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Purpose Breast cancer (BC) risk prediction allows systematic identification of individuals at highest and lowest risk. We extend the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) risk model to incorporate the effects of polygenic risk scores (PRS) and other risk factors (RFs). Methods BOADICEA incorporates the effects of truncating variants in BRCA1 , BRCA2 , PALB2 , CHEK2 , and ATM ; a PRS based on 313 single-nucleotide polymorphisms (SNPs) explaining 20% of BC polygenic variance; a residual polygenic component accounting for other genetic/familial effects; known lifestyle/hormonal/reproductive RFs; and mammographic density, while allowing for missing information. Results Among all factors considered, the predicted UK BC risk distribution is widest for the PRS, followed by mammographic density. The highest BC risk stratification is achieved when all genetic and lifestyle/hormonal/reproductive/anthropomorphic factors are considered jointly. With all factors, the predicted lifetime risks for women in the UK population vary from 2.8% for the 1st percentile to 30.6% for the 99th percentile, with 14.7% of women predicted to have a lifetime risk of ≥17–<30% (moderate risk according to National Institute for Health and Care Excellence [NICE] guidelines) and 1.1% a lifetime risk of ≥30% (high risk). Conclusion This comprehensive model should enable high levels of BC risk stratification in the general population and women with family history, and facilitate individualized, informed decision-making on prevention therapies and screening.

The European Collaborative on Personalized Early Detection and Prevention of Breast Cancer (ENVISION) brings together several international research consortia working on different aspects of the personalized early detection and prevention of breast cancer. In a consensus conference held in 2019, the members of this network identified research areas requiring development to enable evidence-based personalized interventions that might improve the benefits and reduce the harms of existing breast cancer screening and prevention programmes. The priority areas identified were: 1) breast cancer subtype-specific risk assessment tools applicable to women of all ancestries; 2) intermediate surrogate markers of response to preventive measures; 3) novel non-surgical preventive measures to reduce the incidence of breast cancer of poor prognosis; and 4) hybrid effectiveness–implementation research combined with modelling studies to evaluate the long-term population outcomes of risk-based early detection strategies. The implementation of such programmes would require health-care systems to be open to learning and adapting, the engagement of a diverse range of stakeholders and tailoring to societal norms and values, while also addressing the ethical and legal issues. In this Consensus Statement, we discuss the current state of breast cancer risk prediction, risk-stratified prevention and early detection strategies, and their implementation. Throughout, we highlight priorities for advancing each of these areas.Risk-adapted approaches to breast cancer prevention and screening could potentially be more effective than universal approaches, which have important limitations. In this Consensus Statement, representatives of the European Collaborative on Personalized Early Detection and Prevention of Breast Cancer (ENVISION) discuss the current state of breast cancer risk prediction, risk-stratified prevention and early detection strategies, and their implementation. They also present the ENVISION recommendations on priorities for future research in each of these areas with the aim of stimulating and guiding risk-adapted breast cancer prevention and screening programmes.

Risk-stratified breast cancer screening has been proposed as an alternative to age-based screening programs, though its implementation may face challenges and requires support from stakeholders, particularly women. This study used structural equation modeling (SEM) to identify personal factors influencing women’s attitudes, comfort level, and willingness towards risk-stratified screening. Factors analyzed included sociodemographic variables, general health, breast cancer risk perception, screening, and genetic testing history. Three models were tested to assess the direct and indirect effects of statistically significant factors. None of the outcomes were significantly associated with women’s perceived health or history of genetic testing (all p > 0.05). A history of mammography was found to mediate the relationships between age, perceived risk, and personal breast cancer history with the outcomes. Income also mediated the relationships between education, employment, marital status, and the outcomes. A history of mammography and higher income were significantly associated with more favorable attitudes (β_mammo = 0.157; β_income = 0.098), greater comfort (β_mammo = 0.425; β_income = 0.134), and higher willingness (β_mammo = 0.471; β_income = 0.198) towards risk-stratified screening. In contrast, non-white ethnicity and older age were linked to less favorable attitudes (β_ethnicity =  − 0.117; β_age =  − 0.071), lower comfort (β_ethnicity =  − 0.104; β_age =  − 0.269), and decreased willingness (β_ethnicity =  − 0.142; β_age =  − 0.295). This study identified key factors influencing the acceptability of risk-stratified breast cancer screening that could be targeted to facilitate its implementation.

Poly(ADP‐ribose) polymerase (PARP) inhibitors (PARPi) are effective in cancers with defective homologous recombination DNA repair (HRR), including BRCA1/2‐related cancers. A test to identify additional HRR‐deficient tumors will help to extend their use in new indications. We evaluated the activity of the PARPi olaparib in patient‐derived tumor xenografts (PDXs) from breast cancer (BC) patients and investigated mechanisms of sensitivity through exome sequencing, BRCA1 promoter methylation analysis, and immunostaining of HRR proteins, including RAD51 nuclear foci. In an independent BC PDX panel, the predictive capacity of the RAD51 score and the homologous recombination deficiency (HRD) score were compared. To examine the clinical feasibility of the RAD51 assay, we scored archival breast tumor samples, including PALB2‐related hereditary cancers. The RAD51 score was highly discriminative of PARPi sensitivity versus PARPi resistance in BC PDXs and outperformed the genomic test. In clinical samples, all PALB2‐related tumors were classified as HRR‐deficient by the RAD51 score. The functional biomarker RAD51 enables the identification of PARPi‐sensitive BC and broadens the population who may benefit from this therapy beyond BRCA1/2‐related cancers. Synopsis Sensitive and highly specific biomarkers usable in archived formalin fixed parafin embedded (FFPE) tumour samples are needed to extend the use of PARP inhibitors beyond BRCA1/2‐related cancers. The RAD51 score may satisfy this clinical unmet need. The RAD51 score shows complete discriminative capacity in predicting PARP inhibitor response. The RAD51 score is feasible in routine breast tumor samples without prior exposure to DNA damaging agents. Carrying a PALB2 mutation is associated with a low RAD51score. Graphical Abstract Sensitive and highly specific biomarkers usable in archived formalin fixed parafin embedded (FFPE) tumour samples are needed to extend the use of PARP inhibitors beyond BRCA1/2‐related cancers. The RAD51 score may satisfy this clinical unmet need.

Heterozygous carriers of germ-line loss-of-function variants in the DNA repair gene PALB2 are at a highly increased lifetime risk for developing breast cancer. While truncating variants in PALB2 are known to increase cancer risk, the interpretation of missense variants of uncertain significance (VUS) is in its infancy. Here we describe the development of a relatively fast and easy cDNA-based system for the semi high-throughput functional analysis of 48 VUS in human PALB2 . By assessing the ability of PALB2 VUS to rescue the DNA repair and checkpoint defects in Palb2 knockout mouse embryonic stem (mES) cells, we identify various VUS in PALB2 that impair its function. Three VUS in the coiled-coil domain of PALB2 abrogate the interaction with BRCA1, whereas several VUS in the WD40 domain dramatically reduce protein stability. Thus, our functional assays identify damaging VUS in PALB2 that may increase cancer risk. PALB2 is an established breast cancer risk gene but the pathogenicity of many variants remains uncharacterised. Here, the authors present a cDNA-based system for the functional analysis of PALB2 variants of unknown significance.

Purpose Breast cancer risk has conventionally been assessed using family history (FH) and rare high/moderate penetrance pathogenic variants (PVs), notably in BRCA1/2 , and more recently PALB2 , CHEK2 , and ATM . In addition to these PVs, it is now possible to use increasingly predictive polygenic risk scores (PRS) as well. The comparative population-level predictive capability of these three different indicators of genetic risk for risk stratification is, however, unknown. Methods The Canadian heritable breast cancer risk distribution was estimated using a novel genetic mixing model (GMM). A realistically representative sample of women was synthesized based on empirically observed demographic patterns for appropriately correlated family history, inheritance of rare PVs, PRS, and residual risk from an unknown polygenotype. Risk assessment was simulated using the BOADICEA risk algorithm for 10-year absolute breast cancer incidence, and compared to heritable risks as if the overall polygene, including its measured PRS component, and PV risks were fully known. Results Generally, the PRS was most predictive for identifying women at high risk, while family history was the weakest. Only the PRS identified any women at low risk of breast cancer. Conclusion PRS information would be the most important advance in enabling effective risk stratification for population-wide breast cancer screening.

The last decade has witnessed the emergence of international ethics guidelines discussing the importance of disclosing global and also, in certain circumstances, individual genetic research results to participants. This discussion is all the more important considering the advent of pharmacogenomics and the increasing incidence of ‘translational’ genetic research in the post-genomic era. We surveyed both the literature and the ethical guidelines using selective keywords. We then analyzed our data using a qualitative method approach and singled out countries or policies that were representative of certain positions. From our findings, we conclude that at the international level, there now exists an ethical duty to return individual genetic research results subject to the existence of proof of validity, significance and benefit. Even where these criteria are met, the right of the research participant not to know also has to be taken into consideration. The existence of an ethical duty to return individual genetic research results begs several other questions: Who should have the responsibility of disclosing such results and when? To whom should the results be disclosed? How? Finally, will this ethical ‘imperative’ become a legally recognized duty as well?

Approximately half of the familial aggregation of breast cancer remains unexplained. This proportion is less for early-onset disease where familial aggregation is greater, suggesting that other susceptibility genes remain to be discovered. The majority of known breast cancer susceptibility genes are involved in the DNA double-strand break repair pathway. ABRAXAS is involved in this pathway and mutations in this gene impair BRCA1 recruitment to DNA damage foci and increase cell sensitivity to ionizing radiation. Moreover, a recurrent germline mutation was reported in Finnish high-risk breast cancer families. To determine if ABRAXAS could be a breast cancer susceptibility gene in other populations, we conducted a population-based case-control mutation screening study of the coding exons and exon/intron boundaries of ABRAXAS in the Breast Cancer Family Registry. In addition to the common variant p.Asp373Asn, sixteen distinct rare variants were identified. Although no significant difference in allele frequencies between cases and controls was observed for the identified variants, two variants, p.Gly39Val and p.Thr141Ile, were shown to diminish phosphorylation of gamma-H2AX in MCF7 human breast adenocarcinoma cells, an important biomarker of DNA double-strand breaks. Overall, likely damaging or neutral variants were evenly represented among cases and controls suggesting that rare variants in ABRAXAS may explain only a small proportion of hereditary breast cancer.

ObjectiveTo describe primary care providers’ (PCPs) experience and satisfaction with receiving risk communication documents on their patient’s breast cancer (BC) risk assessment and proposed screening action plan.DesignDescriptive cross-sectional study.SettingA survey was distributed to all 763 PCPs linked to 1642 women participating in the Personalized Risk Assessment for Prevention and Early Detection of Breast Cancer: Integration and Implementation (PERSPECTIVE I&I) research project in Quebec, approximately 1–4 months after the delivery of the risk communication documents. The recruitment phase took place from July 2021 to July 2022.ParticipantsPCPs.Main outcome measuresDescriptive analyses were conducted to report participants’ experiences and satisfaction with receiving risk communication. Responses to two open-ended questions were subjected to content analysis.ResultsA total of 168 PCPs answered the survey, from which 73% reported being women and 74% having more than 15 years of practice. Only 38% were familiar with the risk-based BC screening approach prior to receiving their patient risk category. A majority (86%) agreed with the screening approach and would recommend it to their patients if implemented at the population level. A majority of PCPs also reported understanding the information provided (92%) and expressed agreement with the proposed BC screening action plan (89%). Some PCPs recommended simplifying the materials, acknowledging the potential increase in workload and emphasising the need for careful planning of professional training efforts.ConclusionPCPs expressed positive attitudes towards a risk-based BC screening approach and were generally satisfied with the information provided. This study suggests that, if introduced in Canada in a manner similar to the PERSPECTIVE I&I project, risk-based BC screening would likely be supported by most PCPs. However, they emphasised the importance of addressing concerns such as professional training and the potential impact on workload if the approach were to be implemented at the population level. Future qualitative studies are needed to further explore the training needs of PCPs and to develop strategies for integrating this approach with the high workloads faced by PCPs.

Background Younger women at higher-than-population-average risk for breast cancer may benefit from starting screening earlier than presently recommended by the guidelines. The Personalized Risk Stratification for Prevention and Early Detection of Breast Cancer (PERSPECTIVE) approach aims to improve the prevention of breast cancer through differential screening recommendations based on a personal risk estimate. In our study, we used deliberative stakeholder consultations to engage health professionals in an in-depth dialog to explore the feasibility of the proposed implementation strategies for this new personalized breast cancer screening approach. Methods Deliberative stakeholder consultation is a qualitative descriptive study design used to engage health professionals in the discussion, while the mediators play a more passive role. A purposeful sample of 11 health professionals (family physicians and genetic counselors) working in Montreal was used. The deliberations were organized in two phases, including small group deliberations according to the deliberants’ health profession and a mixed group deliberation combining participants from the small groups. Inductive thematic content analysis was performed on the transcripts by two coders to create the deliberative and analytic outputs. Quality of deliberations was assessed quantitatively using the de Vries method and qualitatively using participant observation. Results One of our key findings was that health professionals lacked understanding of the two steps of the screening approach: risk stratification “screening,” which is an evaluation for the level of risk and screening for disease. As part of this confusion, the main topic of concern was a justification of program implementation as a population-wide screening, based on their uncertainty that it will be beneficial for women with near-population risks. Despite the noted difficulties concerning implementation, health professionals acknowledged the substantial benefits of the proposed PERSPECTIVE program. Conclusions Our study was the first to evaluate the perspectives of health professionals on the implementation and benefits of a new program for breast cancer risk stratification with the purpose of personalizing screening for disease. This new multi-step approach to screening requires more clarity in communication with health professionals. To implement and maintain effective screening, engagement of family physicians with other health professionals or even development of a centralized public health system may be needed.