Large- and medium-sized arterial aneurysms in two patients with SMAD4-related juvenile polyposis syndrome.

Germline SMAD4 pathogenic variants (PVs) cause juvenile polyposis syndrome (JPS), which is known for an increased risk of gastrointestinal juvenile polyps and gastrointestinal cancer. Many patients with SMAD4 PV also show signs of hereditary hemorrhagic telangiectasia (HHT) and some patients have aneurysms and dissections of the thoracic aorta. Here we describe two patients with a germline SMAD4 PV and a remarkable clinical presentation including multiple medium-sized arterial aneurysms. More data are needed to confirm whether the more extensive vascular phenotype and the other described features in our patients are indeed part of a broader JPS spectrum.

Development of ileal adenomas after ileal pouch-anal anastomosis versus end ileostomy in patients with familial adenomatous polyposis.

BACKGROUND AND AIMS: Patients with familial adenomatous polyposis (FAP) undergo (procto)colectomy to prevent colorectal cancer from developing. Interestingly, after proctocolectomy with ileal pouch-anal anastomosis (IPAA), most patients develop adenomas in the pouch. This is not well described for patients with end ileostomy. We aimed to compare ileal adenoma development in patients with IPAA with those with end ileostomy. METHODS: This historical cohort study included FAP patients with IPAA or end ileostomy who underwent surveillance endoscopies between 2001 and 2021. Primary outcomes were the proportion of patients with ileal adenomas, location of adenomas, and proportion of patients undergoing surgical excision of pouch/end ileostomy. RESULTS: Overall, 144 patients with IPAA (n = 111) and end ileostomy (n = 33) were included. Five years after surgery, 15% of patients with IPAA had ileal adenomas versus 4% after ileostomy. At 10 years, these estimates were 48% versus 9% and at 20 years were 85% versus 43% (log-rank P < .001). Adenomas developed more often in the pouch body (95%) in the IPAA group and more often at the everted site of the ileostomy (77%) in the ileostomy group. Numbers for surgical excision of the pouch (n = 9) or ileostomy (n = 3) for polyposis or cancer were comparable. Taking into account potential confounders in a multivariable Cox regression analysis, having an IPAA was significantly associated with ileal adenoma development. CONCLUSIONS: After proctocolectomy, FAP patients with IPAA more often developed ileal adenomas than patients with end ileostomy. This could potentially affect long-term management, and patients with end ileostomy might benefit from less-frequent endoscopic surveillance.

A scoping review of practice recommendations for clinicians' communication of uncertainty.

BACKGROUND: Health-care providers increasingly have to discuss uncertainty with patients. Awareness of uncertainty can affect patients variably, depending on how it is communicated. To date, no overview existed for health-care professionals on how to discuss uncertainty. OBJECTIVE: To generate an overview of available recommendations on how to communicate uncertainty with patients during clinical encounters. SEARCH STRATEGY: A scoping review was conducted. Four databases were searched following the PRISMA-ScR statement. Independent screening by two researchers was performed of titles and abstracts, and subsequently full texts. INCLUSION CRITERIA: Any (non-)empirical papers were included describing recommendations for any health-care provider on how to orally communicate uncertainty to patients. DATA EXTRACTION: Data on provided recommendations and their characteristics (eg, target group and strength of evidence base) were extracted. Recommendations were narratively synthesized into a comprehensible overview for clinical practice. RESULTS: Forty-seven publications were included. Recommendations were based on empirical findings in 23 publications. After narrative synthesis, 13 recommendations emerged pertaining to three overarching goals: (a) preparing for the discussion of uncertainty, (b) informing patients about uncertainty and (c) helping patients deal with uncertainty. DISCUSSION AND CONCLUSIONS: A variety of recommendations on how to orally communicate uncertainty are available, but most lack an evidence base. More substantial research is needed to assess the effects of the suggested communicative approaches. Until then, health-care providers may use our overview of communication strategies as a toolbox to optimize communication about uncertainty with patients. PATIENT OR PUBLIC CONTRIBUTION: Results were presented to stakeholders (physicians) to check and improve their practical applicability.

Addition of an online, validated family history questionnaire to the Dutch FIT-based screening programme did not improve its diagnostic yield.

BACKGROUND: Faecal immunochemical testing (FIT) is suboptimal in detecting advanced neoplasia (AN). To increase the sensitivity and yield of a FIT-based screening programme, FIT could be combined with risk factors for AN. We evaluated the incremental yield of adding a family history questionnaire (FHQ) on colorectal cancer (CRC) and Lynch syndrome-associated tumours to the Dutch FIT-based screening programme. METHODS: Six thousand screen-naive individuals, aged 59-75 years, were invited to complete a FIT (FOB-Gold, cut-off 47 µg Hb/g faeces) and a validated online FHQ. Participants with a positive FIT and/or positive FHQ, confirmed after genetic counselling, were referred for colonoscopy. Yield of detecting AN per 1000 invitees for the combined strategy was compared with the FIT-only strategy. RESULTS: Of the 5979 invitees, 1952 (32.6%) completed the FIT only, 2379 (39.8%) completed both the FIT and FHQ and 95 (1.6%) completed the FHQ only. Addition of the FHQ to FIT-based screening resulted in one extra case of AN detected after 16 additional colonoscopies, resulting in a yield of 19.6 (95% CI, 16.4-23.5) for the combined strategy versus 19.5 (95% CI, 16.3-23.3) for the FIT-only strategy (p = 1.0). CONCLUSIONS: The addition of an FHQ to one round of FIT screening did not increase the detection of AN compared with FIT only (ClinicalTrials.gov NCT02698462).

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.

Mendelian randomisation study of height and body mass index as modifiers of ovarian cancer risk in 22,588 BRCA1 and BRCA2 mutation carriers.

BACKGROUND: Height and body mass index (BMI) are associated with higher ovarian cancer risk in the general population, but whether such associations exist among BRCA1/2 mutation carriers is unknown. METHODS: We applied a Mendelian randomisation approach to examine height/BMI with ovarian cancer risk using the Consortium of Investigators for the Modifiers of BRCA1/2 (CIMBA) data set, comprising 14,676 BRCA1 and 7912 BRCA2 mutation carriers, with 2923 ovarian cancer cases. We created a height genetic score (height-GS) using 586 height-associated variants and a BMI genetic score (BMI-GS) using 93 BMI-associated variants. Associations were assessed using weighted Cox models. RESULTS: Observed height was not associated with ovarian cancer risk (hazard ratio [HR]: 1.07 per 10-cm increase in height, 95% confidence interval [CI]: 0.94-1.23). Height-GS showed similar results (HR = 1.02, 95% CI: 0.85-1.23). Higher BMI was significantly associated with increased risk in premenopausal women with HR = 1.25 (95% CI: 1.06-1.48) and HR = 1.59 (95% CI: 1.08-2.33) per 5-kg/m2 increase in observed and genetically determined BMI, respectively. No association was found for postmenopausal women. Interaction between menopausal status and BMI was significant (Pinteraction < 0.05). CONCLUSION: Our observation of a positive association between BMI and ovarian cancer risk in premenopausal BRCA1/2 mutation carriers is consistent with findings in the general population.

Role of germline aberrations affecting CTNNA1, MAP3K6 and MYD88 in gastric cancer susceptibility.

BACKGROUND: In approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1 mutation; however, in most cases the cause remains unknown. Our objective was to assess to what extent these remaining cases may be explained by germline mutations in the novel candidate GC predisposing genes CTNNA1, MAP3K6 or MYD88. METHODS: We sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6 and MYD88 using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes. RESULTS: Predicted deleterious germline variants were not encountered in MYD88, but recurrently observed in CTNNA1 (n=2) and MAP3K6 (n=3) in our cohort of patients with GC. In contrast to deleterious variants in CTNNA1, deleterious variants in MAP3K6 also occur frequently in the general population. CONCLUSIONS: Based on our results MAP3K6 should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1 variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88 germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.

Online decision support for persons having a genetic predisposition to cancer and their partners during reproductive decision-making.

A nationwide pretest-posttest study was conducted in all clinical genetic centres in the Netherlands, to evaluate the effects of an online decision aid to support persons who have a genetic predisposition to cancer and their partners in making an informed decision regarding reproductive options. Main outcomes (decisional conflict, knowledge, realistic expectations, level of deliberation, and decision self-efficacy) were measured before use (T0), immediately after use (T1), and at 2 weeks (T2) after use of the decision aid. Paired sample t tests were used to compute differences between the first and subsequent measurements. T0-T1 and T0-T2 comparisons indicate a significant reduction in mean decisional conflict scores with stronger effects for participants with high baseline decisional conflict. Furthermore, use of the decision aid resulted in increased knowledge levels and improved realistic expectations. Level of deliberation only increased for participants with lower baseline levels of deliberation. Decision self-efficacy increased for those with low baseline scores, whereas those with high baseline scores showed a reduction at T2. It can be concluded that use of the decision aid resulted in several positive outcomes indicative of informed decision-making. The decision aid is an appropriate and highly appreciated tool to be used in addition to reproductive counseling.

Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations.

The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease-associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population-specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad-based oncogenetic testing in some populations.

Duodenal Adenomas in Patients With Multiple Colorectal Adenomas Without Germline APC or MUTYH Mutations.

BACKGROUND: Patients with genetic adenomatous polyposis syndromes have an increased risk for duodenal cancer, and clear surveillance recommendations exist for this group. However, limited data are available on the duodenal phenotype of patients with multiple colorectal adenomas (10-99) without a germline APC or MUTYH mutation. OBJECTIVE: We aimed to assess the frequency, extent, and progression of duodenal adenomas in patients with multiple colorectal adenomas without a germline APC or MUTYH mutation. DESIGN: This was an historical cohort study. SETTINGS: This study was undertaken at 2 polyposis registries: the Academic Medical Center in the Netherlands, and St. Mark's Hospital in the United Kingdom. PATIENTS: We collected data on all patients with 10 to 99 colorectal adenomas and absent APC and MUTYH mutations, who underwent ≥1 esophagogastroduodenoscopy. MAIN OUTCOME MEASURES: The frequency, extent, and progression of duodenal adenomas were measured. Demographic and endoscopic data were collected, described, and compared between patients with and without duodenal adenomas. RESULTS: Eighty-three patients were identified, of which 8 (9.6%) had duodenal adenomas, detected at a median of 58 years (range, 45-75 y). Duodenal adenomas were detected in 6 of 8 patients at first esophagogastroduodenoscopy. At diagnosis, all 8 patients had Spigelman stage I or II disease. Two of 5 patients with duodenal adenomas who underwent follow-up esophagogastroduodenoscopies increased to stage III disease. The other 3 remained stable. No one developed duodenal cancer. No differences in demographic and endoscopic data were found between patients with and without duodenal adenomas. LIMITATIONS: This study was limited by its retrospective design, selection bias, and small sample size. CONCLUSIONS: Duodenal adenomas are found in a minority of patients with multiple colorectal adenomas without a germline APC or MUTYH mutation, at an average age of 58 years, and, at diagnosis, disease severity is mild. These results are a first step in unraveling the duodenal phenotype of these patients, which is needed to provide appropriate upper GI screening and surveillance recommendations. See Video Abstract at http://links.lww.com/DCR/A357.

Colorectal Cancer Risk in Patients With Lynch Syndrome and Inflammatory Bowel Disease.

Lynch syndrome and inflammatory bowel diseases (IBD) are associated with an increased risk of colorectal cancer (CRC). However, it is not clear whether the risk of CRC is even higher for patients with a combination of Lynch syndrome and IBD. We investigated the risk for CRC in this subgroup by establishing a Lynch syndrome cohort from the Radboud University Medical Center (Nijmegen, The Netherlands) and the Academic Medical Center (Amsterdam, The Netherlands). Patients with heterozygous germline mutations in MLH1, MSH2 (and EPCAM deletion-mediated MSH2 methylation), MSH6, or PMS2 who were tested and/or treated from 1998 through 2014 were included. Patients who developed IBD were identified by linkage of this cohort to the Dutch nationwide Pathology Registry (PALGA). Subsequently, we compared the risk of CRC between Lynch syndrome patients with IBD and without IBD. Of 1046 patients with Lynch syndrome, 15 developed IBD (1.4%). Patients with Lynch syndrome and IBD were significantly younger (median age, 38.0 y) than patients with Lynch syndrome without IBD (median age, 52.0 y; P = .001). Nevertheless, a similar proportion of patients in each group developed CRC: 4 of the 15 patients (26.7%) with Lynch syndrome and IBD compared with 311 of the 1031 patients (30.2%) with Lynch syndrome without IBD. Patients with Lynch syndrome and IBD developed CRC at a younger age (median age, 36.0 y) than patients with Lynch syndrome without IBD (median age, 46.0 y; P = .045). However, the cumulative incidence of CRC was similar between groups (P = .121). All patients with Lynch syndrome and IBD who developed CRC had ulcerative colitis, producing a higher cumulative incidence of CRC for this IBD subgroup (P < .001). In conclusion, patients with Lynch syndrome and IBD develop CRC risk at a younger age than patients without IBD; patients with ulcerative colitis are at especially high risk.

Adrenal Lesions in Patients With (Attenuated) Familial Adenomatous Polyposis and MUTYH-Associated Polyposis.

BACKGROUND: The reported proportion of patients with familial adenomatous polyposis who have adrenal lesions varies between 7% and 13% compared with 4% in the general population; the prevalence of adrenal lesions in patients with attenuated familial adenomatous polyposis and MUTYH-associated polyposis is unknown. Data on the clinical relevance and clinical course are limited. OBJECTIVE: We aimed to report on the frequency, characteristics, and progression of adrenal lesions in polyposis patients. DESIGN: This was a historical cohort study. SETTINGS: The study was performed at the Academic Medical Center, Amsterdam. PATIENTS: All of the patients with familial adenomatous polyposis, attenuated familial adenomatous polyposis, and MUTYH-associated polyposis were included. Medical charts and imaging reports were analyzed for data on adrenal lesions. A radiologist reassessed all of the images. Patients had not routinely been screened for adrenal lesions. MAIN OUTCOME MEASURES: The frequency, characteristics, and progression of adrenal lesions in patients with polyposis who underwent abdominal imaging were assessed. Findings were compared with a reference. RESULTS: A total of 39 adrenal lesions were identified in 23 (26%) of 90 patients with familial adenomatous polyposis, 2 (18%) of 11 with attenuated familial adenomatous polyposis, and 5 (24%) of 21 with MUTYH-associated polyposis. Mean age at time of detection was 50.7 years (range, 17.1-83.3 y). Median lesion size at baseline was 1.4 cm (range, 1.0-5.0 cm) versus 1.7 cm (range, 1.0-5.7 cm) after a median of 3.5 years (range, 1.0-11.4 y). Two patients were diagnosed with a hyperfunctioning lesion, and 4 underwent adrenalectomy: 3 lesions appeared benign, and 1 was oncocytic of uncertain malignant potential. The OR for detecting at least 1 lesion in a patient with polyposis versus reference was 6.2 (95% CI, 3.2-12.3), with no significant differences in ORs among the 3 syndromes. LIMITATIONS: The study was limited by its retrospective design. CONCLUSIONS: Adrenal lesions are frequent in patients with polyposis who undergo abdominal imaging. They appear to follow a benign and slowly progressive course and are mostly nonhyperfunctioning. See Abstract Video at http://links.lww.com/DCR/A323.

Accuracy of Hereditary Diffuse Gastric Cancer Testing Criteria and Outcomes in Patients With a Germline Mutation in CDH1.

BACKGROUND & AIMS: Germline mutations in the cadherin 1, type 1, E-cadherin gene (CDH1) cause a predisposition to gastric cancer. We evaluated the ability of the internationally accepted hereditary diffuse gastric cancer (HDGC) criteria to identify individuals with pathogenic mutations in CDH1, and assessed their outcomes. The criteria were as follows: families with 2 or more cases of gastric cancer, with at least 1 patient diagnosed with diffuse gastric cancer (DGC) before age 50; families with 3 or more cases of DGC; families with 1 DGC before the age of 40; and families with a history of DGC and lobular breast cancer, with 1 diagnosis before the age of 50. METHODS: We collected results of a CDH1 mutation analysis of 578 individuals from 499 families tested in The Netherlands between 1999 and 2014 (118 families met the HDGC criteria for testing and 236 did not; there were 145 families with incomplete data and/or availability of only first-degree relatives). Data were linked with family histories and findings from clinical and pathology analyses. The Kaplan-Meier method and Cox regression analysis were used to evaluate the overall survival of patients with and without CDH1 mutations. RESULTS: In a cohort study in The Netherlands, the HDGC criteria identified individuals with a germline CDH1 mutation with a positive predictive value of 14% and 89% sensitivity. There were 18 pathogenic CDH1 mutations in 499 families (4%); 16 of these mutations were detected in the 118 families who met the HDGC criteria for testing. One pathogenic CDH1 mutation was detected in the 236 families who did not meet HDGC criteria and 1 in the 145 families with incomplete data and/or availability of only first-degree relatives. No CDH1 mutations were found in the 67 families whose members developed intestinal-type gastric cancer, or in the 22 families whose families developed lobular breast cancer. Among patients who fulfilled the HDGC criteria and had pathogenic CDH1 mutations, 36% survived for 1 year and 4% survived for 5 years; among patients who fulfilled the HDGC criteria but did not carry pathogenic CDH1 mutations, 48% survived for 1 year and 13% survived for 5 years (P = .014 for comparative survival analysis between patients with and without a CDH1 mutation). CONCLUSIONS: All individuals with a CDH1 mutation had a personal or family history of diffuse gastric cancer. Patients with gastric cancer and germline CDH1 mutations had shorter survival times than patients who met the HDGC criteria but did not have CDH1 mutations.

Repeated participation in pancreatic cancer surveillance by high-risk individuals imposes low psychological burden.

BACKGROUND: When assessing the feasibility of surveillance for pancreatic cancer (PC), it is important to address its psychological burden. The aim of this ongoing study is to evaluate the psychological burden of annual pancreatic surveillance for individuals at high risk to develop PC. METHODS: This is a multicenter prospective study. High-risk individuals who undergo annual pancreatic surveillance with magnetic resonance imaging (MRI) and endoscopic ultrasound (EUS) were invited to complete questionnaires to assess motivations for participating in surveillance, experiences with participation, perceived PC risk, topics of concern, and psychological distress. Questionnaires were sent after intake for participation (T1), after the first MRI and EUS (T2), and after the MRI and EUS 1 (T3), 2 (T4), and 3 years (T5) after first surveillance. RESULTS: In total, 140 out of 152 individuals returned one or more of the questionnaires (response 92%); 477 questionnaires were analyzed. The most frequently reported motivation for participating in surveillance was the possible early detection of (a precursor stage of) cancer (95-100%). Only a minority of respondents experienced MRI and EUS as uncomfortable (10% and 11%, respectively), and respondents dreaded their next EUS investigation less as surveillance progressed. Respondents' cancer worries decreased significantly over time, and both their anxiety and depression scores remained stable and low over the 3-year period of follow-up. CONCLUSIONS: The psychological burden of pancreatic surveillance is low at all assessments. Therefore, from a psychological point of view, participation of high-risk individuals in an annual pancreatic surveillance program is feasible.Copyright © 2015 John Wiley & Sons, Ltd.

Design and Feasibility of an Intervention to Support Cancer Genetic Counselees in Informing their At-Risk Relatives.

Cancer genetic counselees receive individualized information regarding heightened risks and medical recommendations which is also relevant for their at-risk relatives. Unfortunately, counselees often insufficiently inform these relatives. We designed an intervention aimed at improving counselees' knowledge regarding which at-risk relatives to inform and what information to disclose, their motivation to disclose, and their self-efficacy. The intervention, offered by telephone by trained psychosocial workers, is based on the principles of Motivational Interviewing. Phase 1 of the intervention covers agenda setting, exploration, and evaluation, and phase 2 includes information provision, enhancing motivation and self-efficacy, and brainstorming for solutions to disseminate information within the family. Fidelity and acceptability of the intervention were assessed using recordings of intervention sessions and by counselee self-report. A total of 144 counselees participated. Psychosocial workers (n = 5) delivered the intervention largely as intended. Counselees highly appreciated the content of the intervention and the psychosocial workers who delivered the intervention. In the sessions, psychosocial workers provided additional and/or corrective information, and brainstorming for solutions was performed in 70 %. These results indicate that this intervention is feasible and warrants testing in clinical practice. For this, a randomized controlled trial is currently in progress to test the intervention's efficacy.

Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

Improved overall survival after contralateral risk-reducing mastectomy in BRCA1/2 mutation carriers with a history of unilateral breast cancer: a prospective analysis.

Data on survival of BRCA1/2-associated primary breast cancer (PBC) patients who opt for subsequent contralateral risk-reducing mastectomy (CRRM) are scarce and inconsistent. We examined the efficacy of CRRM on overall survival in mutation carriers with a history of PBC. From a Dutch multicentre cohort, we selected 583 BRCA-associated PBC patients, being diagnosed between 1980 and 2011. Over time, 242 patients (42%) underwent CRRM and 341 patients (58%) remained under surveillance. Survival analyses were performed using Cox models, with CRRM as a time-dependent covariate. The median follow-up after PBC diagnosis was 11.4 years. In the CRRM group, four patients developed contralateral breast cancer (2%), against 64 patients (19%) in the surveillance group (p < 0.001). The mortality was lower in the CRRM group than in the surveillance group (9.6 and 21.6 per 1000 person-years of observation, respectively; adjusted hazard ratio 0.49, 95% confidence interval 0.29-0.82). Survival benefit was especially seen in young PBC patients (<40 years), in patients having a PBC with differentiation grade 1/2 and/or no triple-negative phenotype, and in patients not treated with adjuvant chemotherapy. We conclude that CRRM is associated with improved overall survival in BRCA1/2 mutation carriers with a history of PBC. Further research is warranted to develop a model based on age at diagnosis and tumour and treatment characteristics that can predict survival benefit for specific subgroups of patients, aiming at further personalized counselling and improved decision making.

Development of the Informing Relatives Inventory (IRI): Assessing Index Patients' Knowledge, Motivation and Self-Efficacy Regarding the Disclosure of Hereditary Cancer Risk Information to Relatives.

BACKGROUND: Despite the use of genetic services, counselees do not always share hereditary cancer information with at-risk relatives. Reasons for not informing relatives may be categorized as a lack of: knowledge, motivation, and/or self-efficacy. PURPOSE: This study aims to develop and test the psychometric properties of the Informing Relatives Inventory, a battery of instruments that intend to measure counselees' knowledge, motivation, and self-efficacy regarding the disclosure of hereditary cancer risk information to at-risk relatives. METHOD: Guided by the proposed conceptual framework, existing instruments were selected and new instruments were developed. We tested the instruments' acceptability, dimensionality, reliability, and criterion-related validity in consecutive index patients visiting the Clinical Genetics department with questions regarding hereditary breast and/or ovarian cancer or colon cancer. RESULTS: Data of 211 index patients were included (response rate = 62%). The Informing Relatives Inventory (IRI) assesses three barriers in disclosure representing seven domains. Instruments assessing index patients' (positive) motivation and self-efficacy were acceptable and reliable and suggested good criterion-related validity. Psychometric properties of instruments assessing index patients knowledge were disputable. These items were moderately accepted by index patients and the criterion-related validity was weaker. CONCLUSION: This study presents a first conceptual framework and associated inventory (IRI) that improves insight into index patients' barriers regarding the disclosure of genetic cancer information to at-risk relatives. Instruments assessing (positive) motivation and self-efficacy proved to be reliable measurements. Measuring index patients knowledge appeared to be more challenging. Further research is necessary to ensure IRI's dimensionality and sensitivity to change.