Hereditary Breast And Ovarian Cancer Research Articles

Outcomes and the effect of PGT-M in women with hormone-related hereditary tumor syndrome

PurposeTo review the outcome of PGT-M in hormone-related hereditary tumor syndrome and evaluate the effect of ovarian induction on tumor growth in those patients.MethodsMedical records of PGT-M were retrospectively analyzed in patients with hormone-related heritage tumors in our reproductive center. A total of eleven women with hereditary breast and ovarian cancer (HBOC) (including BRCA1/2 mutation carriers), and Lynch syndrome (including MMR gene mutation carriers) were included. Thirteen IVF/PGT-M cycles were performed. Eleven for PGT-M and two for fertility preservation. The ovulation protocol, numbers of oocytes retrieved and two pronuclei (2PN) zygotes, PGT-M results, and clinical outcomes were analyzed. Tumor progression was also estimated by comparing transvaginal ultrasound (TVS), MR, CT, or colonoscopy according to the follow-up requirements of different tumors.ResultsEleven IVF/PGT-M cycles were performed with an antagonist protocol; Two cycles were performed with a mild stimulation protocol. The total dose of gonadotropin (Gn) was 1827 IU per patient (range from 1200 to 2625 IU). The median number of oocytes retrieved was 13 (range from 4 to 30), and the median number of 2PN zygotes was 8 (range from 2 to 16). A total of 32 embryos underwent PGT-M, and 9 (28.1%) embryos were suitable for transfer. Six transfer cycles were performed, and 5 cycles got clinical pregnancy (83%) with five newborns (83%). The follow-up examinations conducted 10-18 months after PGT-M/delivery revealed no new lesions or tumor progression.ConclusionPGT-M results can provide important information for improving the consultation of hormone-related heritage tumor patients regarding their fertility preservation and reproductive options. Ovarian induction for women with hormone-related hereditary tumor syndrome is not associated with tumor progression.

Abstract PO4-09-08: Perceptions and Experiences of Black Women on Family History Sharing and Genetic Testing for Hereditary Breast and Ovarian Cancer

Abstract Black women experience significant disparities in morbidity and mortality related to hereditary breast and ovarian cancer (HBOC). Early identification of women with HBOC is essential for proactive screening and timely diagnosis. However, evidence suggests that Black women receive genetic testing for HBOC at lower rates than their White counterparts. We conducted in-depth qualitative interviews with 107 Black women with a personal or family history of breast or ovarian cancer, to understand their perceptions of their familial risk of HBOC and interest in genetic testing. In phase 1 of this study, participants were recruited from the networks of patient support organizations and historically Black sororities representing mostly highly educated and well insured patients. In phase 2, participants were recruited from a family medicine safety net clinic in Jacksonville, FL for socioeconomic diversity. Participants in both cohorts frequently expressed a lack of awareness about their family cancer history and identified many barriers to family disclosure of a cancer diagnosis. These include a culture of silence around medical issues and a belief that personal difficulties should be kept to oneself. Practical and cultural barriers to family history sharing were magnified among those with lower socioeconomic status. Many participants in both cohorts indicated a strong desire to understand their own risk of HBOC. They also expressed interested in genetic testing to proactively mitigate risk to themselves and future generations. Understanding of the potential relevance of HBOC testing to one’s personal health and post-test actionability was variable across both groups, although perceptions of genetic testing were generally favorable. These findings suggest that culturally tailored educational materials and alternative clinical modalities to collect family health history may be beneficial to improve timely identification of Black women who meet NCCN Guidelines for HBOC testing. Specifically, greater attention should be given to addressing barriers that led to underestimation of HBOC risk among patients experiencing disparities driven by adverse social determinants of health. Citation Format: Kirsten Riggan, Jane Yap, Ewan Cobran, Michele Halyard, Sarah James, Marion Kelly, Daphne Phillips, Megan Allyse. Perceptions and Experiences of Black Women on Family History Sharing and Genetic Testing for Hereditary Breast and Ovarian Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-09-08.

Abstract PO4-15-02: ApoE polymorphism is associated with aggressive tumor phenotypes for breast cancer patients

Abstract Introduction: Apolipoprotein E (APOE) is implicated in several biological processes, such as protein synthesis, cell growth and differentiation, cholesterol transport, lipid metabolism, and tissue repair. APOE has different isoforms (E2, E3, and E4) that combine conflicting relations with cancer risk. This study aimed to evaluate the distribution of different isoforms of APOE among suspected HBOC (Hereditary Breast and Ovarian Cancer Syndrome) patients. Methodology: DNA was extracted from the blood cells of 108 patients. The detection was performed using qPCR after amplifying specific regions containing the polymorphisms. It was considered that all the amplicons containing Cq amplification < 35. The melting curve for each patient was analyzed to determine the frequency of the isoforms E2, E3, E4, and genotypes E2/E2, E2/E3, E2E4, E3/E3, and E3/E4. The allele and genotype were also correlated with hereditary variants previously identified by genetic tests for germline mutations and with tumoral phenotype. The data were expressed in frequency and associated using chi-square tests or Fisher's exact test (SPSS v20.0, p< 0.05). Results A total of 108 patients filling criteria for HBOC syndrome were evaluated. Among them, 15 (13.9%) had a mutation in BRCA1, 5 (4.6%) in BRCA2, and 2 (1.9%) in TP53. Most patients were under 45 years old (n=76, 70.4%), female (n=104, 96.3%), had a high school education (n=44, 44.0%), were non-smokers (n=79, 80.6%) or drinkers (n=76, 78.4%), and had no comorbidities (n=66, 64.1%). Overweight at diagnosis was observed in 61 (68.5%) individuals. The most frequent tumor phenotype and stage were luminal B (n=46, 43.4%) and stage IIIA (n=22, 26.2%), respectively. Neoadjuvant chemotherapy was performed in 40 (47.1%) with a high rate of complete and partial response 18 (36.7%) and 22 (44.9%), respectively. Regarding ApoE polymorphisms, the E2 allele showed the lowest frequency (n=7, 6.5%), E3 was present in 103 (95.4%) cases, while E4 was present in 39 (36.1%). The most frequent genotype was E3/E3 (n=64, 58.3%), followed by E3/E4 (n=34, 31.5%), E2/E3 (n=6, 5.6%), E4 (n=4, 3.7%), and E2/E4 (n=1, 0.9%). No cases of E2/E2 genotype were observed. The presence of E2 was inversely associated with comorbidity frequency (p=0.040) but directly associated with TP53 mutation (p=0.012) and triple-negative tumor phenotype (p=0.027). E3 was not associated with clinical characteristics, but E4 was associated with low Ki-67 immunoreactivity (p=0.033). The E2/E3 phenotype was directly associated with triple-negative tumors (p=0.044) and heterozygous tumors (p=0.011). Conclusion: The ApoE polymorphism, particularly the presence of the E2 allele in heterozygosity, is associated with TP53 mutation and a more aggressive tumor phenotype. Citation Format: Maria Claudia Luciano, Rosane Sant' Ana, Valeska Lima, Paulo Goberlanio Silva, Clarissa Albuquerquye, Flavio Bitencourt, Maria Julia Bezerra, Francisca Fernanda Oliveira, José Fernando De Moura, Isabelle Joyce Fernandes, Fernanda Leite. ApoE polymorphism is associated with aggressive tumor phenotypes for breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-15-02.

Targeted sequencing for hereditary breast and ovarian cancer in BRCA1/2-negative families from the Lynch Memorial Biobank reveals complex genetic architecture and phenocopies

Approximately 20% of breast cancer cases are attributed to increased family risk; yet variation in BRCA1/2 can only explain 20-25% of cases. Historically, only single gene or single variant testing were common in at-risk family members, and further sequencing studies were rarely offered after negative results. In this study, we applied an efficient and inexpensive targeted sequencing approach to provide molecular diagnoses in 245 human samples representing 134 BRCA mutation negative (BRCAX) hereditary breast and ovarian cancer (HBOC) families recruited from 1973-2019 by Dr. Henry Lynch. Sequencing identified 391 variants, which were functionally annotated and ranked based on their predicted clinical impact. Known pathogenic CHEK2 breast cancer variants were identified in five BRCAX families in this study. While BRCAX was an inclusion criterion for this study, we still identified a pathogenic BRCA2 variant (p.Met192ValfsTer13) in one family. A portion of BRCAX families could be explained by other hereditary cancer syndromes that increase HBOC risk: Li-Fraumeni Syndrome (gene: TP53) and Lynch Syndrome (gene: MSH6). Interestingly, many families carried additional Variants of Undetermined Significance (VOUSs) that may further modify phenotypes of syndromic family members. Ten families carried more than one potential VOUS suggesting the presence of complex multi-variant families. Overall, nine BRCAX HBOC families in our study may be explained by known likely-pathogenic/pathogenic variants, and six families carried potential VOUSs, which require further functional testing. To address this, we developed a functional assay where we successfully re-classified one family’s PMS2 VOUS as benign.

Psychosocial barriers and facilitators for cascade genetic testing in hereditary breast and ovarian cancer: a scoping review.

Despite increased awareness and availability of genetic testing for hereditary breast and ovarian cancer (HBOC) syndrome for over 20years, there is still significant underuse of cascade genetic testing among at-risk relatives. This scoping review synthesized evidence regarding psychosocial barriers and facilitators of family communication and/or uptake of cascade genetic testing in relatives from HBOC families. Search terms included 'hereditary breast and ovarian cancer' and 'cascade genetic testing' for studies published from 2012-2022. Through searching common databases, and manual search of references, 480 studies were identified after excluding duplications. Each article was reviewed by two researchers independently and 20 studies were included in the final analysis. CASP, RoBANS 2.0, RoB 2.0, and MMAT were used to assess the quality of included studies. A convergent data synthesis method was used to integrate evidence from quantitative and narrative data into categories and subcategories.Evidence points to 3 categories and 12 subcategories of psychosocial barriers and facilitators for cascade testing: (1) facilitators (belief in health protection and prevention; family closeness; decisional empowerment; family support, sense of responsibility; self-efficacy; supportive health professionals); (2) bidirectional concepts (information; perception of genetic/cancer consequences; negative emotions and attitude); and (3) barriers (negative reactions from family and negative family dynamics). Healthcare providers need to systematically evaluate these psychosocial factors, strengthen facilitators and alleviate barriers to promote informed decision-making for communication of genetic test results and uptake of genetic testing. Bidirectional factors merit special consideration and tailored approaches, as they can potentially have a positive or negative influence on family communication and uptake of genetic testing.

Abstract P69: Immune Landscape of BRCA1/2 -mutated Breast and Ovarian Cancers in an Asian Cohort

Abstract Background: The majority of hereditary breast and ovarian cancers (HBOC) harbor defects in the homologous recombination (HR) DNA repair pathway, such as BRCA1 and BRCA2 mutations, which may influence the response to immune checkpoint blockade (ICB) therapy. Recent clinical trials combining poly-ADP ribose inhibitors and ICB therapy in advanced breast and ovarian cancer have shown promising results. This Asian cohort study set out to determine if immune phenotype, specifically the PD-1/PD-L1 axis, was associated with germline BRCA status in advanced breast and ovarian cancer patients and to develop novel biomarkers of HR deficiency to stratify patients for clinical management. Methods: Tissue microarrays of ovarian tumors and breast tumors were analyzed by multiplex immunohistochemistry (mIHC) to detect the expression of immune markers (CD68, CD8, PD-L1, PD-1) and HR markers (DNA polymerase theta, FANCD2, RAD51, γH2AX, phospho-ATR). The results were used to build a prediction model for BRCA using backward stepwise logistic regression analysis. In addition, we investigated immune infiltration in tumors and performed immune phenotyping on peripheral blood mononuclear cells in a subset of patients. Results: We identified potential BRCA1/2 predictors by mIHC, namely RAD51 and PD-L1 263 for ovarian tumors and FANCD2 and phospho-ATR for breast tumors. The area under the curve was 0.770 (95% confidence interval [CI]: 0.564, 0.977) in ovarian cancer patients and 0.841 (95% CI: 0.682, 0.999) in breast cancer patients. In addition, the proportion of tumor-infiltrating CD68+PD-L1+ macrophages was significantly upregulated in BRCA1-mutated tumors, while the levels of PD-1 in circulating central memory CD8+ T cells were higher in breast cancer patients with germline BRCA2 mutations, compared with non-BRCA. Conclusion: This study provides evidence of the association of the PD-1/PD-L1 axis with germline BRCA status in HBOC, which may aid clinical management. Citation Format: Siao Ting Chong, Felicia Wee, Jiang Feng Ye, Craig Joseph, Xinru Lim, Zhen Wei Neo, Justina Nadia Lee, Nur Diana Binte Ishak, Ming Ren Toh, Ee Ling Chew, Claresta Yeo, Sock Hoai Chan, Jeffrey Lim, Joe Yeong, Joanne Ngeow. Immune Landscape of BRCA1/2 -mutated Breast and Ovarian Cancers in an Asian Cohort [abstract]. In: Proceedings of Frontiers in Cancer Science; 2023 Nov 6-8; Singapore. Philadelphia (PA): AACR; Cancer Res 2024;84(8_Suppl):Abstract nr P69.

Evaluating homologous recombination activity in tissues to predict the risk of hereditary breast and ovarian cancer and olaparib sensitivity.

Homologous recombination (HR) repairs DNA damage including DNA double-stranded breaks and alterations in HR-related genes results in HR deficiency. Germline alteration of HR-related genes, such as BRCA1 and BRCA2, causes hereditary breast and ovarian cancer (HBOC). Cancer cells with HR deficiency are sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors and DNA-damaging agents. Thus, accurately evaluating HR activity is useful for diagnosing HBOC and predicting the therapeutic effects of anti-cancer agents. Previously, we developed an assay for site-specific HR activity (ASHRA) that can quantitatively evaluate HR activity and detect moderate HR deficiency. HR activity in cells measured by ASHRA correlates with sensitivity to the PARP inhibitor, olaparib. In this study, we applied ASHRA to lymphoblastoid cells and xenograft tumor tissues, which simulate peripheral blood lymphocytes and tumor tissues, respectively, as clinically available samples. We showed that ASHRA could be used to detect HR deficiency in lymphoblastoid cells derived from a BRCA1 pathogenic variant carrier. Furthermore, ASHRA could quantitatively measure the HR activity in xenograft tumor tissues with HR activity that was gradually suppressed by inducible BRCA1 knockdown. The HR activity of xenograft tumor tissues quantitatively correlated with the effect of olaparib. Our data suggest that ASHRA could be a useful assay for diagnosing HBOC and predicting the efficacy of PARP inhibitors.

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.

Abstract 5596: Exploring BRCA1-Y1853ter and potential therapeutic targets in BRCA1-BRCT mutated cancers

Abstract The breast cancer gene BRCA1 plays a pivotal role as a tumor suppressor gene. Despite the use of poly (ADP-ribose) polymerase inhibitors (PARPi) in treating BRCA1 mutation carriers, the lack of response or the development of acquired drug resistance underscores the pressing need for new therapeutic targets. One intriguing BRCA1 mutation, BRCA1-Y1853ter, characterized by a minimal truncation, has been identified in multiple individuals with Hereditary Breast and Ovarian Cancer (HBOC) syndrome. We have developed a Halo Tag and adenovirus-based system where wild-type BRCA1 (WT BRCA1) and mutant BRCA1 protein complexes can be studied in multiple cell types. Here, we used this system to affinity purify BRCA1 wild-type and mutant complexes, followed by label-free quantitative proteomics to investigate the dynamic interactome variations between WT BRCA1 and BRCA1 mutant. Contrary to the assumed loss of function, our preliminary findings suggest a potential gain of function, as a significant number of candidate proteins exhibit enhanced binding affinity with the mutant BRCA1. We are currently exploring whether these distinct binding characteristics are shared among various BRCA1-BRCT mutants, which may hint at a common tumorigenesis mechanism. Our overarching hypothesis is that identifying a specific binding partner, shared among various BRCA-BRCT mutants, could unveil a novel therapeutic target with broader applicability in treating BRCA1-related malignancies. Citation Format: Jingjing Chen. Exploring BRCA1-Y1853ter and potential therapeutic targets in BRCA1-BRCT mutated cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5596.

Young Women's Perspectives on Being Screened for Hereditary Breast and Ovarian Cancer Risk During Routine Primary Care

PurposeThe U.S. Preventive Services Task Force recommends screening women to identify individuals eligible for genetic counseling based on a priori hereditary breast and ovarian cancer (HBOC) risk (i.e., risk assessment). However, risk assessment has not been widely integrated into primary care. This qualitative study explored young women's views on implementing routine HBOC risk assessment with a focus on equity and patient-centeredness. MethodsWe conducted group discussions with young women (aged 21–40 years) receiving care in an integrated health care system. Discussion groups occurred in two phases and used a modified deliberative approach that included a didactic component and prioritized developing consensus. Twenty women participated in one of three initial small group discussions (phase one). All 20 were invited to participate in a subsequent large group discussion (phase two), and 15 of them attended. FindingsKey themes and recommendations were as follows. Risk assessment should be accessible, contextualized, and destigmatized to encourage participation and reduce anxiety, particularly for women who do not know their family history. Providers conducting risk assessments must be equipped to address women's informational needs, relieve emotionality, and plan next steps after positive screens. Finally, to minimize differential screening uptake, health care systems must prioritize equity in program design and contribute to external educational and outreach efforts. ConclusionYoung women see pragmatic opportunities for health systems to optimize HBOC screening implementation.

Genetic Basis of Breast and Ovarian Cancer: Approaches and Lessons Learnt from Three Decades of Inherited Predisposition Testing.

Germline variants occurring in BRCA1 and BRCA2 give rise to hereditary breast and ovarian cancer (HBOC) syndrome, predisposing to breast, ovarian, fallopian tube, and peritoneal cancers marked by elevated incidences of genomic aberrations that correspond to poor prognoses. These genes are in fact involved in genetic integrity, particularly in the process of homologous recombination (HR) DNA repair, a high-fidelity repair system for mending DNA double-strand breaks. In addition to its implication in HBOC pathogenesis, the impairment of HR has become a prime target for therapeutic intervention utilizing poly (ADP-ribose) polymerase (PARP) inhibitors. In the present review, we introduce the molecular roles of HR orchestrated by BRCA1 and BRCA2 within the framework of sensitivity to PARP inhibitors. We examine the genetic architecture underneath breast and ovarian cancer ranging from high- and mid- to low-penetrant predisposing genes and taking into account both germline and somatic variations. Finally, we consider higher levels of complexity of the genomic landscape such as polygenic risk scores and other approaches aiming to optimize therapeutic and preventive strategies for breast and ovarian cancer.

Brca2(p.T1942fs/+) dissipates ovarian reserve in rats through oxidative stress in follicular granulosa cells

Pathogenic variants of BRCA1/2 constitute hereditary breast and ovarian cancer (HBOC) syndrome, and BRCA1/2 mutant is a risk for various cancers. Whereas the clinical guideline for HBOC patients has been organized for the therapy and prevention of cancer, there is no recommendation on the female reproductive discipline. Indeed, the role of BRCA1/2 pathogenic variants in ovarian reserve has not been established due to the deficiency of appropriate animal models. Here, we used a rat model of Brca2(p.T1942fs/+) mutant of Sprague-Dawley strain with CRISPR-Cas9 editing to evaluate ovarian reserve in females. Fertility and ovarian follicles were evaluated and anti-Müllerian hormone (AMH) was measured at 8–32 weeks of age with a comparison between the wild-type and the mutant rats (MUT). MUT revealed a significantly smaller number of deliveries with fewer total pups. Furthermore, MUT showed a significant decrease in primordial follicles at 20 weeks and a low AMH level at 28 weeks. RNA-sequencing of the ovary at 10 weeks detected acceleration of the DNA damage repair pathway, which was accompanied by oxidative stress-induced DNA double-strand breaks, a decrease in PTEN, and an increase in mTOR in follicular granulosa cells. In conclusion, Brca2(p.T1942fs/+) dissipates primordial follicles via early activation of granulosa cells through oxidative stress, leading to earlier termination of fertility.

Talking about Familial Breast and Ovarian Cancer Risk-Evaluation of a Psychosocial Training Module for Gynecologists in Germany.

Primary care gynecologists are increasingly integrated into the care of patients with hereditary breast and ovarian cancer (HBOC) risks. These physicians should not only have basic genetic knowledge; they should also feel able to sensitively address an increased HBOC risk and deal with emotional, stressful situations in this context. Our project aimed at developing a training module, 'iKNOWgynetics', addressing psychosocial challenges in the context of HBOC care for primary care gynecologists. We developed the psychosocial training module in three phases: first, we conducted an online survey with n = 35 women with a family history of breast or ovarian cancer to assess patients' experiences and needs. Second, based on the results of the needs assessment, we developed the training module. Third, we evaluated the training by assessing physicians' (n = 109) self-efficacy with regard to communication skills in the context of HBOC before and after the training. In the needs assessment, seven psychosocial themes emerged. These themes, complementing a review of the literature, informed the training curriculum. The training was divided into two parts: (1) communicating with women before genetic testing and (2) care co-management for women with HBOC after genetic testing. After the training, participants reported a significant increase in self-efficacy in three domains: communicating empathetically, educating patients in a comprehensible way and dealing with emotionally challenging situations. Our results highlight the relevance of psychosocial issues for patients with HBOC. A genetic literacy training module that integrates aspects of psychosocial care increases physicians' confidence in dealing with emotionally challenging situations before and after their patients' genetic testing. Thus, such trainings may improve the care of women with hereditary cancer risks.

Germline mutational variants of Turkish ovarian cancer patients suspected of Hereditary Breast and Ovarian Cancer (HBOC) by next-generation sequencing

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is characterized by an increased risk of developing breast cancer (BC) and ovarian cancer (OC) due to inherited genetic mutations. Understanding the genetic variants associated with HBOC is crucial for identifying individuals at high risk and implementing appropriate preventive measures. The study included 630 Turkish OC patients with confirmed diagnostic criteria of The National Comprehensive Cancer Network (NCCN) concerning HBOC. Genomic DNA was extracted from peripheral blood samples, and targeted Next-generation sequencing (NGS) was performed. Bioinformatics analysis and variant interpretation were conducted to identify pathogenic variants (PVs). Our analysis revealed a spectrum of germline pathogenic variants associated with HBOC in Turkish OC patients. Notably, several pathogenic variants in BRCA1, BRCA2, and other DNA repair genes were identified. Specifically, we observed germline PVs in 130 individuals, accounting for 20.63% of the total cohort. 76 distinct PVs in genes, BRCA1 (40 PVs), BRCA2 (29 PVs), ATM (1 PV), CHEK2 (2 PVs), ERCC2 (1 PV), MUTYH (1 PV), RAD51C (1 PV), and TP53 (1PV) and also, two different PVs (i.e., c.135–2 A>G p.? in BRCA1 and c.6466_6469delTCTC in BRCA2) were detected in a 34-year-old OC patient. In conclusion, our study contributes to a better understanding of the genetic variants underlying HBOC in Turkish OC patients. These findings provide valuable insights into the genetic architecture of HBOC in the Turkish population and shed light on the potential contribution of specific germline PVs to the increased risk of OC.

The Genetic Paradigm of Hereditary Breast and Ovarian Cancer (HBOC) in the Afro-Caribbean Population.

Differences in tumor biology and genetic predisposition have been suggested as factors influencing overall survival and increased mortality in Black breast and ovarian cancer patients. Therefore, it is key to evaluate genetic susceptibilities in Afro-Caribbean patients because the black population in the US is not homogeneous. Identifying a high incidence of hereditary breast and ovarian cancer (HBOC) in Afro-Caribbean countries can lead to understanding the pattern of inherited traits in US-Caribbean immigrants and their subsequent generations. The paucity of projects studying the genetic landscape in these populations makes it difficult to design studies aimed at optimizing screening and prophylaxis strategies, which in turn, improve survival and mortality rates. This scoping review identifies and categorizes current research on the genetic paradigm of HBOC in the Afro-Caribbean population. We performed an evaluation of the evidence and generated a summary of findings according to preferred reporting items for systematic review and meta-analysis (PRISMA) Extension for Scoping Reviews guidelines. We included articles that assessed the incidence and prevalence of pathologic germline mutations and experience/barriers for genetic testing in Afro-Caribbean Countries and US-Caribbean patients. Our results highlight countries where genetic landscapes remain severely understudied and support recommending multigene testing in Caribbean-born patients. They highlight a need for further research on the genetic paradigm of HBOC in the Afro-Caribbean population to improve genetic testing/counseling and the subsequent adoption of early detection and risk reduction strategies.

Prophylactic Interventions for Hereditary Breast and Ovarian Cancer Risks and Mortality in BRCA1/2 Carriers.

Hereditary breast and ovarian cancers (HBOCs) pose significant health risks worldwide and are mitigated by prophylactic interventions. However, a meta-analysis of their efficacy and the impact of different genetic variants on their effectiveness is lacking. A systematic review and meta-analysis were conducted, adhering to Cochrane guidelines. The review encompassed studies that involved prophylactic interventions for healthy women with BRCA variants, focusing on cancer incidence and mortality outcomes. The Newcastle-Ottawa Scale was used for risk of bias assessment. We pooled the extracted outcomes using random effects models and conducted subgroup analyses stratified by intervention, variant, and cancer types. A total of 21 studies met the inclusion criteria. The meta-analysis revealed that prophylactic interventions significantly reduced cancer risk and mortality. The subgroup analysis showed a greater protective effect for BRCA2 than BRCA1 variant carriers. Risk-reducing surgeries (RRS) were more effective than chemoprevention, with RRS notably reducing cancer risk by 56% compared to 39% for chemoprevention. Prophylactic oophorectomy significantly reduced HBOC risks, while the effect of prophylactic mastectomy and chemoprevention on mortality was less conclusive. Prophylactic interventions significantly reduce the risk of HBOC and associated mortality. This comprehensive analysis provides insights for future economic evaluations and clinical decision-making in HBOC interventions.

NMR-identification of the interaction between BRCA1 and the intrinsically disordered monomer of the Myc-associated factor X.

The breast cancer susceptibility 1 (BRCA1) protein plays a pivotal role in modulating the transcriptional activity of the vital intrinsically disordered transcription factor MYC. In this regard, mutations of BRCA1 and interruption of its regulatory activity are related to hereditary breast and ovarian cancer (HBOC). Interestingly, so far, MYC's main dimerization partner MAX (MYC-associated factor X) has not been found to bind BRCA1 despite a high sequence similarity between both oncoproteins. Herein, we show that a potential reason for this discrepancy is the heterogeneous conformational space of MAX, which encloses a well-documented folded coiled-coil homodimer as well as a less common intrinsically disordered monomer state-contrary to MYC, which exists mostly as intrinsically disordered protein in the absence of any binding partner. We show that when the intrinsically disordered state of MAX is artificially overpopulated, the binding of MAX to BRCA1 can readily be observed. We characterize this interaction by nuclear magnetic resonance (NMR) spectroscopy chemical shift and relaxation measurements, complemented with ITC and SAXS data. Our results suggest that BRCA1 directly binds the MAX monomer to form a disordered complex. Though probed herein under biomimetic in-vitro conditions, this finding can potentially stimulate new perspectives on the regulatory network around BRCA1 and its involvement in MYC:MAX regulation.

Risk-reducing decisions regarding germline BRCA pathogenic variant: focusing on the timing of genetic testing and RRSO

BackgroundIn Japan, the public insurance policy was revised in 2020 to cover hereditary breast and ovarian cancer (HBOC), including genetic testing and surveillance, for patients with breast cancer (BC). Consequently,...

Prevalence of Variants of Uncertain Significance in Patients Undergoing Genetic Testing for Hereditary Breast and Ovarian Cancer and Lynch Syndrome.

Hereditary Breast and Ovarian Cancer (HBOC) and Lynch Syndrome (LS) are the most common inherited cancer syndromes identified with genetic testing. Testing, though, commonly reveals variants of uncertain significance (VUSs). This is a retrospective observational study designed to determine the prevalence of pathogenic mutations and VUSs in patients tested for HBOC and/or LS and to explore the characteristics of the VUS population. Patients 18-80 years old that met NCCN criteria for HBOC and/or LS genetic screening were tested between 2006 and 2020 at Mount Auburn Hospital in Cambridge, Massachusetts. A total of 663 patients were included in the study, with a mean age of 50 years old and 90% being females. Pathogenic mutations were identified in 12.5% and VUSs in 28.3%. VUS prevalence was associated with race (p-value = 0.019), being particularly higher in Asian populations. Patients with a personal history of breast cancer or family history of breast or ovarian cancer were more likely to have a VUS (personal breast: OR: 1.55; CI: 1.08-2.25; family breast: OR: 1.68; CI: 1.08-2.60, family ovarian OR: 2.29; CI: 1.04-5.45). In conclusion, VUSs appear to be detected in almost one third patients tested for cancer genetic syndromes, and thus future work is warranted to determine their significance in cancer development.

Abstract A067: Perceptions and experiences of Black women on hereditary breast and ovarian cancer genetic testing

Abstract Black women experience significant disparities in morbidity and mortality related to hereditary breast and ovarian cancer (HBOC). Early identification of women with HBOC is essential for proactive screening and timely diagnosis but evidence suggests that Black women receive genetic testing for HBOC at lower rates than their White counterparts. To understand Black women’s perspectives on HBOC genetic testing and potential factors influencing this decision, we conducted in-depth qualitative interviews with 107 Black women with a personal or family history of breast or ovarian cancer. Participants were recruited via the networks of patient support organizations and sororities as well as at a family medicine safety net clinic in Jacksonville, FL. Participants frequently expressed a lack of awareness about their family cancer history; many cancer patients stated that they only became aware of extensive family history upon their own diagnosis. Lack of family history sharing was attributed to a culture of silence around medical issues and a desire to protect family members from difficult information. However, most participants indicated a strong desire to understand their own risk of HBOC and were interested in genetic testing. Participants with a personal diagnosis were motivated to undergo HBOC genetic testing to reduce the risk for future generations. Clinical experiences with the offer of HBOC genetic testing were variable, with a few expressing that they had to make repeated inquiries from a provider to understand the relevance of the test to their own health. These findings suggest that investigation into alternative clinical modalities to collect family health history may be beneficial to identify Black women who meet NCCN Guidelines for HBOC testing. In contrast to the literature suggesting hesitancy for HBOC genetic testing, many participants  perceived genetic results as having a positive impact for their medical decision-making and family's health. The development of patient materials and provider education on cultural and social factors that influence the uptake of HBOC genetic testing is also needed.  Citation Format: Kirsten A. Riggan, Michele Halyard, Sarah E. James, Marion Kelly, Daphne Phillips, Megan A. Allyse. Perceptions and experiences of Black women on hereditary breast and ovarian cancer genetic testing [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A067.