing. Citation Format: Couch FJ, Shimelis H, LaDuca H, Hu C, Hart SN, Polley EC, Pesaran T, Tippin-Davis B, Goldgar DE, Dolinsky JS. Triple negative breast cancer predisposition genes [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 PD1-01.

Abstract PD1-11: Moderate risk genes matter: Multigene testing for hereditary breast cancer

Abstract Background: Many genes have been associated with hereditary breast cancer (BC). For some genes, the associated cancer risks have been debated; however, recent studies have helped resolve some uncertainties. For example, ATM, BARD1, CHEK2, and RAD51D were associated with a moderate risk of BC (odds ratio (OR) 2- to 5-fold) in a recent study by Couch et al. Though many BC susceptibility genes have NCCN® management guidelines for at least one cancer type, some lack recommendations for BC risk management and others are missing altogether due to limited data. We aim to examine the mutation frequencies of genes on a BC focused multigene panel test (MGPT) and the possible clinical impact of these findings. Methods: Sequential BC cases submitted to our laboratory for a BC focused MGPT between March 2012 and December 2016 were retrospectively reviewed. De-identified medical and family history data from test request forms and accompanying medical records as well as MGPT results were analyzed. Panel yield was assessed based on history of single or multiple primary diagnoses (MPD), level of BC risk, and clinical impact of test results. Results: Of 30,161 BC cases tested, 3,174 (10.5%) were positive for a mutation, and 143 (0.5%) had more than one mutation identified. Mutations in high (&amp;gt;5-fold risk) and moderate risk (&amp;lt;5-fold risk) BC genes were detected in 3.9% and 6.6% of BC patients, respectively. Furthermore, 80.0% of the gene mutations identified (8.4% of all BC patients) occurred in genes with NCCN® management guidelines for at least one cancer type. Detection rate also varied based on personal history, with mutations detected in 10.2% of single BC cases only, 12.7% of BC cases with MPD only, and 14.0% of cases with breast and other cancers (see Table for gene specific frequencies). Breast Cancer Only N (%)MPD Only N (%)Breast + Other Cancers N (%)ATM246 (1.0%)62 (1.5%)33 (1.9%)BARD158 (0.2%)19 (0.5%)3 (0.2%)BRCA1273 (1.2%)65 (1.7%)13 (0.8%)BRCA2336 (1.4%)68 (1.8%)36 (2.2%)BRIP169 (0.3%)6 (0.1%)7 (0.4%)CDH112 (0.1%)5 (0.1%)1 (0.1%)CHEK2412 (1.7%)105 (2.6%)58 (3.3%)CHEK2 (p.I157T)122 (0.5%)28 (0.7%)13 (0.7%)MRE11A31 (0.1%)6 (0.1%)2 (0.1%)MUTYH carrier312 (1.3%)44 (0.1%)31 (1.8%)NBN44 (0.2%)5 (0.1%)5 (0.3%)NF139 (0.2%)9 (0.3%)6 (0.4%)PALB2221 (0.9%)43 (1.1%)14 (0.8%)PTEN14 (0.1%)4 (0.1%)1 (0.1%)RAD5057 (0.2%)8 (0.2%)9 (0.5%)RAD51C32 (0.1%)13 (0.3%)2 (0.1%)RAD51D17 (0.1%)5 (0.1%)2 (0.1%)TP5347 (0.2%)16 (0.4%)12 (0.7%) Discussion: Findings from this large clinical testing cohort indicate that clinicians can expect approximately 3.9% and 6.6% of BC patients to have mutations in high and moderate risk genes, respectively. Though these values may shift as gene-specific BC risks continue to be refined, it is clear that moderate risk genes play a significant role in BC susceptibility. Five genes recently added to NCCN® management guidelines (BRIP1, NBN, NF1, RAD51C, and RAD51D) accounted for 9.9% of mutations identified (1.0% of all BC cases). Including these genes in MGPT provides patients and their families clinically relevant information about cancer risks and management options. Further studies are needed on genes such as BARD1 and RAD51D that have recently been shown to predispose to BC but lack guidelines for BC risk management. Citation Format: Jackson M, LaDuca H, Profato-Partlow J, Espenschied C. Moderate risk genes matter: Multigene testing for hereditary breast cancer [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 PD1-11.

Acceptability and usability of iPrevent, a web-based decision support tool for assessment and management of breast cancer risk

Acceptability and usability of iPrevent, a web-based decision support tool for assessment and management of breast cancer risk

Risk management adherence following genetic testing for hereditary cancer syndromes: a Singaporean experience.

Assessing adherence behavior among mutation carriers to cancer risk management guidelines is important for both service improvement and cost-effectiveness analyses, but such real-world data is often lacking. The present study aims to report adherence rates among mutation carriers in a recently established cancer genetics program in Singapore. We conducted a medical chart review of mutation carriers who had attended for genetic counseling and gathered data regarding risk management behavior, including cancer surveillance and/or risk-reducing surgery, and cancers subsequently detected. Of the 52 subjects included in the study, the majority were affected prior to genetic testing (78.8%) and had family history suggestive of a germline mutation (88.5%). The overall adherence rate was 96.2%, including 37 (74.0%) fully-adherent and 13 (26.0%) partially-adherent subjects, with five cancers subsequently detected. Among the 28 BRCA1/2 mutation carriers, adherence to breast cancer risk management was also high (89.3%), although uptake of risk-reducingbilateral salpingo-oophorectomy was not as common (60%). Whilst overall adherence in this cohort was high, BRCA1/2 mutation carriers may require targeted interventions to improve ovarian cancer risk management uptake. Additionally, further education among health professionals and the wider community regarding cancer genetics is needed to ensure the early identification of mutation carriers.

When to Consider Risk-Reducing Mastectomy in BRCA1/BRCA2 Mutation Carriers with Advanced Stage Ovarian Cancer: a Case Study Illustrating the Genetic Counseling Challenges

Germline mutations in BRCA1/BRCA2 significantly increase the risk of breast and ovarian cancer in women. This case report describes a BRCA1 germline mutation identified in a woman with stage IV epithelial ovarian cancer and the provision of genetic counseling about BRCA1-associated breast cancer risk in the three years following diagnosis. The report centers on the patient’s enquiry about risk-reducing breast surgery. We focus on the challenges for health professionals and patients in understanding and balancing the risks and benefits of major prophylactic surgery in the context of a potentially life-limiting cancer diagnosis. Breast cancer risk management in BRCA1/BRCA2 carriers with advanced ovarian cancer is an under-explored area of genetic counseling research. This article includes a case report, a review of the relevant literature and considers some implications for practice.

Cost Effectiveness of Risk-Reducing Mastectomy versus Surveillance in BRCA Mutation Carriers with a History of Ovarian Cancer.

The appropriate management of breast cancer risk in BRCA mutation carriers following ovarian cancer diagnosis remains unclear. We sought to determine the survival benefit and cost effectiveness of risk-reducing mastectomy (RRM) among women with BRCA1/2 mutations following stage II-IV ovarian cancer. We constructed a decision model from a third-party payer perspective to compare annual screening with magnetic resonance imaging (MRI) and mammography to annual screening followed by RRM with reconstruction following ovarian cancer diagnosis. Survival, overall costs, and cost effectiveness were determined by decade at diagnosis using 2015 US dollars. All inputs were obtained from the literature and public databases. Monte Carlo probabilistic sensitivity analysis was performed with a $100,000 willingness-to-pay threshold. The incremental cost-effectiveness ratio (ICER) per year of life saved (YLS) forRRM increased with age and BRCA2 mutation status, with greater survival benefit demonstrated in younger patients with BRCA1 mutations. RRM delayed 5years in 40-year-old BRCA1 mutation carriers was associated with 5months of life gained (ICER $72,739/YLS), and in 60-year-old BRCA2 mutation carriers was associated with 0.8months of life gained (ICER $334,906/YLS). In all scenarios, $/YLS and mastectomies per breast cancer prevented were lowest with RRM performed 5-10years after ovarian cancer diagnosis. For most BRCA1/2 mutation carriers following ovarian cancer diagnosis, RRM performed within 5years is not cost effective when compared with breast cancer screening. Imaging surveillance should be advocated during the first several years after ovarian cancer diagnosis, after which point the benefits of RRM can be considered based on patient age and BRCA mutation status.

Prediction of Breast and Prostate Cancer Risks in Male BRCA1 and BRCA2 Mutation Carriers Using Polygenic Risk Scores.

PurposeBRCA1/2 mutations increase the risk of breast and prostate cancer in men. Common genetic variants modify cancer risks for female carriers of BRCA1/2 mutations. We investigated—for the first time to our knowledge—associations of common genetic variants with breast and prostate cancer risks for male carriers of BRCA1/2 mutations and implications for cancer risk prediction.Materials and MethodsWe genotyped 1,802 male carriers of BRCA1/2 mutations from the Consortium of Investigators of Modifiers of BRCA1/2 by using the custom Illumina OncoArray. We investigated the combined effects of established breast and prostate cancer susceptibility variants on cancer risks for male carriers of BRCA1/2 mutations by constructing weighted polygenic risk scores (PRSs) using published effect estimates as weights.ResultsIn male carriers of BRCA1/2 mutations, PRS that was based on 88 female breast cancer susceptibility variants was associated with breast cancer risk (odds ratio per standard deviation of PRS, 1.36; 95% CI, 1.19 to 1.56; P = 8.6 × 10−6). Similarly, PRS that was based on 103 prostate cancer susceptibility variants was associated with prostate cancer risk (odds ratio per SD of PRS, 1.56; 95% CI, 1.35 to 1.81; P = 3.2 × 10−9). Large differences in absolute cancer risks were observed at the extremes of the PRS distribution. For example, prostate cancer risk by age 80 years at the 5th and 95th percentiles of the PRS varies from 7% to 26% for carriers of BRCA1 mutations and from 19% to 61% for carriers of BRCA2 mutations, respectively.ConclusionPRSs may provide informative cancer risk stratification for male carriers of BRCA1/2 mutations that might enable these men and their physicians to make informed decisions on the type and timing of breast and prostate cancer risk management.

Patient and medical barriers preclude uptake of tamoxifen preventative therapy in women with a strong family history

AimsTo assess the eligibility, uptake and impediments to tamoxifen use in high-risk women attending a risk management clinic due to family history. Patients and methodsAll patients with a germline mutation in a cancer predisposing gene or at high genetic risk (based on family history) attending a Breast and Ovarian cancer risk management clinic from February 2014 to May 2015 received both verbal and written evidence-based information on preventive therapy and were recommended to consider endocrine prevention if not contraindicated. Endocrine therapy initiation, use and cessation were captured. Patient eligibility was analysed and reasons for declining, ceasing or contraindications for medication use were recorded. ResultsDuring the study period, 237 women were seen over 305 consultations for breast surveillance and preventative therapy discussion. They comprised 38 BRCA1 and 42 BRCA2 mutation carriers, 4 with Peutz-Jegher syndrome, 153 with a strong family history. Their median age was 39.4 years. Endocrine preventative was considered and discussed with all but 19 women. Of the remaining 218, 34 chose bilateral prophylactic mastectomy, while endocrine preventative was not recommended in 50 women due to contraindications and 25 women declined treatment due to their intention to fall pregnant. In 118 patients who remained eligible, 18.6% (22) tried prevention and 9.4% (14) remained on therapy. ConclusionsPhysician-reluctance is not a dominant reason for poor uptake of endocrine prevention even by high-risk premenopausal women in a specialised risk management clinic. Many women are not eligible, and most elect for alternative options.

Usefulness of Canadian Public Health Insurance Administrative Databases to Assess Breast and Ovarian Cancer Screening Imaging Technologies for BRCA1/2 Mutation Carriers

PurposeIn Canada, recommendations for clinical management of hereditary breast and ovarian cancer among individuals carrying a deleterious BRCA1 or BRCA2 mutation have been available since 2007. Eight years later, very little is known about the uptake of screening and risk-reduction measures in this population. Because Canada's public health care system falls under provincial jurisdictions, using provincial health care administrative databases appears a valuable option to assess management of BRCA1/2 mutation carriers. The objective was to explore the usefulness of public health insurance administrative databases in British Columbia, Ontario, and Quebec to assess management after BRCA1/2 genetic testing. MethodsOfficial public health insurance documents were considered potentially useful if they had specific procedure codes, and pertained to procedures performed in the public and private health care systems. ResultsAll 3 administrative databases have specific procedures codes for mammography and breast ultrasounds. Only Quebec and Ontario have a specific procedure code for breast magnetic resonance imaging. It is impossible to assess, on an individual basis, the frequency of others screening exams, with the exception of CA-125 testing in British Columbia. Screenings done in private practice are excluded from the administrative databases unless covered by special agreements for reimbursement, such as all breast imaging exams in Ontario and mammograms in British Columbia and Quebec. There are no specific procedure codes for risk-reduction surgeries for breast and ovarian cancer. ConclusionPopulation-based assessment of breast and ovarian cancer risk management strategies other than mammographic screening, using only administrative data, is currently challenging in the 3 Canadian provinces studied.