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BackgroundCommon low-risk variants are presently not used to guide clinical management of familial breast cancer (BC). We explored the additive impact of a 313-variant-based Polygenic Risk Score (PRS313) relative to standard gene testing in non-BRCA1/2Dutch BC families.MethodsWe included 3918 BC cases from 3492 Dutch non-BRCA1/2BC families and 3474 Dutch population controls. The association of the standardised PRS313with BC was estimated using a logistic regression model, adjusted for pedigree-based family history. Family history of the controls was imputed for this analysis. SEs were corrected to account for relatedness of individuals. Using the BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) V.5 model, lifetime risks were retrospectively calculated with and without individual PRS313. For 2586 cases and 2584 controls, the carrier status of pathogenic variants (PVs) in ATM, CHEK2and PALB2was known.ResultsThe family history-adjusted PRS313was significantly associated with BC (per SD OR=1.97, 95% CI 1.84 to 2.11). Including the PRS313in BOADICEA family-based risk prediction would have changed screening recommendations in up to 27%, 36% and 34% of cases according to BC screening guidelines from the USA, UK and the Netherlands (National Comprehensive Cancer Network, National Institute for Health and Care Excellence, and Netherlands Comprehensive Cancer Organisation), respectively. For the population controls, without information on family history, this was up to 39%, 44% and 58%, respectively. Among carriers of PVs in known moderate BC susceptibility genes, the PRS313had the largest impact for CHEK2and ATM.ConclusionsOur results support the application of the PRS313in risk prediction for genetically uninformative BC families and families with a PV in moderate BC risk genes.

ObjectiveWe aimed to determine the long-term yield of pancreatic cancer surveillance in hereditary predisposed high-risk individuals.DesignFrom 2006 to 2019, we prospectively enrolled asymptomatic individuals with an estimated 10% or greater lifetime risk of pancreatic ductal adenocarcinoma (PDAC) after obligatory evaluation by a clinical geneticist and genetic testing, and subjected them to annual surveillance with both endoscopic ultrasonography (EUS) and MRI/cholangiopancreatography (MRI/MRCP) at each visit.Results366 individuals (201 mutation-negative familial pancreatic cancer (FPC) kindreds and 165 PDAC susceptibility gene mutation carriers; mean age 54 years, SD 9.9) were followed for 63 months on average (SD 43.2). Ten individuals developed PDAC, of which four presented with a symptomatic interval carcinoma and six underwent resection. The cumulative PDAC incidence was 9.3% in the mutation carriers and 0% in the FPC kindreds (p<0.001). Median PDAC survival was 18 months (range 1–32). Surgery was performed in 17 individuals (4.6%), whose pathology revealed 6 PDACs (3 T1N0M0), 7 low-grade precursor lesions, 2 neuroendocrine tumours <2 cm, 1 autoimmune pancreatitis and in 1 individual no abnormality. There was no surgery-related mortality. EUS detected more solid lesions than MRI/MRCP (100% vs 22%, p<0.001), but less cystic lesions (42% vs 83%, p<0.001).ConclusionThe diagnostic yield of PDAC was substantial in established high-risk mutation carriers, but non-existent in the mutation-negative proven FPC kindreds. Nevertheless, timely identification of resectable lesions proved challenging despite the concurrent use of two imaging modalities, with EUS outperforming MRI/MRCP. Overall, surveillance by imaging yields suboptimal results with a clear need for more sensitive diagnostic markers, including biomarkers.

Uncertainty is increasingly discussed during genetic counseling due to innovative techniques, e.g., multigene panel testing. Discussions about uncertainty may impact counselees variably, depending on counselors’ communication styles. Ideally, the discussion of uncertainty enables counselees to cope with uncertainty and make well-informed decisions about testing. We examined the impact of how counselors convey uncertainty and address counselees’ uncertainty, and explored the role of individual characteristics. Therefore, a randomized controlled experiment using videos was conducted. Former counselees (N= 224) viewed one video depicting a genetic consultation about multigene panel testing. The extent of counselors’ communication of uncertainty (comprehensive vs. the essence) and their response to counselees’ uncertainty expressions (providing information vs. providing space for emotions vs. normalizing and counterbalancing uncertainty) were systematically manipulated. Individual characteristics, e.g., uncertainty tolerance, were assessed, as well as outcome variables (primary outcomes: feelings of uncertainty and information recall). No effects were found on primary outcomes. Participants were most satisfied when the essence was communicated, combined with providing information or providing space responses (p= 0.002). Comprehensive information resulted in less perceived steering toward testing (p= 0.005). Participants with lower uncertainty tolerance or higher trait anxiety were less confident about their understanding when receiving comprehensive information (p= 0.025). Participants seeking information experienced less uncertainty (p= 0.003), and trusted their counselor more (p= 0.028), when the counselor used information providing responses. In sum, the impact of discussing uncertainty primarily depends on individual characteristics. Practical guidelines should address how to tailor the discussion of uncertainty.

IMPORTANCE: For women with a 20% or more familial risk of breast cancer without a known BRCA1/2 (BRCA1, OMIM 113705; and BRCA2, OMIM 114480) or TP53 (OMIM 151623) variant, screening guidelines vary substantially, and cost-effectiveness analyses are scarce. OBJECTIVE: To assess the cost-effectiveness of magnetic resonance imaging (MRI) screening strategies for women with a 20% or more familial risk for breast cancer without a known BRCA1/2 or TP53 variant. DESIGN, SETTING, AND PARTICIPANTS: In this economic evaluation, conducted from February 1, 2019, to May 25, 2020, microsimulation modeling was used to estimate costs and effectiveness on a lifetime horizon from age 25 years until death of MRI screening among a cohort of 10 million Dutch women with a 20% or more familial risk for breast cancer without a known BRCA1/2 or TP53 variant. A Dutch screening setting was modeled. Most data were obtained from the randomized Familial MRI Screening (FaMRIsc) trial, which included Dutch women aged 30 to 55 years. A health care payer perspective was applied. INTERVENTIONS: Several screening protocols with varying ages and intervals including those of the randomized FaMRIsc trial, consisting of the mammography (Mx) protocol (annual mammography and clinical breast examination) and the MRI protocol (annual MRI and clinical breast examination plus biennial mammography). MAIN OUTCOMES AND MEASURES: Costs, life-years, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated and discounted by 3%. A threshold of €22 000 (US $24 795.87) per QALY was applied. RESULTS: This economic evaluation modeling study estimated that, on a lifetime horizon per 1000 women with the Mx protocol of the FaMRIsc trial, 346 breast cancers would be detected, and 49 women were estimated to die from breast cancer, resulting in 22 885 QALYs and total costs of €7 084 767 (US $7 985 134.61). The MRI protocol resulted in 79 additional QALYs and additional €2 657 266 (US $2 994 964.65). Magnetic resonance imaging performed only every 18 months between the ages of 35 and 60 years followed by the national screening program was considered optimal, with an ICER of €21 380 (US $24 097.08) compared with the previous nondominated strategy in the ranking, when applying the National Institute for Health and Care Excellence threshold. Annual screening alternating MRI and mammography between the ages of 35 and 60 years, followed by the national screening program, gave similar outcomes. Higher thresholds would favor annual MRI screening. The ICER was most sensitive to the unit cost of MRI and the utility value for ductal carcinoma in situ and localized breast cancer. CONCLUSIONS AND RELEVANCE: This study suggests that MRI screening every 18 months between the ages of 35 and 60 years for women with a family history of breast cancer is cost-effective within the National Institute for Health and Care Excellence threshold for all densities. Higher thresholds would favor annual MRI screening. These outcomes support a change of current screening guidelines for this specific risk group and support MRI screening.

Op dit moment wordt kiembaan genetisch onderzoek bij prostaatkanker zelden aangevraagd. Bij mannen met gemetastaseerd prostaatcarcinoom wordt echter relatief vaak een mutatie in een borstkankergen gevonden (met name in BRCA2). In dit artikel worden criteria voor genetisch onderzoek voorgesteld. De uitslag van genetisch onderzoek kan van belang zijn voor familieleden die preventieve maatregelen kunnen nemen om kanker te voorkomen of tijdig op te sporen. De uitslag kan daarnaast ook van belang zijn voor de behandeling van de ziekte. De tijd is rijp om multidisciplinair een werkwijze in te richten waarbij genetisch onderzoek door het behandelteam met de patiënt wordt besproken, de patiënt goed geïnformeerd een keuze kan maken, en de uitslagen in nauwe samenwerking met de klinische genetica worden teruggekoppeld. Voor deze nieuwe werkwijze (mainstreamingvan genetisch onderzoek) is adequate scholing nodig van urologen, oncologen en verpleegkundig specialisten.

BackgroundIn approximately 10% of all gastric cancer (GC) cases, a heritable cause is suspected. A subset of these cases have a causative germline CDH1mutation; 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, MAP3K6or MYD88.MethodsWe sequenced a large cohort of unexplained young and/or familial patients with GC (n=286) without a CDH1germline mutation for germline variants affecting CTNNA1, MAP3K6and MYD88using a targeted next-generation sequencing approach based on single-molecule molecular inversion probes.ResultsPredicted 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 MAP3K6also occur frequently in the general population.ConclusionsBased on our results MAP3K6should no longer be considered a GC predisposition gene, whereas deleterious CTNNA1variants are confirmed as an infrequent cause of GC susceptibility. Biallelic MYD88germline mutations are at most a very rare cause of GC susceptibility as no additional cases were identified.

Most common breast cancer susceptibility variants have been identified through genome-wide association studies (GWAS) of predominantly estrogen receptor (ER)-positive disease. We conducted a GWAS using 21,468 ER-negative cases and 100,594 controls combined with 18,908 BRCA1 mutation carriers (9,414 with breast cancer), all of European origin. We identified independent associations at P < 5 × 10−8with ten variants at nine new loci. At P < 0.05, we replicated associations with 10 of 11 variants previously reported in ER-negative disease or BRCA1 mutation carrier GWAS and observed consistent associations with ER-negative disease for 105 susceptibility variants identified by other studies. These 125 variants explain approximately 16% of the familial risk of this breast cancer subtype. There was high genetic correlation (0.72) between risk of ER-negative breast cancer and breast cancer risk for BRCA1 mutation carriers. These findings may lead to improved risk prediction and inform further fine-mapping and functional work to better understand the biological basis of ER-negative breast cancer.

Recognition of individuals with a genetic predisposition to gastric cancer (GC) enables preventive measures. However, the underlying cause of genetic susceptibility to gastric cancer remains largely unexplained. We performed germline whole-exome sequencing on leukocyte DNA of 54 patients from 53 families with genetically unexplained diffuse-type and intestinal-type GC to identify novel GC-predisposing candidate genes. As young age at diagnosis and familial clustering are hallmarks of genetic tumor susceptibility, we selected patients that were diagnosed below the age of 35, patients from families with two cases of GC at or below age 60 and patients from families with three GC cases at or below age 70. All included individuals were tested negative for germline CDH1 mutations before or during the study. Variants that were possibly deleterious according to in silico predictions were filtered using several independent approaches that were based on gene function and gene mutation burden in controls. Despite a rigorous search, no obvious candidate GC predisposition genes were identified. This negative result stresses the importance of future research studies in large, homogeneous cohorts.

Purpose:Female breast cancer patients carrying a BRCA1/2 mutation have an increased risk of second primary breast cancer. Rapid genetic counseling and testing (RGCT) before surgery may influence choice of primary surgical treatment. In this article, we report on the psychosocial impact of RGCT.Methods:Newly diagnosed breast cancer patients at risk for carrying a BRCA1/2 mutation were randomized to an intervention group (offer of RGCT) or a usual care control group (ratio 2:1). Psychosocial impact and quality of life were assessed with the Impact of Events Scale, Hospital Anxiety and Depression Scale, Cancer Worry Scale, and the EORTC QLQ-C30 and QLQ-BR23. Assessments took place at study entry and at 6- and 12-month follow-up visits.Results:Between 2008 and 2010, 265 patients were recruited into the study. Completeness of follow-up data was more than 90%. Of the 178 women in the intervention group, 177 had genetic counseling, of whom 71 (40%) had rapid DNA testing and 59 (33%) received test results before surgery. Intention-to-treat and per-protocol analyses showed no statistically significant differences between groups over time in any of the psychosocial outcomes.Conclusions:In this study, RGCT in newly diagnosed breast cancer patients did not have any measurable adverse psychosocial effects.Genet Med 18 2, 137–144.

Purpose: Little is known about reasons why eligible breast cancer patients decline BRCA mutation testing. They may withdraw at different stages during genetic counseling for different reasons. We prospectively studied perceived benefits and barriers to genetic counseling and BRCA testing in 102 newly diagnosed breast cancer patients approached for genetic counseling at the start of radiotherapy.Methods: Patients completed questionnaires and participated in interviews at different stages of the counseling protocol.Results: Participation was not influenced by distress, knowledge about hereditary breast cancer, previous genetic testing in relatives, or perceived risks and barriers. Immediate decliners (n = 23) do not believe genetic testing is relevant for them. Patients who decline after pedigree compilation (n = 14) are more hesitant and anxious about the influence of the test result on their future often wishing to postpone further testing. Late decliners (n = 7) withdraw afraid of the test result and/or after a relative's objection. These decliners are not easily identified upon approach because they are similar to patients who receive a DNA test result (n = 58). Notwithstanding their decline, 81% agreed to the timing or would have preferred an earlier approach for genetic counseling.Conclusion: Decliners may make more informed decisions after tailored health education, including adequate risk information.

Purpose: There is no consensus on how best to communicate risk in breast cancer genetic counseling. We studied risk communication in completed series of counseling visits and assessed associations with counselees' postcounseling risk perception and satisfaction.Methods: Pre- and postcounseling questionnaires and videorecordings of all visits were available for 51 affected and unaffected women from families with no known BRCA1/2 mutation, who fulfilled criteria for DNA testing. We developed a checklist for assessing risk communication and counselors' behaviors.Results: General risks were mainly communicated in initial visits, while counselee-specific risks were discussed mainly in concluding visits. The risks discussed most often were conveyed only numerically or qualitatively, and most were only stated positively or negatively. Counselors regularly helped counselees to understand the information, but seldom built on counselees' pre-existing perspective. Counselees' breast cancer risk perception after counseling was unrelated to whether this risk had been explicitly stated. The number of general risks discussed was negatively associated with counselees' satisfaction about counseling.Conclusion: Findings suggest that counselors' authority prevails over mutuality with individual counselees, in their communication about risks.

ObjectiveTo estimate the risk of breast cancer associated with diagnostic radiation in carriers of BRCA1/2 mutations.DesignRetrospective cohort study (GENE-RAD-RISK).SettingThree nationwide studies (GENEPSO, EMBRACE, HEBON) in France, United Kingdom, and the Netherlands,Participants1993 female carriers of BRCA1/2 mutations recruited in 2006-09.Main outcome measureRisk of breast cancer estimated with a weighted Cox proportional hazards model with a time dependent individually estimated cumulative breast dose, based on nominal estimates of organ dose and frequency of self reported diagnostic procedures. To correct for potential survival bias, the analysis excluded carriers who were diagnosed more than five years before completion of the study questionnaire.ResultsIn carriers of BRCA1/2 mutations any exposure to diagnostic radiation before the age of 30 was associated with an increased risk of breast cancer (hazard ratio 1.90, 95% confidence interval 1.20 to 3.00), with a dose-response pattern. The risks by quarter of estimated cumulative dose <0.0020 Gy, ≥0.0020-0.0065 Gy, ≥0.0066-0.0173 Gy, and ≥0.0174 Gy were 1.63 (0.96 to 2.77), 1.78 (0.88 to 3.58), 1.75 (0.72 to 4.25), and 3.84 (1.67 to 8.79), respectively. Analyses on the different types of diagnostic procedures showed a pattern of increasing risk with increasing number of radiographs before age 20 and before age 30 compared with no exposure. A history of mammography before age 30 was also associated with an increased risk of breast cancer (hazard ratio 1.43, 0.85 to 2.40). Sensitivity analysis showed that this finding was not caused by confounding by indication of family history.ConclusionIn this large European study among carriers of BRCA1/2 mutations, exposure to diagnostic radiation before age 30 was associated with an increased risk of breast cancer at dose levels considerably lower than those at which increases have been found in other cohorts exposed to radiation. The results of this study support the use of non-ionising radiation imaging techniques (such as magnetic resonance imaging) as the main tool for surveillance in young women with BRCA1/2 mutations.