Implementing mainstream genetic counseling within the area-wide network of the German Consortium Hereditary Breast and Ovarian Cancer (GC-HBOC): Satisfaction of primary care providers with the provided state-of-the-art training by the Cologne Center.

The German Cancer Society (Deutsche Krebsgesellschaft DKG) has published a position paper to address the challenges of cancer patient care in the era of genomic medicine. The German Consortium Hereditary Breast and Ovarian Cancer (GC-HBOC) has implemented this recommendation in its care concept for families at risk. Core elements are the outcome-oriented evaluation of structured and standardized clinical measures and reporting recommendations derived therefrom to primary care providers and patients. A cross-sector network with certified breast cancer and gynecological cancer centers was founded in 2015, starting from the Cologne Center of the GC-HBOC. To guarantee the knowledge transfer for mainstream genetic counseling, the Cologne center has established an educational program for physicians and specialized nurses in order to pilot trans-sectoral knowledge transfer on risk assessment and risk-stratified care. It consists of face-to-face lectures with written knowledge test, attending a genetic case conference and genetic counseling sessions with the opportunity to counsel under supervision. The lectures were accompanied by a structured evaluation of the participants' satisfaction and feedback of the needs in mainstream genetic counseling. Thereby, the network ensures that genetic counseling and testing is provided according to state-of-the-art knowledge and allows physicians to participate in knowledge-generating care outside the university setting and patients to receive care close to home. After multiple feedback cycles to improve the educational program, the GC-HBOC, in cooperation with the German Cancer Society, has now adopted this concept and developed a common and uniform online curriculum funded by the Federal Ministry of Health. https://www.krebsgesellschaft.de/fortbildung-familiaerer-krebs.html.

Satisfaction and Quality of Life of Healthy and Unilateral Diseased BRCA1/2 Pathogenic Variant Carriers after Risk-Reducing Mastectomy and Reconstruction Using the BREAST-Q Questionnaire.

Risk-reducing mastectomy (RRM) is the most efficient form of breast cancer (BC) risk reduction in BRCA1/2 pathogenic variant (pV) carriers. However, this intervention in physical integrity is associated with significant morbidity. We assessed long-term perception of satisfaction and health-related quality of life (QoL) after bilateral RRM and reconstruction using the validated BREAST-Q. We searched the prospective database of the Center for Hereditary Breast and Ovarian Cancer Cologne for previvors and survivors who underwent bilateral RRM from 1994 to 2015 and evaluated the results of their BREAST-Q scores. The study enrolled 43 previvors and 90 survivors after a mean follow-up of 46.3 ± 45.3 months after RRM. Satisfaction and QoL were independent of the technique of RRM or type of reconstruction but depended on the time of RRM. Compared to survivors, previvors had significantly higher mean satisfaction scores in their psychosocial, sexual, and physical well-being (chest) in both modules. Among previvors and survivors, higher psychological well-being correlated with a higher satisfaction with information and higher satisfaction with outcome. As psychological well-being correlated with satisfaction with information and outcome, we developed decision aids to improve shared decision making and long-term satisfaction with the decision and the postoperative outcome.

First international workshop of the ATM and cancer risk group (4-5 December 2019).

The first International Workshop of the ATM and Cancer Risk group focusing on the role of Ataxia-Telangiectasia Mutated (ATM) gene in cancer was held on December 4 and 5, 2019 at Institut Curie in Paris, France. It was motivated by the fact that germline ATM pathogenic variants have been found to be associated with different cancer types. However, due to the lack of precise age-, sex-, and site-specific risk estimates, no consensus on management guidelines for variant carriers exists, and the clinical utility of ATM variant testing is uncertain. The meeting brought together epidemiologists, geneticists, biologists and clinicians to review current knowledge and on-going challenges related to ATM and cancer risk. This report summarizes the meeting sessions content that covered the latest results in family-based and population-based studies, the importance of accurate variant classification, the effect of radiation exposures for ATM variant carriers, and the characteristics of ATM-deficient tumors. The report concludes that ATM variant carriers outside of the context of Ataxia-Telangiectasia may benefit from effective cancer risk management and therapeutic strategies and that efforts to set up large-scale studies in the international framework to achieve this goal are necessary.

Quality and Quantity: How to Organize a Countrywide Genetic Counseling and Testing.

BACKGROUND: About 30% of all women with breast or ovarian cancer exhibit a family history of the disease. So far, the genetic cause could be deciphered in about 30% of these cases. The results demonstrate a high genetic heterogeneity, with high-risk and moderate-risk genes and low-risk variants contributing alone or in concert to the development of cancer. Furthermore, it has been shown that the genotype significantly determines the phenotype and that knowledge of the phenotype is as important as the genotype to offer adequate and risk-adapted prevention to persons at risk. For newly identified risk genes, however, the phenotype is not sufficiently characterized at first, and thus prevention measures are not sufficiently evaluated. SUMMARY: The German Consortium for Hereditary Breast and Ovarian Cancer has developed a concept for collecting the missing data in the context of knowledge-generating care and at the same time ensuring care based on the best available knowledge. Core elements of this concept are: structured and standardized care, an outcome-oriented evaluation based on a comprehensive registry, networking with certified breast and gynecological cancer centers combined with regular training on state-of-the-art care for doctors, and compilation of comprehensible patient information. This comprehensive concept has been incorporated into contracts for specialized care with health insurers and thus ensures nationwide care at the highest scientific and clinical levels. KEY MESSAGES: This article describes how to implement a concept of evidence-generating care for risk-adjusted prevention in a nationwide health care system.

Risk-Adjusted Prevention. Perspectives on the Governance of Entitlements to Benefits in the Case of Genetic (Breast Cancer) Risks.

This article is a revised version of our proposal for the establishment of the legal concept of risk-adjusted prevention in the German healthcare system to regulate access to risk-reduction measures for persons at high and moderate genetic cancer risk (Meier et al. Risikoadaptierte Prävention'. Governance Perspective für Leistungsansprüche bei genetischen (Brustkrebs-)Risiken, Springer, Wiesbaden, 2018). The German context specifics are summarized to enable the source text to be used for other country-specific healthcare systems. Establishing such a legal concept is relevant to all universal and free healthcare systems similar to Germany's. Disease risks can be determined with increasing precision using bioinformatics and biostatistical innovations ('big data'), due to the identification of pathogenic germ line mutations in cancer risk genes as well as non-genetic factors and their interactions. These new technologies open up opportunities to adapt therapeutic and preventive measures to the individual risk profile of complex diseases in a way that was previously unknown, enabling not only adequate treatment but in the best case, prevention. Access to risk-reduction measures for carriers of genetic risks is generally not regulated in healthcare systems that guarantee universal and equal access to healthcare benefits. In many countries, including Austria, Denmark, the UK and the US, entitlement to benefits is essentially linked to the treatment of already manifest disease. Issues around claiming benefits for prophylactic measures involve not only evaluation of clinical options (genetic diagnostics, chemoprevention, risk-reduction surgery), but the financial cost and-from a social ethics perspective-the relationship between them. Section 1 of this chapter uses the specific example of hereditary breast cancer to show why from a medical, social-legal, health-economic and socio-ethical perspective, regulated entitlement to benefits is necessary for persons at high and moderate risk of cancer. Section 2 discusses the medical needs of persons with genetic cancer risks and goes on to develop the healthy sick model which is able to integrate the problems of the different disciplines into one scheme and to establish criteria for the legal acknowledgement of persons at high and moderate (breast cancer) risks. In the German context, the social-legal categories of classical therapeutic medicine do not adequately represent preventive measures as a regular service within the healthcare system. We propose risk-adjusted prevention as a new legal concept based on the heuristic healthy sick model. This category can serve as a legal framework for social law regulation in the case of persons with genetic cancer risks. Risk-adjusted prevention can be established in principle in any healthcare system. Criteria are also developed in relation to risk collectives and allocation (Sects. 3, 4, 5).

Benchmarking of a checklist for the identification of familial risk for breast and ovarian cancers in a prospective cohort.

The detection of deleterious germline mutations in BRCA1 and BRCA2 considerably influences the clinical management of healthy and diseased carriers. Therefore, the identification of persons at risk who could uptake genetic counseling and testing is pivotal. We developed a checklist with validated criteria to improve the identification, and prospectively evaluate the incidence, of familial cancer history in 5091 breast cancer patients. The rate of 30.4% of patients at high genetic risk underpins the demand for care in risk identification and counseling. The easy-to-use instrument promotes the implementation and dissemination of risk counseling by physicians.

Correction: Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers.

This Article was originally published under a CC BY-NC-SA 4.0 license, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the Article have been modified accordingly.

Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers.

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2×10 -53 ). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2×10 -20 ). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.

Evaluation of copy-number variants as modifiers of breast and ovarian cancer risk for BRCA1 pathogenic variant carriers.

Genome-wide studies of patients carrying pathogenic variants (mutations) in BRCA1 or BRCA2 have reported strong associations between single-nucleotide polymorphisms (SNPs) and cancer risk. To conduct the first genome-wide association analysis of copy-number variants (CNVs) with breast or ovarian cancer risk in a cohort of 2500 BRCA1 pathogenic variant carriers, CNV discovery was performed using multiple calling algorithms and Illumina 610k SNP array data from a previously published genome-wide association study. Our analysis, which focused on functionally disruptive genomic deletions overlapping gene regions, identified a number of loci associated with risk of breast or ovarian cancer for BRCA1 pathogenic variant carriers. Despite only including putative deletions called by at least two or more algorithms, detection of selected CNVs by ancillary molecular technologies only confirmed 40% of predicted common (>1% allele frequency) variants. These include four loci that were associated (unadjusted P<0.05) with breast cancer (GTF2H2, ZNF385B, NAALADL2 and PSG5), and two loci associated with ovarian cancer (CYP2A7 and OR2A1). An interesting finding from this study was an association of a validated CNV deletion at the CYP2A7 locus (19q13.2) with decreased ovarian cancer risk (relative risk=0.50, P=0.007). Genomic analysis found this deletion coincides with a region displaying strong regulatory potential in ovarian tissue, but not in breast epithelial cells. This study highlighted the need to verify CNVs in vitro, but also provides evidence that experimentally validated CNVs (with plausible biological consequences) can modify risk of breast or ovarian cancer in BRCA1 pathogenic variant carriers.

Genome-wide association study in BRCA1 mutation carriers identifies novel loci associated with breast and ovarian cancer risk.

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 × 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 × 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 × 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2×10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.

A breast cancer risk haplotype in the caspase-8 gene.

Recent large-scale studies have been successful in identifying common, low-penetrance variants associated with common cancers. One such variant in the caspase-8 (CASP8) gene, D302H (rs1045485), has been confirmed to be associated with breast cancer risk, although the functional effect of this polymorphism (if any) is not yet clear. In order to further map the CASP8 gene with respect to breast cancer susceptibility, we performed extensive haplotype analyses using single nucleotide polymorphisms (SNP) chosen to tag all common variations in the gene (tSNP). We used a staged study design based on 3,200 breast cancer and 3,324 control subjects from the United Kingdom, Utah, and Germany. Using a haplotype-mining algorithm in the UK cohort, we identified a four-SNP haplotype that was significantly associated with breast cancer and that was superior to any other single or multi-locus combination (P=8.0 x 10(-5)), with a per allele odds ratio and 95% confidence interval of 1.30 (1.12-1.49). The result remained significant after adjustment for the multiple testing inherent in mining techniques (false discovery rate, q=0.044). As expected, this haplotype includes the D302H locus. Multicenter analyses on a subset of the tSNPs yielded consistent results. This risk haplotype is likely to carry one or more underlying breast cancer susceptibility alleles, making it an excellent candidate for resequencing in homozygous individuals. An understanding of the mode of action of these alleles will aid risk assessment and may lead to the identification of novel treatment targets in breast cancer.

Association of the BRCA1 missense variant R1699W with a malignant phyllodes tumor of the breast.

Familial breast carcinomas that are attributable to BRCA1 or BRCA2 mutations have characteristic morphologic and immunhistochemical features. BRCA1-associated carcinomas are poorly differentiated infiltrating ductal carcinomas frequently exhibiting morphologic features of typical or atypical medullary carcinomas such as prominent lymphocytic infiltrate and pushing margins. We report on a patient carrying the deleterious BRCA1 germline mutation R1699W, who presented with a malignant phyllodes tumor of the breast. The re-investigation of archival material by a reference pathologist of the German Consortium for Hereditary Breast and Ovarian Cancer (GCHBOC) revealed BRCA-associated pronounced pushing margins. In a total of 618 unrelated index patients who are registered in the GCHBOC database, no other phyllodes tumor has been described, while 10 carriers of the R1699W mutant have been identified. We conclude that the histopathologic appearance of the phyllodes tumor indicates an association with the BRCA1 mutation R1699W although it is a rare event in BRCA-positive families.