High-risk pathogenic germline variants in blood relatives of BRCA1/2 negative probands.

BACKGROUND: Tailored, preventive cancer care requires the identification of pathogenic germline variants (PGVs) among potentially at-risk blood relatives (BRs). Cascade testing is carried out for BRs of probands who are positive for PGVs of an inherited cancer but not for negative probands. This study was conducted to examine the prevalence of PGVs for BRs of PGV-negative probands. METHODS: PGV prevalence was assessed for 682 BRs of 281 probands with BRCA1/BRCA2 wild-type hereditary breast and ovarian cancer (HBOC) syndrome. RESULTS: PGVs were discovered in 22 (45.8%) of the 48 BRs of the PGV-positive probands and in 14 (2.2%) of 634 BRs of the PGV-negative probands. Eleven PGVs on high-risk BRCA1, BRCA2, and TP53 genes were present only in BRs and not in the probands (probands vs BRs in Fisher exact test; p = 0.0104; odds ratio [OR] = 0.000 [0.000-0.5489 of 95% confidence interval]), partly due to the nature of the selection criteria. The enrichment of high-risk PGVs among BRs was also significant as compared with a non-cancer East Asian population (p = 0.0016; OR = 3.0791 [1.5521-5.6694]). PGV prevalence, risk class of gene, and genotype concordance were unaffected by the cancer history among BRs. CONCLUSION: These findings imply the necessity to construct a novel testing scheme to complement cascade testing.

Management and Clinical Outcomes of Breast Cancer in Women Diagnosed with Hereditary Cancer Syndromes in a Clinic-Based Sample from Colombia.

This study aimed to investigate prognosis and survival differences in 82 breast cancer patients with germline pathogenic/likely pathogenic variants (PVs) treated and followed at the Breast Unit of the Instituto Nacional de Cancerología, Colombia (INC-C) between 2018 and 2021. Median age at diagnosis was 46 years, with 62.2% presenting locally advanced tumors, 47.6% histological grade 3, and 35.4% with triple-negative breast cancer (TNBC) subtype. Most carriers, 74.4% (61/82), had PVs in known breast cancer susceptibility genes (i.e., "associated gene carriers" group, considered inherited breast cancer cases): BRCA2 (30), BRCA1 (14), BARD1 (4), RAD51D (3), TP53 (2), PALB2 (2), ATM (2), CHEK2 (1), RAD51C (1), NF1 (1), and PTEN (1). BRCA1-2 represented 53.7%, and homologous recombination DNA damage repair (HR-DDR) genes associated with breast cancer risk accounted for 15.9%. Patients with PVs in non-breast-cancer risk genes were combined in a different category (21/82; 25.6%) (i.e., "non-associated gene carriers" group, considered other breast cancer cases). Median follow-up was 38.1 months, and 24% experienced recurrence, with 90% being distant. The 5-year Disease-Free Survival (DFS) for inherited breast cancer cases was 66.5%, and for other breast cancer cases it was 88.2%. In particular, for carriers of PVs in the BRCA2 gene, it was 37.6%. The 5-year Overall Survival (OS) rates ranged from 68.8% for those with PVs in BRCA2 to 100% for those with PVs in other HR-DDR genes. Further studies are crucial for understanding tumor behavior and therapy response differences among Colombian breast cancer patients with germline PVs.

BRCA1 Intragenic Duplication Combined with a Likely Pathogenic TP53 Variant in a Patient with Triple-Negative Breast Cancer: Clinical Risk and Management.

For patients with hereditary breast and ovarian cancer, the probability of carrying two pathogenic variants (PVs) in dominant cancer-predisposing genes is rare. Using targeted next-generation sequencing (NGS), we investigated a 49-year-old Caucasian woman who developed a highly aggressive breast tumor. Our analyses identified an intragenic germline heterozygous duplication in BRCA1 with an additional likely PV in the TP53 gene. The BRCA1 variant was confirmed by multiplex ligation probe amplification (MLPA), and genomic breakpoints were characterized at the nucleotide level (c.135-2578_442-1104dup). mRNA extracted from lymphocytes was amplified by RT-PCR and then Sanger sequenced, revealing a tandem duplication r.135_441dup; p.(Gln148Ilefs*20). This duplication results in the synthesis of a truncated and, most likely, nonfunctional protein. Following functional studies, the TP53 exon 5 c.472C > T; p.(Arg158Cys) missense variant was classified as likely pathogenic by the Li-Fraumeni Syndrome (LFS) working group. This type of unexpected association will be increasingly identified in the future, with the switch from targeted BRCA sequencing to hereditary breast and ovarian cancer (HBOC) panel sequencing, raising the question of how these patients should be managed. It is therefore important to record and investigate these rare double-heterozygous genotypes.

Walking the tightrope: Fertility preservation among hereditary breast and ovarian Cancer syndrome Previvors.

INTRODUCTION: Fertility-related concerns cause significant anxiety among patients with Hereditary Breast and Ovarian Cancer Syndrome (HBOC). The Society of Gynecologic Oncology and the American Society for Reproductive Medicine recommend patients diagnosed with HBOC receive early referral to a reproductive endocrinologist. However, evidence about fertility trends in this patient population are limited and guidelines are scarce. The aim of this study is to compare fertility preservation among patients with HBOC to control patients undergoing fertility treatment without a diagnosis of infertility. METHODS: This retrospective study included patients who presented to a single academic institution for fertility preservation in the setting of diagnosis of HBOC. In this study, HBOC patients are referred to as those who had tested positive for pathogenic mutations in BRCA1, BRCA2 or were at high-risk for HBOC based on a strong family history (defined as >3 family members diagnosed with HBOC) without a genetic mutation. HBOC patients were matched in a 1:1 fashion to a control group undergoing fertility preservation without a diagnosis of infertility or HBOC. All analysis was done using SPSS version 9.4 (SAS Institute, Cary, NC). RESULTS: Between August 1st, 2016 and August 1st, 2022, 81 patients presented to the study center for consultation in the setting of HBOC. Of those who presented, 48 (59.2%) ultimately underwent oocyte cryopreservation and 33 (40.7%) underwent embryo cryopreservation. Patients who underwent oocyte cryopreservation due to BRCA1 status were more likely to present for fertility consultation at a younger age compared to control patients (32.6 vs. 34.7 years, p = 0.03) and were more likely to undergo oocyte cryopreservation at a younger age (32.1 vs. 34.6 years, p = 0.007). There was no difference in age at initial consultation or age at procedure for patients with BRCA2 or patients with a strong family history compared to control patients (p > 0.05). There was no difference in the mean age of patients with HBOC at presentation for consultation for embryo cryopreservation or the mean age the patient with HBOC underwent embryo cryopreservation compared to control patients (p > 0.05). Patients with BRCA1 or BRCA2 did not have expedited time from consultation to first cycle start (p > 0.05). After adjusting for factors including anti-Müllerian hormone (AMH) level and age, patients considered in the HBOC group due to family history had less time between consultation and oocyte cryopreservation cycle compared to control patients. (179 vs. 317 days, p = 0.045). There was no difference in time from consultation to starting cycle for embryo cryopreservation for patients with HBOC compared to controls (p > 0.05). CONCLUSION: Patients with HBOC did not undergo expedited fertility treatment compared to control patients undergoing oocyte and embryo cryopreservation for non-infertility reasons. Patients diagnosed with BRCA1 had more oocytes retrieved compared to the control population which is possibly due to earlier age of presentation in the setting of recommended age of risk reducing surgery being age 35-40. When age matched, cycle outcomes did not differ between HBOC and control patients. Given the known cancer prevention benefit and recommendations for risk-reducing surgery, future studies should focus on guidelines for fertility preservation for patients with HBOC.

Role of Breast Cancer Risk Estimation Models to Identify Women Eligible for Genetic Testing and Risk-Reducing Surgery.

Hereditary breast and ovarian cancer (HBOC) syndrome is responsible for approximately 10% of breast cancers (BCs). The HBOC gene panel includes both high-risk genes, i.e., a four times higher risk of BC (BRCA1, BRCA2, PALB2, CDH1, PTEN, STK11 and TP53), and moderate-risk genes, i.e., a two to four times higher risk of BC (BARD1, CHEK2, RAD51C, RAD51D and ATM). Pathogenic germline variants (PGVs) in HBOC genes confer an absolute risk of BC that changes according to the gene considered. We illustrate and compare different BC risk estimation models, also describing their limitations. These models allow us to identify women eligible for genetic testing and possibly to offer surgical strategies for primary prevention, i.e., risk-reducing mastectomies and salpingo-oophorectomies.

Ovarian surveillance including endometrial cytology for patients with hereditary breast and ovarian cancer before risk-reducing salpingo-oophorectomy: A retrospective analysis.

AIM: Ovarian surveillance in women with hereditary breast and ovarian cancer who do not undergo risk-reducing salpingo-oophorectomy has been controversial. Therefore, this study aimed to demonstrate the clinical features of ovarian surveillance at our institution using a technique that combines serum cancer antigen 125 measurements, transvaginal ultrasonography, and uterine endometrial cytology. METHODS: We retrospectively examined 65 women, who had not undergone risk-reducing salpingo-oophorectomy diagnosed with hereditary breast and ovarian cancer between 2000 and 2021 at our hospital. Clinical information was obtained and analyzed through a chart review. The details of the treatment course were reviewed for patients who had developed ovarian cancer. RESULTS: Overall, 5 of the 65 women were diagnosed with ovarian cancer based on abnormal findings during periodic surveillance. All patients who developed ovarian cancer were asymptomatic, even if the cancer was at an advanced stage. Two of the 65 patients had endometrial cytology abnormalities, both of whom had ovarian cancer. All patients who developed ovarian cancer underwent primary debulking surgery, and complete gross resection was achieved. None of the patients experienced ovarian cancer recurrence. CONCLUSIONS: The ovarian surveillance strategy at our institution for women with hereditary breast and ovarian cancer who do not undergo risk-reducing salpingo-oophorectomy can identify asymptomatic ovarian cancer and contribute to achieving complete gross resection during primary surgery. Ovarian surveillance may contribute to a reduction in ovarian cancer mortality.

Decision-making for bilateral risk-reducing mastectomy for an increased lifetime breast cancer risk: A qualitative metasynthesis.

OBJECTIVE: Previvor is a term applied to a person with an identified, elevated lifetime cancer risk but without an actual cancer diagnosis. Previvorship entails the selection of risk management strategies. For women with a genetic mutation that increases their predisposition for a breast cancer diagnosis, bilateral risk-reducing mastectomy (BRRM) is the most effective prevention strategy. However, BRRM can change a woman's breast appearance and function. The purpose of this qualitative metasynthesis (QMS) was to better understand the decision-making process for BRRM among previvors. METHODS: A theory-generating QMS approach was used to analyze and synthesize qualitative findings. Research reports were considered for inclusion if: (1) women over 18 years of age possessed a genetic mutation increasing lifetime breast cancer risk or a strong family history of breast cancer; (2) the sample was considering, or had completed, BRRM; (3) the results reported qualitative findings. Exclusion criteria were male gender, personal history of breast cancer, and research reports which did not separate findings based on cancer diagnosis and/or risk-reduction surgery. RESULTS: A theory and corresponding model emerged, comprised of seven themes addressing the decision-making process for or against BRRM. While some factors to decision-making were decisive for surgery, others were more indefinite and contributed to women changing, processing, or suspending their decision-making for a period of time. CONCLUSIONS: Regardless of the decision previvors make about BRRM, physical and psychosocial well-being should be considered and promoted through shared decision-making in the clinical setting.

Counselling Framework for Germline BRCA1/2 and PALB2 Carriers Considering Risk-Reducing Mastectomy.

Female BRCA1/2 and PALB2 germline pathogenic variant carriers have an increased lifetime risk of breast cancer and may wish to consider risk-reducing mastectomy (RRM) for surgical prevention. Quantifying the residual lifetime risk and absolute benefit from RRM requires careful consideration of a patient's age, pathogenic variant, and their personal history of breast or ovarian cancer. Historically, patients have been counselled that RRM does not necessarily prolong survival relative to high-risk surveillance, although recent studies suggest a possible survival benefit of RRM in BRCA1 carriers. The uptake of RRM has increased dramatically over the last several decades yet varies according to sociodemographic factors and geographic region. The increased adoption of nipple-sparing mastectomy techniques, ability to avoid axillary staging, and availability of reconstructive options for most germline pathogenic variant carriers has helped to minimize the morbidity of RRM. Preoperative discussions should include evidence regarding postmastectomy sensation, the potential for supplemental surgery, pregnancy-related chest wall changes, and the need for continued clinical surveillance. Approaches that include sensation preservation and robotic nipple-sparing mastectomy are an area of evolving research that may be more widely adopted in the future.

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

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: Horizon 2020, German Cancer Aid, Federal Ministry of Education and Research, Köln Fortune.

Development of a Hereditary Breast and Ovarian Cancer and Genetics Curriculum for Community Health Workers: KEEP IT (Keeping Each other Engaged Program via IT) Community Health Worker Training.

We developed a curriculum for community health workers (CHWs) using an innovative, community-engaged focus group and Delphi process approach. Equipping CHWs with knowledge of hereditary breast and ovarian cancer syndrome (HBOC) and genetics could help enhance identification of women at risk for HBOC, referral, and navigation through genetic services. We conducted focus groups with five CHWs and a three-round Delphi process with eight experts. In the first round of the Delphi process, participants rated and commented on draft curriculum modules. The second round involved live video discussion to highlight points of confusion and concern in the modules. The curriculum was revised and refined based on quantitative and qualitative data and reassessed by the experts in Round 3. Ultimately, agreement was achieved on eight of 10 modules when assessing for clarity of learning objectives, seven out of 10 when assessing for adult learning theory, and nine out of 10 when assessing for participants' ability to learn desired knowledge. We plan to virtually deliver this curriculum to CHWs to enhance their HBOC and genomic competencies. By equipping CHWs to understand and participate in genomics education, we can enable more equitable participation in genomics-informed clinical care and research. Beyond this curriculum, the Delphi methodology can further be used to design content for new CHW curriculums.

"There should be one spot that you can go:" BRCA mutation carriers' perspectives on cancer risk management and a hereditary cancer registry.

Individuals who carry BRCA1 or BRCA2 pathogenic variants are recommended to have extensive cancer prevention screening and risk-reducing surgeries. Uptake of these recommendations is variable, and there remains room for improvement in the risk management of BRCA carriers. This paper explores female BRCA carriers' experiences with the current model of care and their perspectives on (and interest in) an inherited cancer registry. Findings can inform the development of a dedicated high-risk screening and management program for these patients. Quantitative and qualitative data were gathered through a provincial descriptive survey and semi-structured qualitative interviews to assess BRCA carriers' opinions toward risk management services in the province of Newfoundland and Labrador (NL), Canada. Survey (n = 69) and interview data (n = 15) revealed continuity and coordination challenges with the current system of care of high-risk individuals. Respondents suggested an inherited cancer registry would help identify high-risk individuals and provide a centralized system of risk management for identified carriers. Respondents identified concerns about the privacy of their registry data, including who could access it. Findings suggest BRCA carriers see great value in an inherited cancer registry. Specifically, participants noted it could provide a centralized system to help improve the coordination of burdensome, life-long risk management. Important patient concerns about protecting their privacy and their health data confidentiality must be addressed in patient and public information and informed consent documents about a registry.

A case of simultaneous breast cancer and ovarian cancer based on a hereditary breast and ovarian cancer syndrome.

We experienced a relatively rare case of synchronous breast and ovarian cancer in a patient with hereditary breast and ovarian cancer syndrome (HBOC). Here, we report the usefulness of laparoscopic examination to determine the subsequent treatment strategy in cases of suspected concurrent multiple carcinomas. Our patient was diagnosed with breast cancer following detection of a right breast mass. She was diagnosed with HBOC as she was found to be harboring a germline pathogenic variant of breast cancer susceptibility gene 1 (BRCA1). Preoperative images suggested the presence of neoplastic masses in the abdominal cavity, and the possibility of metastatic peritoneal dissemination of breast cancer or concurrent overlapping of gynecological malignancies was considered. We decided to employ laparoscopic examination, and if simultaneous overlapping of cancers was suspected, we planned to further evaluate whether primary debulking surgery (PDS) for gynecological cancer was possible or not. Laparoscopy revealed the presence of ovarian cancer with neoplastic lesions on the bilateral ovaries and disseminations in the pelvic and abdominal cavities. The total predictive index was 0; therefore, PDS was considered feasible. We performed a total mastectomy, followed by laparotomy, and optimal surgery was achieved. The final diagnosis was simultaneous stage IIB invasive ductal breast carcinoma and stage IIIC high-grade serous ovarian carcinoma. In this case of suspected concurrent multiple carcinomas, laparoscopy was beneficial for decision-making regarding subsequent surgical treatment. We believe that the use of laparoscopy will enable simultaneous surgery for breast cancer and ovarian cancer to become one of the treatment strategies in the future.

[Application of genetic counseling and preventive surgery in hereditary breast-ovarian cancer syndrome based on a rare family].

Objective: To investigate the genetic, clinical and pathological characteristics of families with hereditary breast-ovarian cancer syndrome (HBOCS) and to explore the implementation of genetic counseling and preventive surgery. Methods: Four siblings with HBOCS in Cancer Hospital/Chinese Academy of Medical Sciences were selected as the study subjects. BRCA gene testing and genetic counseling were performed, family history was traced and family map was drawn. Results: There were 7 cancer patients (Ⅰ 2, Ⅱ 4, Ⅱ 8, Ⅲ 7, Ⅲ 10, Ⅲ 11, Ⅲ 12) in three generations in the family. One patient (Ⅲ 7) had breast cancer and ovarian cancer successively. The first generation (Ⅰ 2) developed cancer at age 60, the second generation (Ⅱ4 and Ⅱ8) developed cancer at 55. The third generation (Ⅲ 7, Ⅲ 10, Ⅲ 11, Ⅲ 12) developed cancer at the age of 42-50 years. Four HBOCS patients were treated in our hospital, and all of them were found to have deleterious BRCA1 mutation. Two had already developed ovarian cancer (Ⅲ 10, Ⅲ 12), while in one case (Ⅲ 11), tubal carcinoma was found during preventive total hysterectomy and pelvic lymph node metastasis was found after the supplementary staging surgery. The other patient without cancer underwent preventive bilateral salpingectomy(Ⅲ 15). Conclusion: The HBOCS family reported in this study is relatively rare, the onset time of tumor was younger generation by generation. It is very important to pay attention to the genetic counseling of ovarian cancer patients and to timely detect the HBOCS families for genetic testing and prophylactic surgery.

Identifying Mediators of Intervention Effects Within a Randomized Controlled Trial to Motivate Cancer Genetic Risk Assessment Among Breast and Ovarian Cancer Survivors.

BACKGROUND: A theory-guided Tailored Counseling and Navigation (TCN) intervention successfully increased cancer genetic risk assessment (CGRA) uptake among cancer survivors at increased risk of hereditary breast and ovarian cancer (HBOC). Understanding the pathways by which interventions motivate behavior change is important for identifying the intervention's active components. PURPOSE: We examined whether the TCN intervention exerted effects on CGRA uptake through hypothesized theoretical mediators. METHODS: Cancer survivors at elevated risk for HBOC were recruited from three statewide cancer registries and were randomly assigned to three arms: TCN (n = 212), Targeted Print (TP, n = 216), and Usual Care (UC, n = 213). Theoretical mediators from the Extended Parallel Process Model, Health Action Planning Approach, and Ottawa Decision Support Framework were assessed at baseline and 1-month follow-up; CGRA uptake was assessed at 6 months. Generalized structural equation modeling was used for mediation analysis. RESULTS: The TCN effects were most strongly mediated by behavioral intention alone (ß = 0.49 and 0.31) and by serial mediation through self-efficacy and intention (ß = 0.041 and 0.10) when compared with UC and TP, respectively. In addition, compared with UC, the TCN also increased CGRA through increased perceived susceptibility, knowledge of HBOC, and response efficacy. CONCLUSIONS: Risk communication and behavioral change interventions for hereditary cancer should stress a person's increased genetic risk and the potential benefits of genetic counseling and testing, as well as bolster efficacy beliefs by helping remove barriers to CGRA. System-level and policy interventions are needed to further expand access.

It is recommended that cancer survivors at increased risk for heredity seek cancer genetic risk assessment (CGRA), which includes cancer genetic counseling and genetic testing. A Tailored Counseling and Navigation (TCN) intervention successfully increased CGRA uptake among women with a history of cancer who enrolled in a randomized controlled trial. Understanding reasons for TCN's effectiveness can guide future interventions that use risk messages and behavior change techniques. We conducted mediation analyses, which enabled identification of the TCN's active components. Eligible breast and ovarian cancer survivors (n = 641) were recruited from three statewide cancer registries and were assigned to three groups: TCN, Targeted Print, and Usual Care. Mediator variables drawn from behavioral and risk communication theories were assessed at baseline and 1-month follow-up; CGRA uptake was assessed at 6 months. The strongest mediator was intention to obtain a CGRA, followed by self-efficacy, perceived risk, knowledge of hereditary breast and ovarian cancer, and perceived CGRA benefits. Risk communication and behavioral change interventions for hereditary cancer should stress a person's increased genetic risk and the potential benefits of genetic counseling and testing, as well as bolster efficacy beliefs by helping remove CGRA barriers. System-level and policy interventions are needed to further expand access.

Co-Occurrence of Germline Genomic Variants and Copy Number Variations in Hereditary Breast and Colorectal Cancer Patients.

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is an autosomal dominant disease associated with a high risk of developing breast, ovarian, and other malignancies. Lynch syndrome is caused by mutations in mismatch repair genes predisposing to colorectal and endometrial cancers, among others. A rare phenotype overlapping hereditary colorectal and breast cancer syndromes is poorly characterized. Three breast and colorectal cancer unrelated patients fulfilling clinical criteria for HBOC were tested by whole exome sequencing. A family history of colorectal cancer was reported in two patients (cases 2 and 3). Several variants and copy number variations were identified, which potentially contribute to the cancer risk or prognosis. All patients presented copy number imbalances encompassing PMS2 (two deletions and one duplication), a known gene involved in the DNA mismatch repair pathway. Two patients showed gains covering the POLE2 (cases 1 and 3), which is associated with DNA replication. Germline potentially damaging variants were found in PTCH1 (patient 3), MAT1A, and WRN (patient 2). Overall, concurrent genomic alterations were described that may increase the risk of cancer appearance in HBOC patients with breast and colorectal cancers.

Clinical Impact of Polygenic Risk Score for Breast Cancer Risk Prediction in 382 Individuals with Hereditary Breast and Ovarian Cancer Syndrome.

Single nucleotide polymorphisms are currently not considered in breast cancer (BC) risk predictions used in daily practice of genetic counselling and clinical management of familial BC in Germany. This study aimed to assess the clinical value of incorporating a 313-variant-based polygenic risk score (PRS) into BC risk calculations in a cohort of German women with suspected hereditary breast and ovarian cancer syndrome (HBOC). Data from 382 individuals seeking counselling for HBOC were analysed. Risk calculations were performed using the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm with and without the inclusion of the PRS. Changes in risk predictions and their impact on clinical management were evaluated. The PRS led to changes in risk stratification based on 10-year risk calculations in 13.6% of individuals. Furthermore, the inclusion of the PRS in BC risk predictions resulted in clinically significant changes in 12.0% of cases, impacting the prevention recommendations established by the German Consortium for Hereditary Breast and Ovarian Cancer. These findings support the implementation of the PRS in genetic counselling for personalized BC risk assessment.

CA125 Levels in BRCA mutation carriers - a retrospective single center cohort study.

BACKGROUND: Ovarian cancer screening in BRCA1/2 mutation carriers utilizes assessment of carbohydrate antigen 125 (CA125) and transvaginal ultrasound (TVU), despite low sensitivity and specificity. We evaluated the association between CA125 levels, BRCA1/2 mutation status and menopausal status to provide more information on clinical conditions that may influence CA125 levels. METHODS: We retrospectively analyzed repeated measurements of CA125 levels and clinical data of 466 women at high risk for ovarian cancer. CA125 levels were compared between women with and without deleterious mutations in BRCA1/2. Pearson's correlation was used to determine the association between age and CA125 serum level. Differences in CA125 levels were assessed with the Mann-Whitney U test. The effect of BRCA1/2 mutation status and menopausal status on the change in CA125 levels was determined by Two-factor analysis of variance (ANOVA). RESULTS: The CA125 serum levels of premenopausal women (median, 13.8 kU/mL; range, 9.4 - 19.5 kU/mL) were significantly higher than in postmenopausal women (median, 10.4 kU/mL; range, 7.7 - 14.0 kU/mL; p < .001). There was no significant difference in the CA125 levels of BRCA mutation carriers and non-mutation carriers across all age groups (p = .612). When investigating the combined effect of BRCA1/2 mutation and menopausal status, variance analysis revealed a significant interaction between BRCA1/2 mutation status and menopausal status on CA125 levels (p < .001). There was a significant difference between the CA125 levels of premenopausal and postmenopausal women, with a large effect in BRCA mutation carriers (p < .001, d = 1.05), whereas in non-mutation carriers there was only a small effect (p < .001, d = 0.32). CONCLUSION: Our findings suggest that hereditary mutations in BRCA1/2 affect the decline of CA125 levels with increasing age. To prove a definite effect of this mutation on the CA125 level, prospective trials need to be conducted to define new cut-off levels of CA 125 in mutation carriers and optimize ovarian cancer screening.

Interventions to support decision making in people considering germline genetic testing for BRCA 1/2 pathogenic and likely pathogenic variants: A scoping review.

Pathogenic and likely pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) are medically actionable and may inform hereditary breast and ovarian cancer (HBOC) treatment and prevention. However, rates of germline genetic testing (GT) in people with and without cancer are suboptimal. Individuals' knowledge, attitudes, and beliefs may influence GT decisions. While genetic counseling (GC) provides decision support, the supply of genetic counselors is insufficient to meet demand. Accordingly, there is a need to explore the evidence on interventions that aim to support BRCA1/2 testing decisions. We conducted a scoping review of PubMed, CINAHL, Web of Science, and PsycINFO using search terms related to HBOC, GT, and decision making. First, we screened records to identify peer-reviewed reports that described interventions to support BRCA1/2 testing decisions. Next, we reviewed full-text reports and excluded studies that lacked statistical comparisons or enrolled previously tested individuals. Finally, we extracted study characteristics and findings into a table. All records and reports were reviewed independently by two authors; decisions were tracked in Rayyan, and discrepancies were resolved through discussion. Of 2116 unique citations, 25 met the eligibility criteria. Articles were published between 1997 and 2021 and described randomized trials and nonrandomized, quasi-experimental studies. Most studies tested technology-based (12/25, 48%) or written (9/25, 36%) interventions. Nearly half (12/25, 48%) of interventions were designed to complement traditional GC. Of the interventions compared to GC, 75% (6/8) increased or had a noninferior effect on knowledge, and 67% (4/6) decreased or had a noninferior effect on decisional conflict. Intervention effects on GT uptake were mixed, which may reflect evolving eligibility criteria for GT. Our findings suggest novel interventions may promote informed GT decision making, but many were developed to complement traditional GC. Trials that assess the effects of decision support interventions in diverse samples and evaluate implementation strategies for efficacious interventions are warranted.

Adherence to risk-reducing salpingo-oophorectomy guidelines among gynecologic oncologists compared to general gynecologists.

BACKGROUND: Risk-reducing bilateral salpingo-oophorectomy reduces mortality from high-grade serous carcinoma in patients with hereditary breast and ovarian cancer associated gene mutations. Ideal surgical management includes 5 steps outlined in 2005 by the Society of Gynecologic Oncology and the American College of Obstetricians and Gynecologists. In addition, it is recommended that pathologic examination include serial sectioning of specimens. In practice, risk-reducing salpingo-oophorectomy is performed by both gynecologic oncologists and general gynecologists. To ensure optimal detection of occult malignancy, standardized adherence to outlined guidelines is necessary. OBJECTIVE: This study aimed to evaluate the adherence to optimal surgical and pathologic examination guidelines and to compare the rate of occult malignancy at the time of surgery between 2 provider types. STUDY DESIGN: Institutional review board exemption was obtained. A retrospective review of patients undergoing risk-reducing bilateral salpingo-oophorectomy without hysterectomy from October 1, 2015, to December 31, 2020, at 3 sites within a healthcare system was conducted. The inclusion criteria included age ≥18 years and a documented indication for surgery being a mutation in BRCA1 or BRCA2 or a strong family history of breast and/or ovarian cancer. Compliance with 5 surgical steps and pathologic specimen preparation was based on medical record documentation. Multivariable logistic regression was used to determine differences in adherence between provider groups and surgical and pathologic examination guidelines. A P value of <.025 was considered statistically significant for the 2 primary outcomes after Bonferroni correction was applied to adjust for multiple comparisons. RESULTS: A total of 185 patients were included. Among the 96 cases performed by gynecologic oncologists, 69 (72%) performed all 5 steps of surgery, 22 (23%) performed 4 steps, 5 (5%) performed 3 steps, and none performed 1 or 2 steps. Among the 89 cases performed by general gynecologists, 4 (5%) performed all 5 steps, 33 (37%) performed 4 steps, 38 (43%) performed 3 steps, 13 (15%) performed 2 steps, and 1 (1%) performed 1 step. Gynecologic oncologists were more likely to document adherence to all 5 recommended surgical steps in their surgical dictation (odds ratio, 54.3; 95% confidence interval, 18.1-162.7; P<.0001). Among the 96 cases documented by gynecologic oncologists, 41 (43%) had serial sectioning of all specimens performed, compared with 23 of 89 cases (26%) performed by general gynecologists. No difference in adherence to pathologic guidelines was identified between the 2 provider groups (P=.0489; note: P value of >.025). Overall, 5 patients (2.70%) had occult malignancy diagnosed at the time of risk-reducing surgery, with all surgeries performed by general gynecologists. CONCLUSION: Our results demonstrated greater compliance with surgical guidelines for risk-reducing bilateral salpingo-oophorectomy in gynecologic oncologists than in general gynecologists. No considerable difference was determined between the 2 provider types in adherence to pathologic guidelines. Our findings demonstrated a need for institution-wide protocol education and implementation of standardized nomenclature to ensure provider adherence to evidence-based guidelines.

Distress, anxiety, and depression in persons with hereditary cancer syndromes: Results from a nationwide cross-sectional study in Germany.

BACKGROUND: Persons with hereditary cancer syndromes (carriers) have a higher risk of developing cancer early. They are confronted with decisions regarding prophylactic surgeries, communication within their families, and childbearing. The present study aims to assess distress, anxiety, and depression in adult carriers and identify risk groups and predictors; clinicians can use to screen for particularly distressed persons. METHODS: N = 223 participants (n = 200 women, n = 23 men) with different hereditary cancer syndromes affected and unaffected by cancer answered questionnaires measuring their distress, anxiety, and depression levels. The sample was compared to the general population using one-sample t-tests. The n = 200 women with (n = 111) and without cancer (n = 89) were then compared and predictors for increased levels of anxiety and depression were identified using stepwise linear regression analyses. RESULTS: 66% reported clinical relevant distress, 47% reported clinical relevant anxiety, and 37% reported clinical relevant depression. Compared to the general population, carriers experienced increased distress, anxiety, and depression. Additionally, women with cancer suffered from more depressive symptoms than those without cancer. Past psychotherapy for a mental disorder and high distress were identified as predictors for increased anxiety and depression in female carriers. CONCLUSIONS: The results suggest that the psychosocial consequences of hereditary cancer syndromes are serious. Clinicians could regularly screen carriers regarding anxiety and depression. The NCCN Distress Thermometer can be combined with questions about past psychotherapy to identify especially vulnerable persons. Further studies are needed to develop psychosocial interventions.