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.

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.

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.

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.

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.

The pathogenic role of the BRCA2 c.7847C>T (p.Ser2616Phe) variant in breast and ovarian cancer predisposition.

Substantial numbers of variants of unknown significance (VUSs) have been identified in BRCA1/2 through genetic testing, which poses a significant clinical challenge because the contribution of these VUSs to cancer predisposition has not yet been determined. Here, we report 10 Japanese patients from seven families with breast or ovarian cancer harboring the BRCA2 c.7847C>T (p.Ser2616Phe) variant that was interpreted as a VUS. This variant recurs only in families from Japan and has not been reported in the global general population databases. A Japanese patient with Fanconi anemia with compound heterozygous variants c.7847C>T (p.Ser2616Phe) and c.475+1G>A in BRCA2 was reported. In silico predictions and quantitative cosegregation analysis suggest a high probability of pathogenicity. The clinical features of the variant carriers were not specific to, but were consistent with, those of patients with hereditary breast and ovarian cancer. A validated functional assay, called the mixed-all-nominated-in-one-BRCA (MANO-B) method and the accurate BRCA companion diagnostic (ABCD) test, demonstrated the deleterious effects of the variant. Altogether, following the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, this variant satisfied the "PS3," "PM2," "PM3," and "PP3" criteria. We thus conclude that the BRCA2 c.7847C>T (p.Ser2616Phe) variant is a "likely pathogenic" variant that is specifically observed in the Japanese population, leading to a breast and ovarian cancer predisposition.

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.

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.

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.

Risk-reducing salpingo-oophorectomy for Japanese women with hereditary breast and ovarian cancer: a single-institution 10-year experience.

BACKGROUND: For women diagnosed with hereditary breast and ovarian cancer, the clinical guidelines recommend risk-reducing salpingo-oophorectomy at age 35-40 years or after completion of childbearing. However, there is limited information regarding the current status of risk-reducing salpingo-oophorectomy in Japan. METHODS: To clarify factors influencing decision-making for risk-reducing salpingo-oophorectomy among Japanese women diagnosed with hereditary breast and ovarian cancer and their clinical outcomes, we analyzed the medical records of 157 Japanese women with germline BRCA pathogenic variants (BRCA1 n = 85, BRCA2 n = 71 and both n = 1) at our institution during 2011-21. Specimens obtained from risk-reducing salpingo-oophorectomy were histologically examined according to the sectioning and extensively examining the fimbriated end protocol. RESULTS: The risk-reducing salpingo-oophorectomy uptake rate was 42.7% (67/157). The median age at risk-reducing salpingo-oophorectomy was 47 years. Older age, married state and parity were significantly associated with risk-reducing salpingo-oophorectomy (P < 0.001, P = 0.002 and P = 0.04, respectively). History of breast cancer or family history of ovarian cancer did not reach statistical significance (P = 0.18 and P = 0.14, respectively). Multivariate analyses revealed that older age (≥45 years) and married state may be independent factors associated with risk-reducing salpingo-oophorectomy. Interestingly, the annual number of risk-reducing salpingo-oophorectomy peaked in 2016-17 and has increased again since 2020. The rate of occult cancers at risk-reducing salpingo-oophorectomy was 4.5% (3/67): ovarian cancer (n = 2) and serous tubal intraepithelial carcinoma (n = 1). CONCLUSION: Age and marital status significantly affected decision-making for risk-reducing salpingo-oophorectomy. This is the first study to suggest possible effects of Angelina Jolie's risk-reducing salpingo-oophorectomy in 2015 and the National Health Insurance introduced for risk-reducing salpingo-oophorectomy in 2020. The presence of occult cancers at risk-reducing salpingo-oophorectomy supports clinical guidelines recommending risk-reducing salpingo-oophorectomy at younger ages.

Impact of BRCA1/2 cascade testing on anxiety, depression, and cancer worry levels among unaffected relatives in a multiethnic Asian cohort.

Cascade testing for families with BRCA pathogenic variants is important to identify relatives who are carriers. These relatives can benefit from appropriate risk management and preventative strategies arising from an inherited increased risk of breast, ovarian, prostate, melanoma, and pancreatic cancers. Cascade testing has the potential to enable cost-effective cancer control even in low- and middle-income settings, but few studies have hitherto evaluated the psychosocial impact of cascade testing in an Asian population, where the cultural and religious beliefs around inheritance and destiny have previously been shown to influence perception and attitudes toward screening. In this study, we evaluated the short- and long-term psychosocial impact of genetic testing among unaffected relatives of probands identified through the Malaysian Breast Cancer Genetics Study and the Malaysian Ovarian Cancer Study, using validated questionnaires (Hospital Anxiety and Depression Scale and Cancer Worry Scale) administered at baseline, and 1-month and 2-year post-disclosure of results. Of the 305 unaffected relatives from 98 independent families who were offered cascade testing, 256 (84%) completed predictive testing and family history of cancers was the only factor significantly associated with uptake of predictive testing. We found that the levels of anxiety, depression, and cancer worry among unaffected relatives decreased significantly after result disclosure and remained low 2-year post-result disclosure. Younger relatives and relatives of Malay descent had higher cancer worry at both baseline and after result disclosure compared to those of Chinese and Indian descent, whereas relatives of Indian descent and those with family history of cancers had higher anxiety and depression levels post-result disclosure. Taken together, the results from this Asian cohort highlight the differences in psychosocial needs in different communities and inform the development of culture-specific genetic counseling strategies.

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.

[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.

Brca1L63X /+ rat is a novel model of human BRCA1 deficiency displaying susceptibility to radiation-induced mammary cancer.

Women who are heterozygous for deleterious BRCA1 germline mutations harbor a high risk of hereditary breast cancer. Previous Brca1-heterozygous animal models do not recapitulate the breast cancer phenotype, and thus all currently used knockout models adopt conditional, mammary-specific homozygous Brca1 loss or addition of Trp53 deficiency. Herein, we report the creation and characterization of a novel Brca1 mutant rat model harboring the germline L63X mutation, which mimics a founder mutation in Japan, through CRISPR-Cas9-based genome editing. Homozygotes (Brca1L63X/L63X ) were embryonic lethal, whereas heterozygotes (Brca1L63X/+ ) showed apparently normal development. Without carcinogen exposure, heterozygotes developed mammary carcinoma at a comparable incidence rate with their wild-type (WT) littermates during their lifetime. Intraperitoneal injection of 1-methyl-1-nitrosourea (25 or 50 mg/kg) at 7 weeks of age induced mammary carcinogenesis at comparable levels among the heterozygotes and their littermates. After exposure to ionizing radiation (0.1-2 Gy) at 7 weeks of age, the heterozygotes, but not WT littermates, displayed dose-dependent mammary carcinogenesis with 0.8 Gy-1 excess in hazard ratio during their middle age; the relative susceptibility of the heterozygotes was more prominent when rats were irradiated at 3 weeks of age. The heterozygotes had tumors with a lower estrogen receptor α immunopositivity and no evidence of somatic mutations of the WT allele. The Brca1L63X/+ rats thus offer the first single-mutation, heterozygous model of BRCA1-associated breast cancer, especially with exposure to a DNA break-inducing carcinogen. This implies that such carcinogens are causative and a key to breast cancer prevention in individuals who carry high-risk BRCA1 mutations.

Current Approaches to Germline Cancer Genetic Testing.

The prevalence of genetic predisposition to cancer is greater than initially appreciated, yet most affected individuals remain undiagnosed. Deleterious germline variants in cancer predisposition genes are implicated in 1 in 10 cases of advanced cancer. Next-generation sequencing technologies have made germline and tumor DNA sequencing more accessible and less expensive. Expanded access to clinical genetic testing will improve identification of individuals with genetic predisposition to cancer and provide opportunities to effectively reduce morbidity through precision cancer therapies and surveillance. Cross-disciplinary clinical education in genomic medicine is needed to translate advances in genomic medicine into improved health outcomes.

Lapses in breast cancer screening for highly penetrant mutation carriers during pregnancy and lactation.

BACKGROUND AND OBJECTIVES: Screening for breast cancer in highly penetrant mutation carriers during pregnancy and lactation is challenging and consensus guidelines are lacking. This study evaluates the lapse in screening and the interval pregnancy-associated breast cancer rate. METHODS: A single-institution retrospective cohort study of pregnant and lactating patients with known pathogenic germline mutations was performed. Lapse in screening was defined as the interval between the last screening imaging exam obtained before last menstrual period and the subsequent screening imaging. RESULTS: Out of 685 patients, 42 had 1-3 evaluable pregnancies (54 total - 28 managed in High Risk Breast Clinic and 26 by OB/GYN). Mutations were observed in patients in BRCA1 (49%), BRCA2 (36%), CDH1 (5%), CHEK2 (2%), ATM (2%), NF1 (3%), and MSH2 (3%). The average screening lapse was 25 [19, 30] months for patients followed in the High Risk Clinic versus 32.5 [21, 65.75] months for patients followed with Routine Care (p = 0.035). We identified three cases of pregnancy-associated breast cancer (interval cancer rate 6%). CONCLUSIONS: Patients with highly penetrant mutations are at risk for the development of interval pregnancy-associated breast cancer. Development of consistent screening guidelines and adherence to those guidelines is needed for this patient population.

Prevalence of Americans reporting a family history of cancer indicative of increased cancer risk: Estimates from the 2015 National Health Interview Survey.

The collection and evaluation of family health history in a clinical setting presents an opportunity to discuss cancer risk, tailor cancer screening recommendations, and identify people with an increased risk of carrying a pathogenic variant who may benefit from referral to genetic counseling and testing. National recommendations for breast and colorectal cancer screening indicate that men and women who have a first-degree relative affected with these types of cancers may benefit from talking to a healthcare provider about starting screening at an earlier age and other options for cancer prevention. The prevalence of reporting a first-degree relative who had cancer was assessed among adult respondents of the 2015 National Health Interview Survey who had never had cancer themselves (n = 27,999). We found 35.6% of adults reported having at least one first-degree relative with cancer at any site. Significant differences in reporting a family history of cancer were observed by sex, age, race/ethnicity, educational attainment, and census region. Nearly 5% of women under age 50 and 2.5% of adults under age 50 had at least one first-degree relative with breast cancer or colorectal cancer, respectively. We estimated that 5.8% of women had a family history of breast or ovarian cancer that may indicate increased genetic risk. A third of U.S. adults who have never had cancer report a family history of cancer in a first-degree relative. This finding underscores the importance of using family history to inform discussions about cancer risk and screening options between healthcare providers and their patients.

Awareness of genetic counseling and genetic testing for hereditary gynecologic cancers among Korean healthcare providers: A survey.

We conducted a survey to evaluate the awareness of genetic counseling and testing for hereditary gynecologic cancers among Korean healthcare providers. We performed an on-the-spot survey using 29 questions on respondents' basic information, awareness of pre/post-test genetic counseling, genetic information management, and related social issues. We surveyed healthcare providers who attended the 2019 Hereditary Gynecologic Cancer Symposium organized by the Korean Society of Gynecologic Oncology. Of the 108 attendees, 85 (78.7%) participated in the survey. Among them, 45% (37/83) and 40% (33/83) did not have a separate clinic and had a dedicated team for genetic counseling in their institutions, respectively. Most respondents (60/76, 79%) recommended genetic testing for all women diagnosed with epithelial ovarian cancer. Many respondents simultaneously (20/85, 24%) or sequentially (45/85, 53%) tested for both pathogenic somatic and germline variants, whereas a few respondents (2/85, 2%) checked for only pathogenic somatic variants using tissue samples. Only 20% (17/85) of the respondents recommended genetic testing for all women with endometrial cancer; meanwhile, 68% (58/86) offered the test based on the results of the screening test or family history. Risk-reducing salpingo-oophorectomy was recommended to unaffected women with pathogenic BRCA1/2 variants by 69.4% of the respondents (59/85). Most respondents (73/85, 85.9%) needed a manual on bioethics law; a few required a clinical update of hereditary cancer (73/85, 85.9%). The awareness of genetic counseling and testing and the pattern of clinical practice for hereditary gynecologic cancers differ among institutions and regions in Korea. A discussion on these issues and the development of an integrated manual for healthcare providers are required.

Hereditary gynecologic tumors and precision cancer medicine.

Gynecologic cancers are more often caused by genetic factors than other cancers. Genetic testing has become a promising avenue for the prevention, prognosis, and treatment of cancers. This review describes molecular features of gynecologic tumors linked to hereditary syndromes, gives an overview of the current state of clinical management, and clarifies the role of gynecology in the treatment of hereditary tumors. Typical hereditary gynecologic tumors include hereditary breast and ovarian cancer, Lynch syndrome, Peutz-Jeghers syndrome, and Cowden syndrome. Multigene panel testing, which analyzes a preselected subset of genes for genetic variants, has recently become the first-choice test because it can provide more accurate risk assessment than a single test. Furthermore, comprehensive genomic cancer profiling enables personalized cancer treatment and aids in germline findings.

Increased Co-Occurrence of Pathogenic Variants in Hereditary Breast and Ovarian Cancer and Lynch Syndromes: A Consequence of Multigene Panel Genetic Testing?

The probability of carrying two pathogenic variants (PVs) in dominant cancer-predisposing genes for hereditary breast and ovarian cancer and lynch syndromes in the same patient is uncommon, except in populations where founder effects exist. Two breast cancer women that are double heterozygotes (DH) for both BRCA1/BRCA2, one ovarian cancer case DH for BRCA1/RAD51C, and another breast and colorectal cancer who is DH for BRCA2/PMS2 were identified in our cohort. Ages at diagnosis and severity of disease in BRCA1/BRCA2 DH resembled BRCA1 single-carrier features. Similarly, the co-existence of the BRCA2 and PMS2 mutations prompted the development of breast and colorectal cancer in the same patient. The first BRCA1/BRCA2 DH was identified by HA-based and Sanger sequencing (1 of 623 families with BRCA PVs). However, this ratio has increased up to 2.9% (1 DH carrier vs. 103 single PV carriers) since using a custom 35-cancer gene on-demand panel. The type of cancer developed in each DH patient was consistent with the independently inherited condition, and the clinical outcome was no worse than in patients with single BRCA1 mutations. Therefore, the clinical impact, especially in patients with two hereditary syndromes, lies in genetic counseling tailor-made for each family based on the clinical guidelines for each syndrome. The number of DH is expected to be increased in the future as a result of next generation sequencing routines.