The Breast

Clinical genome sequencing in patients with hereditary breast and ovarian cancer: Concept, implementation and benefits

Hereditary breast and ovarian cancer (HBOC) is one of the most frequent genetic cancer predisposition syndromes. Individuals at risk are identified mainly by family history and histopathological criteria. The current standard genetic testing is exome or panel sequencing. However, many high-risk families remain genetically unexplained. Genome sequencing has the potential to increase the diagnostic yield. This single-center real-world study aims to evaluate advantages of short-read genome sequencing (GS) in HBOC families. We report genome sequencing results of 818 index patients, who fulfilled clinical criteria for genetic testing. Data analysis showed less sequencing gaps and a more uniform coverage compared to a large cohort of in-house exomes. Samples were sequenced at an average depth of 41.2x for the HBOC core genes. Pathogenic variants were found in 9 of 13 core genes in 12.2 % of the patients. GS allowed the classification of a BRCA1 duplication and detected a whole-exon inversion in BARD1, as well as a deep intronic CHEK2 variant. Furthermore, we successfully used the BRIDGES-PRS in our HBOC cohort and found a significant effect size compared to the control cohort (p = 4.804

Early prediction of menopausal status after chemotherapy in women with early breast cancer in order to optimize adjuvant endocrine therapy

High impact of chemotherapy on ovarian reserve in breast cancer survivors of reproductive age: A systematic review and meta-analysis

Systematic literature review and trial-level meta-analysis of aromatase inhibitors vs tamoxifen in patients with HR+/HER2− early breast cancer

The benefit of adding polygenic risk scores, lifestyle factors, and breast density to family history and genetic status for breast cancer risk and surveillance classification of unaffected women from germline CHEK2 c.1100delC families

Real-world utilization of aromatase inhibitors, tamoxifen, and ovarian function suppression in premenopausal patients with early hormone receptor-positive, HER2-negative breast cancer with increased recurrence risk

Real-world risk of recurrence and treatment outcomes with adjuvant endocrine therapy in patients with stage II-III HR+/HER2- early breast cancer

BRCA1/2 testing for genetic susceptibility to cancer after 25 years: A scoping review and a primer on ethical implications

Mutations in the genes called BRCA1 and BRCA2 are associated with significantly elevated lifetime risk of developing breast and ovarian cancer. This year marks 25 years since genetic tests for BRCA1/2 mutations became available to the public. Currently, comprehensive guidelines exist regarding BRCA1/2 testing and preventive measures in mutation carriers. As such, BRCA1/2 testing represents a precedent not only in genetic testing and management of genetic cancer risk, but also in bioethics. The goal of the current research was to offer a review and an ethical primer of the main ethical challenges related to BRCA testing. A systematic scoping review was undertaken following the PRISMA Extension for Scoping Reviews (PRISMA-ScR). Four databases were searched and 18 articles that met the inclusion criteria were synthetized narratively into a conceptual map. Ethical discussions revolved around the BRCA1/2 gene discovery, how tests are distributed for clinical use, the choice to undergo testing, unresolved issues in receiving and disclosing test results, reproductive decision-making, and culture-specific ethics. Several unique properties of the latest developments in testing circumstances (e.g., incorporation of BRCA1/2 testing in multi-gene or whole genome sequence panels and tests sold directly to consumers) significantly raised the complexity of ethical debates. Multidisciplinary ethical discussion is necessary to guide not only individual decision making but also societal practices and medical guidelines in light of the new technologies available and the latest results regarding psychological, social, and health outcomes in cancer previvors and survivors affected by BRCA mutations.

Adjuvant ovarian function suppression and aromatase inhibitors in premenopausal patients with hormone receptor and HER2 positive breast cancer, by timing of chemotherapy and trastuzumab and response to neoadjuvant therapy

Large-scale meta-analysis and precision functional assays identify FANCM regions in which PTVs confer different risks for ER-negative and triple-negative breast cancer

Hormonal factors predictive of fertility in patients with breast cancer interrupting adjuvant endocrine therapy to attempt pregnancy in POSITIVE trial

Physicians’ knowledge, practice, and attitudes on fertility and pregnancy-related issues in young women with advanced breast cancer: results of the ABC6 and ABC7 survey

Comparison of oncological outcomes of premenopausal with ovarian function suppression versus postmenopausal women in ER+/HER2- breast cancer

Joint analysis of germline genetic data from over 29,000 cases with suspected hereditary breast and ovarian cancer (HBOC) as part of the NASGE initiative

As multigene panel testing is becoming routine in clinical care, there are recommendations at national and international level, as to which genes should be analyzed in the context of a hereditary breast and ovarian cancer (HBOC). However, the individual composition of gene panels offered by testing laboratories vary, resulting in a different variant diagnostic rate. Therefore, we performed a retrospective NGS dataset analysis of suspected HBOC patients who had been tested at different German diagnostic laboratories that are part of the NASGE network. We collected 29,317 HBOC datasets and compared the diagnostic yield applying the most common panel recommendations and an internal HBOC gene panel. Additionally, we analyzed the data concerning other potential tumor risk syndromes (TRS) not caused by pathogenic variants in the core panel genes. At least one pathogenic variant causative for an autosomal-dominant TRS was identified in 4235 datasets, resulting in an overall diagnostic yield of 14.4 %. The diagnostic yield of pathogenic variants varied depending on the applied HBOC panel (between 5 and 26 genes) from 9.0 % to 13.8 % with the internal HBOC panel having a yield of 12.7 %. Notably, in about 1 % of cases, a pathogenic variant outside the established HBOC core genes was identified, indicating the presence of other TRS. These results are consistent with previous observations that a significant proportion of patients with HBOC predisposition were not detected by the guideline-based gene panels and suggest that expanded diagnostics compared to currently recommended multigene panels may identify additional patients at high risk for developing cancer.

Clinical significance of serum estradiol monitoring in women receiving adjuvant aromatase inhibitor for hormone receptor-positive early breast cancer

Fertility and ovarian function preservation in young women with breast cancer: A joint analysis of the Joven & Fuerte and PREFER prospective studies

A complex survivorship intervention utilizing electronic patient-reported outcomes in breast and gynecologic Cancer: the linking you to support and advice [LYSA] trial

Those living beyond a cancer diagnosis experience unmet supportive care needs due to fragmented post-treatment pathways and limited integration of digital health tools. The Linking You to Support and Advice (LYSA) trial assessed the feasibility of a complex-intervention which incorporated a nurse- and dietitian-led multidisciplinary clinic and a digital platform for capturing and responding to electronic Patient-Reported Outcome (ePRO) data for women with early-stage breast and gynecologic cancer less than 12 months post-primary curative therapy. The LYSA trial was an unblinded, randomized, controlled, feasibility trial co-designed with public and patient involvement, conducted across two cancer centers in Ireland. Participants were randomized to the experimental arm, receiving bi-monthly ePRO assessments and trigger-initiated responses to ePROs for 12 months; or the active comparator arm, receiving usual care. Primary feasibility outcomes included participant enrolment, ePRO survey completion, and healthcare professional engagement triggered by ePRO assessments. Secondary outcomes focused on symptom scores, health-related quality of life (HRQOL), and patient satisfaction. A process evaluation explored factors affecting implementation. The trial met its three predefined feasibility outcomes: 200 participants were enrolled (84% breast, 16% gynecologic), >85% of baseline and endpoint surveys were completed, and >70% of participants in the experimental arm engaged in nurse and dietetic consultations following ePRO symptom triggers. The experimental arm demonstrated significant improvements in fatigue (p = 0.018), anxiety (p = 0.012), depression (p < 0.001) and HRQOL (p = 0.031) scores. The process evaluation indicated high levels of satisfaction with the intervention, with positive feedback on the multidisciplinary approach and responsive symptom management. LYSA demonstrates the feasibility and acceptability of an ePRO-led survivorship approach, with potential HRQOL and symptom benefits, warranting a powered efficacy trial.

A deep intronic recurrent CHEK2 variant c.1009-118_1009-87delinsC affects pre-mRNA splicing and contributes to hereditary breast cancer predisposition

Germline CHEK2 pathogenic variants confer an increased risk of female breast cancer (FBC). Here we describe a recurrent germline intronic variant c.1009-118_1009-87delinsC, which showed a splice acceptor shift in RNA analysis, introducing a premature stop codon (p.Tyr337PhefsTer37). The variant was found in 21/10,204 (0.21%) Czech FBC patients compared to 1/3250 (0.03%) controls (p = 0.04) and in 4/3639 (0.11%) FBC patients from an independent German dataset. In addition, we found this variant in 5/2966 (0.17%) Czech (but none of the 443 German) ovarian cancer patients, three of whom developed early-onset tumors. Based on these observations, we classified this variant as likely pathogenic.

Clinicopathological characteristics of gene-positive breast cancer in the United Arab Emirates

Breast cancer is the most prevalent cancer in the United Arab Emirates (UAE). This is the first study to provide data on predisposition of breast cancer susceptibility genes with associated clinical and pathological aspects in the UAE. A retrospective chart review for breast cancer patients undergoing genetic testing from 2016 to 2018. According to National Comprehensive Cancer Network (NCCN) guidelines genetic testing was offered. The analyzed data included; age, ethnicity, family cancer history, pathogenic variant, histopathology, stage, molecular subtype and proliferation. 309 patients underwent genetic testing with a positive result in 130 patients (11.9%) over a period of 36 months. In 34.6% pathogenic and likely pathogenic variants were identified. BRCA2 was the most common gene identified. The mean age was 42.9 years (±9.01). Positive family history was identified in 66 patients (50.7%). Majority had stage 1 or 2 disease (66.2%), invasive ductal carcinoma (81.5%) and hormone receptor positive cancer (45.3%). This is the first study in the UAE to describe the clinical and pathological characteristics of hereditary breast cancer in a mixed ethnic group with dominant Arabic population. Further genetic studies will be required in the UAE population, as the prevalence of breast cancer continues to rise.

Clinical implications of incorporating genetic and non-genetic risk factors in CanRisk-based breast cancer risk prediction