Women with pathogenic BRCA1 and BRCA2 mutations possess a high risk of developing breast and ovarian cancer. They face difficult choices when considering preventive options. This study presents the ...development process of the first decision aids to support this complex decision-making process in the German healthcare system.
A six-step development process based on the International Patient Decision Aid Standards was used, including a systematic literature review of existing decision aids, a topical medical literature review, preparation of the decision aids, focus group discussions with women with BRCA1/2 mutations, internal and external reviews by clinical and self-help experts, and user tests. All reviews were followed by iterative revisions.
No existing decision aids were transferable to the German setting. The medical research revealed a need to develop separate decision aids for women with BRCA1/2 mutations (A) without a history of cancer (previvors) and (B) with a history of unilateral breast cancer (survivors). The focus group discussions confirmed a high level of approval for the decision aids from both target groups. Additionally, previvors requested more information on risk-reducing breast surgery, risk-reducing removal of both ovaries and Fallopian tubes, and psychological aspects; survivors especially wanted more information on breast cancer on the affected side (e.g. biological parameters, treatment, and risk of recurrence).
In a structured process, two target-group-specific DAs for previvors/survivors with BRCA1/2 mutations were developed to support decision-making on risk-adapted preventive options. These patient-oriented tools offer an important addition to existing specialist medical care in Germany.
Women carrying BRCA1/2 pathogenic variants are exposed to elevated risks of developing breast cancer (BC) and are faced by a complex decision-making process on preventative measures, i.e., ...risk-reducing mastectomy (RRM), and intensified breast surveillance (IBS). In this prospective cohort study we investigated the effect of anxiety, personality factors and coping styles on the decision-making process on risk management options in women with pathogenic variants in BRCA1/2.
Breast cancer unaffected and affected women with a pathogenic variant in the BRCA1 or BRCA2 gene were psychologically evaluated immediately before (T0), 6 to 8 weeks (T1) and 6 to 8 months (T2) after the disclosure of their genetic test results. Uptake of RRM and IBS was assessed at T2. Psychological data were gathered using questionnaires on risk perception, personality factors, coping styles, decisional conflict, depression and anxiety, including the Hospital Anxiety and Depression Scale (HADS). We performed tests on statistical significance and fitted a logistic regression based on significance level.
A total of 98 women were included in the analysis. Baseline anxiety levels in women opting for RRM were high but decreased over time, while they increased in women opting for intensified breast surveillance (IBS). Elevated levels of anxiety after genetic test result disclosure (T1) were associated with the decision to undergo RRM (p < 0.01; OR = 1.2, 95% CI = 1.05-1.42), while personal BC history and personality factors seemed to be less relevant.
Considering psychosocial factors influencing the decision-making process of women with pathogenic variants in BRCA1/2 may help improving their genetic and psychological counselling. When opting for IBS they may profit from additional medical and psychological counselling.
Retrospectively registered at the German Clinical Trials Register under DRKS00027566 on January 13, 2022.
Breast cancer (BC) risk prediction models consider cancer family history (FH) and germline pathogenic variants (PVs) in risk genes. It remains elusive to what extent complementation with polygenic ...risk score (PRS) and non-genetic risk factor (NGRFs) data affects individual intensified breast surveillance (IBS) recommendations according to European guidelines.
For 425 cancer-free women with cancer FH (mean age 40·6 years, range 21–74), recruited in France, Germany and the Netherlands, germline PV status, NGRFs, and a 306 variant-based PRS (PRS306) were assessed to calculate estimated lifetime risks (eLTR) and estimated 10-year risks (e10YR) using CanRisk. The proportions of women changing country-specific European risk categories for IBS recommendations, i.e. ≥20 % and ≥30 % eLTR, or ≥5 % e10YR were determined.
Of the women with non-informative PV status, including PRS306 and NGRFs changed clinical recommendations for 31·0 %, (57/184, 20 % eLTR), 15·8 % (29/184, 30 % eLTR) and 22·4 % (41/183, 5 % e10YR), respectively whereas of the women tested negative for a PV observed in their family, clinical recommendations changed for 16·7 % (25/150), 1·3 % (2/150) and 9·5 % (14/147). No change was observed for 82 women with PVs in high-risk genes (BRCA1/2, PALB2). Combined consideration of eLTRs and e10YRs identified BRCA1/2 PV carriers benefitting from IBS <30 years, and women tested non-informative/negative for whom IBS may be postponed.
For women who tested non-informative/negative, PRS and NGRFs have a considerable impact on IBS recommendations. Combined consideration of eLTRs and e10YRs allows personalizing IBS starting age.
Horizon 2020, German Cancer Aid, Federal Ministry of Education and Research, Köln Fortune.
•Breast cancer (BC) risk prediction considers cancer family history and germline pathogenic variants (PVs).•Polygenic risk score (PRS) and non-genetic risk factors (NGRFs) may affect intensified breast surveillance (IBS) recommendations.•For women without PVs, PRS and NGRFs considerably impact IBS recommendations.•Comprehensive risk calculation may personalize IBS starting ages.
Popeye domain containing1 (Popdc1), also named Bves, is an evolutionary conserved membrane protein. Despite its high expression level in the heart little is known about its membrane localization and ...cardiac functions. The study examined the hypothesis that Popdc1 might be associated with the caveolae and play a role in myocardial ischemia tolerance. To address these issues, we analyzed hearts and cardiomyocytes of wild type and Popdc1-null mice. Immunoconfocal microscopy revealed co-localization of Popdc1 with caveolin3 in the sarcolemma, intercalated discs and T-tubules and with costameric vinculin. Popdc1 was co-immunoprecipitated with caveolin3 from cardiomyocytes and from transfected COS7 cells and was co-sedimented with caveolin3 in equilibrium density gradients. Caveolae disruption by methyl-β-cyclodextrin or by ischemia/reperfusion (I/R) abolished the cellular co-localization of Popdc1 with caveolin3 and modified their density co-sedimentation. The caveolin3-rich fractions of Popdc1-null hearts redistributed to fractions of lower buoyant density. Electron microscopy showed a statistically significant 70% reduction in caveolae number and a 12% increase in the average diameter of the remaining caveolae in the mutant hearts. In accordance with these changes, Popdc1-null cardiomyocytes displayed impaired Ca(+2)i transients, increased vulnerability to oxidative stress and no pharmacologic preconditioning. In addition, induction of I/R injury to Langendorff-perfused hearts indicated a significantly lower functional recovery in the mutant compared with wild type hearts while their infarct size was larger. No improvement in functional recovery was observed in Popdc1-null hearts following ischemic preconditioning. The results indicate that Popdc1 is a caveolae-associated protein important for the preservation of caveolae structural and functional integrity and for heart protection.
Objective
Women carrying a BRCA1/2 pathogenic variant have an increased risk for breast cancer and may opt for risk‐reducing bilateral mastectomy. In this study, we examine which demographic, ...psychosocial, and personality factors are associated with their decision to undergo risk‐reducing bilateral mastectomy.
Methods
Cancer‐unaffected women with a pathogenic variant in BRCA1 or BRCA2 were recruited before receiving their genetic test result and completed follow‐up including decision to undergo mastectomy over 6–8 months after genetic test result disclosure. Anxiety, depression, breast cancer worry, personality and sociodemographic data were assessed.
Results
A total of 125 cancer‐unaffected women were included in the analysis. Participants were found to have higher anxiety levels than the general female population regardless of mastectomy decision. Breast cancer worry was higher among women who opted for risk‐reducing mastectomy and did not decrease over time. By contrast, women who did not opt for surgery experienced decreasing levels of breast cancer worry. Regression analysis found that women with a pathogenic variant in BRCA1, younger women and women with higher breast cancer worry were more likely to opt for surgery.
Conclusions
Our study provides valuable insights into the factors that influence women with a BRCA1/2 pathogenic variant to undergo risk‐reducing mastectomy. These findings may be helpful in understanding individual differences in decision‐making concerning preventive options and show the need to address negative anticipatory feelings associated with carrying a pathogenic variant in a high breast cancer risk gene in clinical care.
We examined how often genetic clinicians correctly identify psychosocial difficulties in women at high breast cancer risk and explored effects of this assessment and the genetic test result on ...counselees' distress. A prospective observational study of counselee-clinician dyads was performed in three French, German and Spanish genetic clinics, involving 709 counselees (participation rate, 83.4%) and 31 clinicians (participation rate, 100%). Counselee-clinician agreement in perceived psychosocial difficulties was measured after the pre-test genetic consultation. Multivariate mixed linear models accounting for clinicians were tested. Predicted distress levels were assessed after the pre- (T1) and post-test result disclosure consultations (T2). Depending on the difficulty domain, clinicians adequately assessed the presence or absence of difficulties in 51% ("familial issues") to 59% ("emotions") of counselees. When counselees' and clinicians' perceptions disagreed, difficulties were generally underestimated by clinicians. Counselees' distress levels remained stable from T1 to T2, irrespective of clinicians' appraisal adequacy, and the genetic test result disclosure. Psychological referral need were found in 20-42% of counselees, more frequently observed for difficulties in the "emotions" domain. Our findings suggest that the genetic test result is a suboptimal indicator for psychological referral. Instead, clinicians should focus on emotions expressed by counselees to appraise their needs for psychological support.
Abstract
The interaction of Neisseria meningitidis with both peripheral and brain endothelial cells is a critical event in the development of invasive meningococcal disease. In this study, we used in ...vitro models based on human brain microvascular endothelial cells (HBMEC), and peripheral endothelial EA.hy926 cells, to investigate their roles in the inflammatory response towards meningococcal infection. Both cell lines were infected with two pathogenic N. meningitidis isolates and secretion of the cytokine interleukin-6 (IL-6), the CXC chemokine IL-8 and the monocyte chemoattractant protein-1 (MCP-1) were estimated by ELISA. Neisseria meningitidis was able to stimulate the production of IL-6 and IL-8 by HBMEC and EA.hy926 cells in a time- and concentration-dependent manner. Interestingly, HBMEC released significant higher amounts of IL-6 and IL-8. Moreover, we observed that heat-killed bacteria stimulated high levels of IL-8. In addition, capsule expression had an inhibitory effect on IL-8 release. We extended our study and included serogroup C strains belonging to sequence type 11 clonal complex (cc) from a recent outbreak in France, as well as isolates belonging to the hypervirulent clonal complexes cc8, cc18, cc32 and cc269 and analyzed their ability to induce the secretion of IL-8 from both cell lines. Although individual variations were observed among different isolates, no clear correlations were observed between strain origin, clinical presentation and IL-8 levels.
Peripheral and brain microvascular endothelial cells differentially release IL-8, IL-6 and MCP-1 upon infection with Neisseria meningitidis.
Background
Increasingly complex genetics counseling requires guidance to facilitate counselees' psychosocial adjustment. We explored networks of inter‐relationships among coping strategies and ...specific psychosocial difficulties in women tested for hereditary breast or ovarian cancer.
Methods
Of 752 counselees consecutively approached, 646 (86%) completed questionnaires addressing coping strategies (Brief‐COPE) and psychosocial difficulties (PAHC) after the initial genetic consultation (T1), and 460 (61%) of them again after the test result (T2). We applied network analysis comparing partial correlations among these questionnaire scales, according to the type of genetic test ‐ single gene‐targeted or multigene panel, test result and, before and after testing.
Results
Overall, 98 (21.3%), 259 (56.3%), 59 (12.8%) and 44 (9.6%) women received a pathogenic variant, uninformative negative (panel testing), variant of uncertain significance (VUS) or true negative (targeted testing) result, respectively. In most networks, connections were strongest between avoidance and general negative emotions. Cognitive restructuring was inter‐related to lower psychosocial difficulties. Avoidance and familial/social relationship difficulties were strongly related in women receiving a pathogenic variant. Stronger inter‐relationships were also noticed between avoidance and worries about personal cancer and concerns about hereditary predisposition in women receiving a VUS result. Differences in the prominence of inter‐relationships were observed by type of testing and assessment time.
Conclusions
Network analysis may be fruitful to highlight prominent inter‐relationships among coping strategies and psychosocial difficulties, in women tested for HBOC susceptibility, offering guidance for counseling.
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