Search

Background: Ovarian Cancer is one of the leading causes of cancer death among women worldwide and the therapeutic landscape to treat it is constantly evolving. One of the major points of decision for the treatment choice is the presence of some genomic alterations that could confer sensitivity to the new available therapies including inhibitors of poly (ADP-ribose) polymerase (PARPi) with BRCA1 and 2 genes playing the most important role. Methods and results: We performed the search for any somatic and/or germline alteration in patient's samples by next generation sequencing (NGS). On two patients, our bioinformatic tools allowed us to correctly classify the c.2463_2464delTA BRCA1 new variant. Conclusions: The novel BRCA1 c.2463_2464delTA variant which falls into the DNA Binding Domain (DBD) of the BRCA1 gene can be considered as a variant of clinical significance due to the peculiar family and personal history of patients. [ABSTRACT FROM AUTHOR]

Introduction: Recently, genes involved in homologous recombination repair (HRR) pathway have been extensively studied. However, the landscapes of HRR gene mutations remain poorly defined in Chinese high-risk breast cancer (BC) patients. Our study aims to identify the status of germline and somatic HRR gene mutations and their association with clinicopathological features in these patients. Materials and methods: A total of 100 high-risk BC patients from our institution who underwent paired peripheral blood germline and BC tissues somatic 26 genes next-generation sequencing (NGS) from January 2018 to July 2023 were enrolled for retrospective analysis. Results: Out of 100 high-risk BC patients, 55 (55%) had at least one germline or somatic mutation in HRR genes. Among them, 22% carried germline pathogenic variants (19 BRCA1/2 and 3 non-BRCA genes), 9% harbored somatic pathogenic mutations (3 BRCA1/2 and 6 non-BRCA genes). Among high-risk factors, family history and early onset BC showed a correlation with HRR gene mutations (p < 0.05). BRCA1 germline and HRR gene somatic mutations showed a correlation with TNBC, but BRCA2 germline mutations were associated with Luminal B/HER2-negative BC (p < 0.05). Patients with HRR gene somatic pathogenic variant more likely had a lympho-vascular invasion and distant metastasis (p < 0.05). Conclusion: The prevalence of HRR gene germline and somatic mutations were higher in Chinese BC patients with high risk factors. We strongly recommend that these high-risk BC patients receive comprehensive gene mutation testing, especially HRR genes, which are not only related to genetic consultation for BC patients and provide a theoretical basis for necessary prevention and individualized treatment. [ABSTRACT FROM AUTHOR]

Prostate cancer (PCa) ranks among the most prevalent malignancies in men, with notable associations to Hereditary Breast and Ovarian Cancer Syndrome (HBOC) and Lynch Syndrome, both linked to germline likely pathogenetic variant/pathogenetic variant (LPV/PV) in genes involved in DNA repair. Among these genes, BRCA2 in PCa patients is the most frequently altered. Despite progresses, challenges in BRCA carriers detection persist, with a quarter of PCa cases lacking family history. To address these challenges, a multidisciplinary expert panel from six Italian Scientific Societies, formulated a care pathway to integrate BRCA testing into routine clinical practice in different Italian geographical areas. The development process, promoted by the Italian Society of Uro-Oncology (SIUrO), involved three key stages. A preliminary meeting convened teams from different Italian regions to establish minimal requirements for a mini-counseling program (defined as a pre-test consultation carried out by clinicians responsible of patients' management) and propose care pathway models. At the same time, a comprehensive survey was launched to highlight regional variations in BRCA testing and identify eventual obstacles to testing activities. A subsequent meeting synthesized care pathway proposals and formulated a unified framework, acknowledging regional legislative variations as enriching factors. Lastly, implementation of the unified framework was promoted by the project faculty and identified regional team leaders. Survey results revealed significant regional disparities in BRCA testing, reimbursement policies, and access to genetic counseling. The proposed mini-counseling program outlined essential steps for patient identification, information provision, and multidisciplinary review, aiming to streamline BRCA testing processes. Expert recommendations emphasized offering tumor genetic testing to metastatic PCa patients eligible for PARP-i treatment and outlined criteria for genetic counseling and germline testing. Key considerations included family history and tumor characteristics. In conclusion, the proposed care pathway represents a critical step towards integrating BRCA testing into routine PCa care, aiming to optimize patient management and familial risk assessment within the constraints of the Italian healthcare system. Highlights: • BRCA likely pathogenetic/pathogenetic variants significantly increase the risk of developing prostate cancer (PCa) and enhance sensitivity to PARP-inhibitor treatment, underscoring the clinical need to incorporate genetic testing into the routine management of PCa patients. • A comprehensive survey revealed significant regional disparities in BRCA testing availability, reimbursement policies, and access to genetic counseling across different geographical regions of Italy. • A multidisciplinary panel from six Italian Scientific Societies, led by the Italian Society of Uro-Oncology (SIUrO), developed a care pathway to integrate BRCA testing into routine clinical practice within the Italian healthcare system. [ABSTRACT FROM AUTHOR]

In 2023, a breast cancer risk assessment and a subsequent positive test for the BRCA-2 genetic mutation brought me to the uncomfortable intersection of a longstanding career as an advocate for high-quality medical evidence to support shared patient-provider decision making and a new role as a high-risk patient. My search for studies of available risk-management options revealed that the most commonly recommended approach for women with a ⩾20% lifetime breast cancer risk, intensive screening including annual mammography and/or magnetic resonance imaging beginning at age 25–40 years, was supported only by cancer-detection statistics, with almost no evidence on patient-centered outcomes—mortality, physical and psychological morbidity, or quality of life—compared with standard screening or a surgical alternative, bilateral risk-reducing mastectomy. In this commentary, I explore parallels between the use of the intensive screening protocol and another longstanding women's health recommendation based on limited evidence, the use of hormone therapy (HT) for postmenopausal chronic disease prevention, which was sharply curtailed after the publication of the groundbreaking Women's Health Initiative trial in 2002. These declines in HT utilization were followed by marked decreases in breast cancer incidence, providing a compelling lesson on the critical importance of a solid evidentiary basis for women's health decisions. Known harms accompanying the benefits of breast screening—overdiagnosis, psychological effects, and mammography-associated radiation-exposure risks—make empirical measurement of patient-centered outcomes essential. Yet, published research on intensive screening of women at high breast cancer risk has largely ignored these outcomes, leaving patients, providers, and guideline developers lacking the evidence needed for best practice. Outcomes research is both feasible and urgently needed to inform care decisions and health policy for this patient population. [ABSTRACT FROM AUTHOR]

Simple Summary: The role of detecting germline BRCA mutation (gBRCAm) has evolved over the years from its primary use in early detection, risk reduction and cascade testing to becoming an important predictive marker that influences cancer treatment. In the treatment of breast cancer, ovarian cancer, prostate and pancreatic cancer, gBRCAm plays a crucial role in predicting the benefit of poly (adenosine diphosphate [ADP]—ribose) polymerase (PARP) inhibitors (PARPis). In this review article, we will examine the evidence for the latest predictive and therapeutic approaches in BRCA-associated cancers with a focus on the use of PARPis alone or in combination with other treatments in gBRCAm. The mechanisms of PARPi resistance, the cost-effectiveness of PARPis as a therapy as well as predictive markers beyond gBRCAm will also be discussed. Background: Identifying patients with gBRCAm is crucial to facilitate screening strategies, preventive measures and the usage of targeted therapeutics in their management. This review examines the evidence for the latest predictive and therapeutic approaches in BRCA-associated cancers. Clinical Description: Data supports the use of adjuvant olaparib in patients with gBRCAm high-risk HER2-negative breast cancer. In advanced gBRCAm HER2-negative breast cancer, the PARPis talazoparib and olaparib have demonstrated benefit over standard chemotherapy. In ovarian cancer, olaparib, niraparib or rucaparib can be used as monotherapy in frontline maintenance. Olaparib and bevacizumab as a combination can also be used as frontline maintenance. In the relapsed platinum-sensitive setting, olaparib, niraparib and rucaparib are effective maintenance options in BRCAm patients who are PARPi naive. Both olaparib and rucaparib are effective options in BRCAm metastatic castrate-resistant prostate cancer (mCRPC). Evidence also exists for the benefit of PARPi combinations in mCRPC. In metastatic pancreatic cancer, olaparib can be used in gBRCAm patients who are responding to platinum chemotherapy. However, there may be a development of PARPi resistance. Understanding the pathophysiology that contributes to such resistance may allow the development of novel therapeutics. Combination therapy appears to have promising results in emerging trials. Seeking avenues for subsidised genetic testing can reduce the total costs of cancer management, leading to improve detection rates. Conclusion: Identifying breast, ovarian, pancreatic and prostate cancer patients with gBRCAm plays a crucial predictive role in selecting those who will benefit significantly from PARPi therapy. The use of PARPi in gBRCAm HBOC-related cancers has resulted in significant survival benefits. Beyond BRCA1/2, HRR gene assessment and the consideration of other cancer predisposition syndromes may allow more patients to be eligible for and benefit from targeted therapies. [ABSTRACT FROM AUTHOR]

Aim: To investigate current management of advanced epithelial ovarian cancer (OC) in the UK. Materials & methods: A cross-sectional survey with 55 healthcare professionals involved in the care of OC patients was conducted via telephone/videoconference in March/May 2023. Results: Respondents reported that homologous recombination deficiency (HRD) status and brca mutations were routinely tested before planning maintenance treatment. All respondents agreed that cytoreductive surgery should be considered at first recurrence, and 65% recommended using the Descriptive Evaluation of Preoperative Selection Criteria for Operability in Recurrent Ovarian Cancer (DESKTOP) III criteria to guide secondary cytoreduction. Platinum responders typically receive poly (ADP-ribose) polymerase inhibitor maintenance therapy, regardless of HRD status. Conclusion: Respondents reinforce that most primary OC patients in the UK have known HRD and BRCA mutation status, and the role of secondary cytoreduction is increasingly recognized. Plain Language Summary The study aimed to explore how advanced epithelial ovarian cancer is managed in the United Kingdom. In early 2023, a survey was conducted with 55 healthcare professionals who care for ovarian cancer patients. Findings showed that testing for homologous recombination deficiency (HRD) and BRCA mutations is standard before planning maintenance treatment. Most healthcare professionals agreed on considering surgery at the first recurrence and 65% recommended using specific criteria for this secondary surgery. Patients who respond to platinum treatments usually receive maintenance therapy. Overall, HRD and BRCA status are well known for most primary ovarian cancer patients, and secondary surgery is increasingly recognized as important. Article highlights The OC-NOW survey, including UK-based healthcare professionals (HCPs) involved in the secondary care management of ovarian cancer, was conducted using telephone/videoconference structured interviews between March and May 2023. Most respondents were from England (85.5%), and 69% were gynecological, medical or clinical oncologists. Surveyed HCPs reported that homologous recombination deficiency (HRD) status and BRCA mutation were routinely tested before planning maintenance treatment. All respondents agreed that cytoreductive surgery should be considered at first recurrence and indicated that access to anti-angiogenic/vascular endothelial growth factor inhibitor therapy is important at first recurrence. The HCPs reported that patients who responded to platinum typically received poly (ADP-ribose) polymerase inhibitor maintenance therapy, regardless of HRD status. At first relapse, the DESKTOP III criteria were used by most HCPs (65.5%) to select candidates for secondary cytoreduction (SC), with up to 30% of patients who responded to platinum-based therapies deemed eligible for SC in 82.8% of centers. [ABSTRACT FROM AUTHOR]

Breast cancer (BRCA) is one of the pivotal causes of female death worldwide. And the morbidity and mortality of breast cancer have increased rapidly. Immune checkpoints are important to maintain immune tolerance and are regarded as important therapeutic targets. However, research for BRCA were limited to single immune checkpoint-related gene (ICG) and few studies have systematically explored expression profile of Immune checkpoint-related genes or attempted to construct a prognostic gene risk model based on immune checkpoint-related genes. We identified immune checkpoint-related differentially expressed genes (DEGs) in BRCA and normal breast tissues from TCGA database. A 7-gene signature was created by utilizing the univariate Cox regression model with least absolute shrinkage and selection operator (LASSO) Cox regression method. In addition, we conducted a nomogram to predict the prognostic significance. This tool enables quantitative prediction of patient prognosis, serving as a valuable reference for clinical decision-making, thereby improving patient outcomes. Relationships between our risk model and clinical indicators, TME (Tumor Microenvironment), immune cell infiltration, immune response and drug susceptibility were investigated. A set of in vitro cell assays was conducted to decipher the relationship between MAP2K6 and proliferation, invasion, migration, colony formation and apoptosis rate of breast cancer cells. As a result, we established a prognostic model composed of seven ICGs in BRCA. Based on the median risk score, BRCA patients were equally assigned into two groups of high- and low-risk. High-risk BRCA patients have poorer OS (overall survival) than low-risk patients. In addition, there were remarkable differences between these two groups in clinicopathological features, TME, immune cell infiltration, immune response and drug susceptibility. The results of GO and KEGG analyses indicated that DEGs between the high- and low-risk groups were involved in immune-related biological processes and pathways. GSEA analysis also showed that a number of immune-related pathways were notably enriched in the low-risk group. Finally, results of cell-based assays indicated that MAP2K6 may play a pivotal role in the initiation and progression of breast cancer as a tumor suppressor gene. In conclusion, we created a novel ICG signature that has the potential to predict the survival and drug sensitivity of BRCA patients. Furthermore, this study indicated that MAP2K6 may serve as a novel target for BRCA therapy. [ABSTRACT FROM AUTHOR]

Aim: Pancreatic Neuroendocrine tumors (pNETs) are a heterogeneous group of neoplasms whose tumor biology is still little known. Thanks to next-generation sequencing, pathogenic mutations in base-excision-repair MUTYH gene and homologous recombination genes CHEK2 and BRCA2 seem to have a role in the development of pNETs. Research design & methods: We assumed that Homologous Recombination Deficiency (HRD) could be a critical pathogenetic mechanism for pNETs. We evaluated the HR status in a case series of 33 patients diagnosed with pNET at the Modena Cancer Center using the AmoyDX HRD Focus assay. Results: The AmoyDx test did not identify any HRD-positive patients (median GSS equal to 1.1, positive score: >50), and no pathogenic BRCA variants were detected. However, thanks to the SNP analysis, a consistent number of partial or complete single-copy deletions or duplications in several chromosomes. Conclusion: The AmoyDX HRD focus assay performed well on pancreatic samples, despite being originally designed for ovarian cancer and used on samples stored for over a year. Larger studies are needed to further assess the role of HRD assays in pNETs research. Article highlights Pancreatic Neuroendocrine Tumors (pNETs) are rare, heterogeneous neoplasms with limited genomic insights, particularly regarding homologous recombination deficiency (HRD). This study evaluates HRD status in a cohort of patients with pNETs, using the AmoyDX HRD Focus Assay, a cost-effective alternative to other commercially available HRD tests. The AmoyDX assay demonstrated high feasibility in analyzing formalin-fixed paraffin-embedded (FFPE) tissue samples older than 12 months, with a success rate of 93.75%. None of the 30 analyzed pNET samples tested positive for HRD, and no pathogenic variants of BRCA1 or BRCA2 were found. Three patients exhibited BRCA variants of uncertain significance (VUS). Chromosome 11 abnormalities, particularly in the MEN1 gene locus, were detected in 50% of patients, confirming the potential role of gene deletions in pNET tumorigenesis. This study contributes to the limited literature on HRD in pNETs and supports the application of HRD testing in expanding our molecular understanding of these rare tumors. [ABSTRACT FROM AUTHOR]

Cancer-associated gene fusions serve as a potential source of highly immunogenic neoantigens. In this study, we identified fusion proteins from fusion genes and extracted fusion peptides to accurately predict Breast cancer (BRCA) neo-antigen candidates by high-throughput artificial intelligence computation. Firstly, Deepsurv was used to evaluate the prognosis of patients, providing a landscape of prognostic fusion genes in BRCA. Next, AGFusion was utilized to generate full-length fusion protein sequences and annotate functional domains. Advanced neural networks and Transformer-based analyses were implemented to predict the binding of fusion peptides to 112 types of HLA, thereby forming a new immunotherapy candidates' library of BRCA neo-antigens (n = 7791, covering 88.41% of patients). Among them, 15 neo-antigens were validated and factually translated into mass spectrometry data of BRCA patients. Finally, AlphaFold2 was applied to predict the binding sites of these neo-antigens to MHC (HLA) molecules. Notably, we identified a prognostic neoantigen from the TBC1D4–COMMD6 fusion that significantly improves patient prognosis and extensively binds to 16 types of HLA alleles. These highly immunogenic and tumor-specific neoantigens offer emerging targets for personalized cancer immunotherapies and act as prospective predictors for tumor survival prognosis and responses to immune checkpoint therapies. [ABSTRACT FROM AUTHOR]

Between December 2014 and May 2020, the United States Food and Drug Administration approved 9 indications for poly (ADP-ribose) polymerase (PARP) inhibitor use in ovarian cancer. Between June 2022 and September 2022, all 3 indications for PARP inhibitor treatment of recurrent ovarian cancer were withdrawn. Between November 2022 and September 2023, all 3 indications for PARP inhibitor maintenance therapy in recurrent ovarian cancer were restricted. The 3 indications for PARP inhibitor maintenance therapy in newly diagnosed advanced ovarian cancer are unchanged. This article reviews the timelines and data leading to regulatory changes for PARP inhibitor use in ovarian cancer in the United States. [ABSTRACT FROM AUTHOR]

Ovarian carcinosarcoma in hereditary breast and ovarian cancer syndrome is rare. A 43‐year‐old woman with a family history of prostate and uterine or ovarian cancer had an 8‐cm mass in the right ovary. Although computed tomography suggested peritoneal dissemination to the Douglas pouch, she wanted to preserve her fertility; therefore, she underwent a right salpingo‐oophorectomy. Histopathological diagnosis was carcinosarcoma consisting of high‐grade serous carcinoma and sarcomatous components, including cartilage. Three weeks later, she underwent radical surgery. The disease was classified as advanced stage IIIB (FIGO 2014). A germline BRCA2 pathogenic variant was identified. After postoperative adjuvant chemotherapy, maintenance therapy with a poly(adenosine diphosphate‐ribose) polymerase (PARP) inhibitor was continued for 25 months without recurrence. A detailed examination of a mass in her left breast at her first visit revealed a ductal carcinoma in situ. PARP inhibitors may be effective as maintenance therapy for advanced ovarian carcinosarcoma with germline BRCA mutations. [ABSTRACT FROM AUTHOR]

Abstract Cancer-associated gene fusions serve as a potential source of highly immunogenic neoantigens. In this study, we identified fusion proteins from fusion genes and extracted fusion peptides to accurately predict Breast cancer (BRCA) neo-antigen candidates by high-throughput artificial intelligence computation. Firstly, Deepsurv was used to evaluate the prognosis of patients, providing a landscape of prognostic fusion genes in BRCA. Next, AGFusion was utilized to generate full-length fusion protein sequences and annotate functional domains. Advanced neural networks and Transformer-based analyses were implemented to predict the binding of fusion peptides to 112 types of HLA, thereby forming a new immunotherapy candidates’ library of BRCA neo-antigens (n = 7791, covering 88.41% of patients). Among them, 15 neo-antigens were validated and factually translated into mass spectrometry data of BRCA patients. Finally, AlphaFold2 was applied to predict the binding sites of these neo-antigens to MHC (HLA) molecules. Notably, we identified a prognostic neoantigen from the TBC1D4–COMMD6 fusion that significantly improves patient prognosis and extensively binds to 16 types of HLA alleles. These highly immunogenic and tumor-specific neoantigens offer emerging targets for personalized cancer immunotherapies and act as prospective predictors for tumor survival prognosis and responses to immune checkpoint therapies.

Risk reduction salpingo-oophorectomy (RRSO) is usually performed in women with hereditary breast and ovarian cancer (HBOC) syndrome for BRCA1 and BRCA2 gene mutation carriers, resulting in surgical menopause, which is more associated with a high risk of cardiovascular and metabolic disease than in premenopausal and natural menopausal women. This study assessed the prevalence of cardiovascular and metabolic outcomes in women who underwent salpingo-oophorectomy as a preventive measure against HBOC. This meta-analysis assessed prevalence rates for four metabolic/cardiovascular conditions: myocardial infarction, hypertension, hypercholesterolemia, and type 2 diabetes mellitus. DerSimonian and Laird random-effects models were applied to all analyses, with 95% confidence interval (CI). Heterogeneity was assessed with I². We used OpenMeta Analyst software for statistical analysis. A total of five retrospective studies and one observational study involving 1,320 patients were included. The average body mass index (BMI) was 25.97 kg/m2 and the average waist circumference was 87.94 cm. The analysis across a mean 4.94-year follow-up revealed prevalence rates for acute myocardial infarction of 1.5% (95% CI 0.3–2.7; P = 0.077; I²=56.25%), hypertension of 28% (95% CI 6.9–49.1; P < 0.001; I2 = 98.42%), hypercholesterolemia of 27.2% (95% CI 6.8–47.6; P < 0.001; I²=98.67%), and type 2 diabetes mellitus of 3.3% (95% CI 1.1–5.5; P < 0.001; I²=82.44%). Our findings suggest that there is no marked increase in cardiovascular risk among women with HBOC undergoing RRSO. [ABSTRACT FROM AUTHOR]

Abstract Background Breast cancer is the most frequent cancer among women. Genetics are the main risk factor for breast cancer. Statistics show that 15–25% of breast cancers are inherited among those with cancer-prone relatives. BRCA1, BRCA2, TP53, CDH1, PTEN, and STK11 are the most frequent genes for familial breast cancer, which occurs 80% of the time. In rare situations, moderate-penetrance gene mutations such CHEK2, BRIP1, ATM, and PALB2 contribute 2–3%. Methods A search of the PubMed database was carried out spanning from 2005 to July 2024, yielding a total of 768 articles that delve into the realm of familial breast cancer, concerning genes and genetic syndromes. After exclusion 150 articles were included in the final review. Results We report on a set of 20 familial breast cancer -associated genes into high, moderate, and low penetrance levels. Additionally, 10 genetic disorders were found to be linked with familial breast cancer. Conclusion Familial breast cancer has been linked to several genetic diseases and mutations, according to studies. Screening for genetic disorders is recommended by National Comprehensive Cancer Network recommendations. Evaluation of breast cancer candidate variations and risk loci may improve individual risk assessment. Only high- and moderate-risk gene variations have clinical guidelines, whereas low-risk gene variants require additional investigation. With increasing use of NGS technology, more linkage with rare genes is being discovered.

Abstract The BRCA1/2 pathogenic variant (PV) increases the risk of breast and ovarian cancer; thus, risk-reducing salpingo-oophorectomy (RRSO) and mastectomy (RRM) are recommended. We evaluated the effects of the graphical display of cancer risk compared with those of numerical presentation on the decision-making for risk-reducing (RR) surgery. A total of 471 women representing the Korean population were recruited. The lifetime risk of breast/ovarian cancer were given numerically followed by graphically in hypothetical BRCA1/2 PV-positive cases. Subsequently, the study participants were asked for their willingness to undergo RRSO/RRM. When the ovarian cancer risk was shown as 44.0%, the percentage of study participants who chose RRSO was 41.0% after numerical presentation versus 39.9% after graphical display, of which the difference was not significant. When the breast cancer risk was presented as 72.0%, 30.4% of the participants opted for RRM under numerical presentation, whereas this increased to 38.6% under graphical display, of which the difference was significant (p

Abstract The somatic BRCA1 or BRCA2 Pathogenic Variant (PV)/Likely PV (LPV) from Next Generation Sequencing (NGS) is the most important biomarker for PARP inhibitor use and maintenance-targeted therapies. A discrepancy in the detection rates of BRCA1 and BRCA2 PV/LPV was identified among the NGS platforms. The objective of this study was to compare the somatic BRCA results from two distinct platforms using the same cohort and to identify the causes of these differences. Patients with epithelial ovarian cancer who concurrently underwent tumor NGS using two different platforms between January 2022 and June 2023 were included in this study. The two platforms used were in-house tumor NGS (Illumina NextSeq 550Dx, SureSelectXT library kit, and datasets from 1000 Genomes, ESP6500, ExAC, and ClinVar) and GreenPlan homologous recombination deficiency (HRD) test (Illumina NextSeq 550Dx, customized Twist Bioscience library kit, and datasets from COSMIC and OncoKB). The results of somatic mutations in BRCA1 and BRCA2 were compared between the two platforms. Of the 118 patients, 11.9% (n = 14) exhibited a discordant interpretation of BRCA1 or BRCA2 between the two platforms. Eleven patients (9.3%) exhibited negative results in the in-house platform but positive results (eight seven as PV of BRCA1, one as PV of BRCA2, one as LPV of BRCA1, and two as LPV of BRCA2) in the GreenPlan HRD test, while three patients (2.6%) had positive BRCA pathogenic variants (two as PV of BRCA1 [c.3340G > T, c.5152 + 3 A > C], one as LPV of BRCA2 [c.8174G > T], and one as LPV of BRCA1 [c.5017_5019delCAC]) in the in-house platform but a negative result in the GreenPlan HRD test. The discordance rate of somatic BRCA1 or BRCA2 mutations from different platforms was approximately 12%. In the case of the strong implication of BRCA PV/LPV with a negative result with one genetic test, different platforms could be considered in limited cases. Careful interpretation and further studies for the cross-validation of gene analysis platforms are needed.

Background: The homologous recombination deficiency (HRD) score serves as a promising biomarker to identify patients who are eligible for treatment with PARP inhibitors (PARPi). Previous studies have suggested a 3-biomarker Genomic Instability Score (GIS) threshold of ≥ 42 as a valid biomarker to predict response to PARPi in patients with ovarian cancer and breast cancer. However, the GIS threshold for prostate cancer (PCa) is still lacking. Here, we conducted an exploratory analysis to investigate an appropriate HRD score threshold and to evaluate its ability to predict response to PARPi in PCa patients. Methods: A total of 181 patients with metastatic castration-resistant PCa were included in this study. Tumor tissue specimens were collected for targeted next-generation sequencing for homologous recombination repair (HRR) genes and copy number variation (CNV) analysis. The HRD score was calculated based on over 50,000 single-nucleotide polymorphisms (SNP) distributed across the human genome, incorporating three SNP-based assays: loss of heterozygosity, telomeric allelic imbalance, and large-scale state transition. The HRD score threshold was set at the last 5th percentile of the HRD scores in our cohort of known HRR-deficient tumors. The relationship between the HRD score and the efficacy in 16 patients of our cohort who received PARPi treatment were retrospectively analyzed. Results: Genomic testing was succeeded in 162 patients. In our cohort, 61 patients (37.7%) had HRR mutations (HRRm). BRCA mutations occurred in 15 patients (9.3%). The median HRD score was 4 (ranged from 0 to 57) in the total cohort, which is much lower than that in breast and ovarian cancers. Patients who harbored HRRm and BRCA or TP53 mutations had higher HRD scores. CNV occured more frequently in patients with HRRm. The last 5th percentile of HRD scores was 43 in the HRR-mutant cohort and consequently HRD high was defined as HRD scores ≥43. In the 16 patients who received PARPi in our cohort, 4 patients with a high HRD score achieved an objective response rate (ORR) of 100% while 12 patients with a low HRD score achieved an ORR of 8.3%. Progression-free survival (PFS) in HRD high patients was longer compared to HRD low patients, regardless of HRRm. Conclusions: A HRD score threshold of 43 was established and preliminarily validated to predict the efficacy of PARPi in this study. Future studies are needed to further verify this threshold.

Background: Breast cancer (BRCA), the hormone related malignant tumor, is well-known for poor prognosis. ZNF208 mainly acts as a transcription factor in various tumors, and the single nucleotide polymorphisms (SNPs) of ZNF208 are related to telomere length. Nevertheless, its role in breast tumorigenesis is largely unknown. Methods: We systematically investigated the gene expression, prognostic value, and promoter methylation of ZNF208 in BRCA with Gene Expression Profiling Interactive Analysis (GEPIA) and DNA Methylation Interactive Visualization Database (DNMIVD). Meanwhile, we clarified the association of ZNF208 with tumor-infiltrating immune cells (TICs) from Tumor Immune Estimation Resource (TIMER). Furthermore, we determined the biological process and functional enrichment from Cancer single-cell state atlas (CancerSEA). Finally, we verified our results with prognostic analysis and immunohistochemistry (IHC) assay. Results: We discovered that ZNF208 was downregulated in breast cancer, and low expression of ZNF208 predicted worse prognosis of BRCA patients. The promoter methylation level of ZNF208 was obviously increased, and ZNF208 was associated with TlCs in BRCA. In addition, ZNF208 could inhibit the metastasis and invasion biological processes, and regulate the MAPK and RAS signaling pathways in BRCA. Conclusion: Our findings illustrate that ZNF208 can function as a tumor suppressor and predict prognosis of breast cancer. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy has emerged as an effective, personalized treatment for certain patients, particularly for those with hematological malignancies. However, its efficacy in breast cancer has been marginal—perhaps due to cold, immune-excluded, or immune-desert tumors. Natural killer T (NKT) cells play a critical role in cancer immune surveillance and are reduced in cancer patients. Thus, we hypothesized that NKT cells could serve as a surrogate marker for immune function. In order to assess which breast cancer patients would likely benefit from immune cell-based therapies, we have developed a quantitative method to rapidly assess NKT function using stimulation with artificial antigen presenting cells followed by quantitative real-time PCR for IFN-γ. We observed a significant reduction in the percentage of circulating NKT cells in breast cancer patients, compared to healthy donors; however, the majority of patients had functional NKT cells. When we compared BC patients with highly functional NKT cells, as indicated by high IFN-γ induction, to those with little to no induction, following stimulation of NKT cells, there was no significant difference in NKT cell number between the groups, suggesting functional loss has more impact than physical loss of this subpopulation of T cells. In addition, we assessed the percentage of tumor-infiltrating lymphocytes and PD-L1 expression within the tumor microenvironment in the low and high responders. Further characterization of immune gene signatures in these groups identified a concomitant decrease in the induction of TNFα, LAG3, and LIGHT in the low responders. We next investigated the mechanisms by which breast cancers suppress NKT-mediated anti-tumor immune responses. We found that breast cancers secrete immunosuppressive lipids, and treatment with commonly prescribed medications that modulate lipid metabolism, can reduce tumor growth and restore NKT cell responses. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to assess homologous recombination deficiency (HRD) status and its correlation with carboplatin treatment response in early triple-negative breast cancer (TNBC) patients. Methods: Tumor tissues from 225 consecutive TNBC patients were evaluated with an HRD panel and homologous recombination-related (HRR) gene expression data. HRD positivity was defined as a high HRD score and/or BRCA1/2 pathogenic or likely pathogenic mutation. Clinicopathological factors, neoadjuvant treatment response, and prognosis were analyzed with respect to HRD status in these TNBC patients. Results: HRD positivity was found in 53.3% of patients and was significantly related to high Ki67 levels (P = 0.001). In patients who received neoadjuvant chemotherapy, HRD positivity (P = 0.005) or a high HRD score (P = 0.003) was significantly associated with a greater pathological complete response (pCR) rate, especially in those treated with carboplatin-containing neoadjuvant regimens (HRD positivity vs. negativity: 50.00% vs. 17.65%, P = 0.040). HRD positivity was associated with favorable distant metastasis-free survival (hazard ratio HR 0.49, 95% confidence interval CI 0.26–0.90, P = 0.022) and overall survival (HR 0.45, 95% CI 0.20–0.99, P = 0.049), irrespective of carboplatin treatment. Conclusion: TNBC patients with high HRDs had high Ki67 levels and BRCA mutations. HRD-positive TNBC patients treated with carboplatin had a higher pCR rate. Patients with HRD positivity had a better prognosis, irrespective of carboplatin treatment, warranting further evaluation. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common cancer among women worldwide, and its incidence rate is still increasing, especially among younger women. Nationally, it constitutes one-fifth of all cancer cases and almost 40% of all female cancers. With a median age of 51 years, breast cancer is diagnosed at least a decade earlier, and at more advanced stages compared to Western societies. Hereditary cancers account for 10% or more of all cancer burden worldwide. With expanded indications, increased number of genes tested, and significant decline in cost of testing, such proportion will probably increase. Individuals with pathogenic variants of BRCA1 and BRCA2 are at higher risk of breast, ovarian, pancreatic and many other cancers. Over the past two decades, several highly penetrant cancer-susceptibility genes were identified across almost all tumor sites, thus increasing the need for comprehensive cancer genetic programs that address the testing process, counselling patients and at-risk family members, and then deal with all testing results and its consequences. In addition to its important role in preventing more cancers in index patients themselves and among their close relatives, identification of pathogenic or likely pathogenic variants, mostly in BRCA1 or BRCA2 , may inform therapeutic decisions in common cancers including breast, ovarian, prostate and pancreatic cancers. In this manuscript, we describe the experience of a comprehensive cancer center, in a resource-limited country in establishing a comprehensive clinical cancer genetics program that can serve as an example for others who share similar demographic and financial restrains. [ABSTRACT FROM AUTHOR]

Patients with metastatic prostate cancer (mPCa) with BReast CAncer gene (BRCA) mutations benefit from targeted treatments (eg, olaparib). In addition, family members of affected patients have increased risk of hereditary cancers and benefit from early detection and prevention. International guidelines recommend genetic testing in mPCa; however, the value for money of testing patients with mPCa and cascade testing of blood-related family members has not been assessed. In this context, we evaluated the cost-effectiveness of germline BRCA testing in patients with mPCa followed by cascade testing of first-degree relatives (FDRs) of mutation carriers. We conducted a cost-utility analysis of germline BRCA testing using 2 scenarios: (1) testing patients with mPCa only and (2) testing patients with mPCa and FDRs of those who test positive. A semi-Markov multi–health-state transition model was constructed using a lifetime time horizon. The analyses were performed from an Australian payer perspective. Decision uncertainty was characterized using probabilistic analyses. Compared with no testing, BRCA testing in mPCa was associated with an incremental cost of AU$3731 and a gain of 0.014 quality-adjusted life-years (QALYs), resulting in an incremental cost-effectiveness ratio of AU$265 942/QALY. Extending testing to FDRs of variant-positive patients resulted in an incremental cost-effectiveness ratio of AU$16 392/QALY. Probability of cost-effectiveness at a willingness-to-pay of AU$75 000/QALY was 0% in the standalone mPCa analysis and 100% in the cascade testing analysis. BRCA testing when performed as a standalone strategy in patients with mPCa may not be cost-effective but demonstrates significant value for money after the inclusion of cascade testing of FDRs of mutation carriers. • Testing men with metastatic castration-resistant prostate cancer for BReast CAncer gene mutations informs their treatment options with poly–adenosine diphosphate ribose polymerase (PARP) inhibitors; furthermore, testing family members of the men who harbor the mutation could alert them to their risk of developing hereditary cancers. The value of extending genetic testing to family members (ie, cascade testing) is unknown. • Previous economic evaluations of PARP inhibitors in metastatic castration-resistant prostate cancer have overlooked the need for genetic testing to appropriately target treatment. This article is the first evaluation of codependent technologies (germline testing and olaparib therapy) in metastatic prostate cancer (mPCa). • Our evaluation suggests that germline BReast CAncer gene testing-guided treatment with PARP in mPCa is not cost-effective when restricted to the patient with mPCa, yet provides significant value for money after the inclusion of cascade testing of first-degree relatives of mutation carriers. [ABSTRACT FROM AUTHOR]

Purpose of Review: To describe current and future strategies to reduce the burden of ovarian cancer through prevention. Recent Findings: Current strategies in genetic testing are missing a substantial number of individuals at risk, representing a missed opportunity for ovarian cancer prevention. Past efforts at screening and early detection have thus far failed to improve ovarian cancer mortality, and novel techniques are needed. Surgical prevention is highly effective, but surgical menopause from oophorectomy has significant side effects. Novel surgical strategies aimed at reducing risk while minimizing these harms are currently being studied. Summary: To maximize ovarian cancer prevention, a multi-pronged approach is needed. We propose that more inclusive and accurate genetic testing to identify more individuals at risk, novel molecular screening and early detection, surgical prevention that maximizes quality of life while reducing risk, and broader adoption of targeted and opportunistic salpingectomy will together reduce the burden of ovarian cancer. [ABSTRACT FROM AUTHOR]

Genetic testing in patients with ovarian carcinoma (OC) is crucial, as around 10–15% of these women have a genetic predisposition to OC. Although guidelines have recommended universal germline testing for all patients with OC for a decade, implementation has proved challenging, thus resulting in low germline-testing rates (around 30–50%). Many new initiatives to improve genetic-testing rates have emerged, but most have been carried out at the local level, leading to differences in workflows within and between countries. We present an example of a nationwide implementation project that has successfully led to a uniform, high-quality genetic-testing workflow for women with OC. Nationwide multidisciplinary meetings generated consensus on the preferred workflow for OC genetic testing: the "Tumor-First" workflow. This workflow means starting by testing the tumor DNA for the presence of pathogenic variants in OC-risk genes, thus providing a prescreen to germline testing while yielding information on the effectiveness of treatment with PARP inhibitors. This new workflow efficiently stratifies genetic counseling and germline testing and reduces healthcare costs. Although challenging, the nationwide implementation of this workflow was successful, resulting in tumor-DNA testing rates exceeding 80%. In this article, we present our structured implementation approach, illustrate our implementation strategies—which were tailored to identified factors important to implementation—and share the lessons learned from the Tumor-First implementation project. This knowledge could facilitate the future implementation of workflows aimed at optimizing the recognition of hereditary cancers. [ABSTRACT FROM AUTHOR]

Objective: This study analyzes the development, benefits, trial evidence, and price of new breast cancer drugs with US Food and Drug Administration (FDA) approval. Methods: We identified 26 drugs with 42 FDA-approved indications for early and metastatic breast cancer (2000–2023). Data were collected from FDA labels, clinicaltrials.gov, and Medicare and Medicaid. Overall survival (OS) and progression-free survival (PFS) hazard ratios (HRs) and tumor response's relative risk (RR) alongside objective response rate (ORR) were meta-analyzed. Results: The median development time for breast cancer drugs was 7.8 years (95% CI 6.2–10.8). 26% of treatments were considered innovative ("first-in-indication") with 88% acting via a targeted mechanism. 64% were small molecules, 19% antibodies, and 18% antibody-drug conjugates. 38% were approved for HR + and 31% for HER2 + breast cancer. 6 indications were for early and 36 for metastatic breast cancer. Indications utilized FDA's special programs: orphan (2%), fast track (24%), accelerated approval (19%), priority review (74%), breakthrough therapy (44%). Approval was predominantly supported by phase 3 trials (88%) of randomized controlled design (66%), enrolling a median of 585 patients (IQR 417–752) at 181 centers (IQR 142–223) across 19 countries (IQR 17–20). New drugs' HR were 0.78 for OS (95% CI 0.74–0.82) and 0.59 for PFS (95% CI 0.54–0.64) with a RR for tumor response of 1.61 (95% CI 1.46–1.76). Median improvements of OS were 2.8 months (IQR 1.8–5.8) and PFS were 4.4 months (IQR 2.2–7.1). In single-arm trials, the average ORR was 31% (95% CI 10–53). In meta-regressions, the correlation between OS/PFS was 0.34 (p = 0.031) and OS/response was 0.01 (p = 0.435). 60% of treatments had a 'high-value' ESMO-MCBS score with 14% demonstrating improvements in quality of life. The median price was $16,013 per month (95% CI 13,097–17,617). There was no association between prices and patient benefit. The median value per life year gained was $62,419 (IQR 25,840–86,062). Conclusions: Over the past two decades, the development of innovative and effective drugs transformed the treatment landscape for breast cancer patients. Yet, investigators and regulators must safeguard that highly-priced new drugs demonstrate improvements in patient-centered clinical endpoints: overall survival and quality of life. [ABSTRACT FROM AUTHOR]

Pancreatic adenocarcinoma remains a malignancy with a grim prognosis and scarce personalized treatment options. Pathogenic variants of DNA damage repair (DDR) genes are emerging as molecular targets, as they confer a higher sensitivity to DNA-damaging agents. This study aimed at assessing the activity of chlorambucil as salvage therapy in metastatic pancreatic cancer patients bearing a germline pathogenetic variant or variant of uncertain significance on a DDR-related gene. Platinum-pretreated metastatic pancreatic cancer patients harbouring a germline variant on a DDR gene received chlorambucil at a daily oral dose of 6 mg/m2 for 42 every 56 days for the first cycle and for 14 every 28 days for the following cycles, until disease progression or unacceptable toxicity. The primary endpoint was 6-month progression-free survival rate (PFS-6). Median progression-free survival (PFS) and overall survival (OS) were secondarily described. Twenty patients were enrolled between December 2020 and September 2022. PFS-6 was 5%, median PFS and OS were 1.6 months and 3.0 months, respectively. Grade-3 adverse events were observed in 25% of patients, while no Grade-4 toxicity was reported. Single agent chlorambucil did not show sufficient signal of activity to warrant its further investigation in metastatic pancreatic cancer patients bearing a DDR-related germline alteration. [ABSTRACT FROM AUTHOR]

The somatic BRCA1 or BRCA2 Pathogenic Variant (PV)/Likely PV (LPV) from Next Generation Sequencing (NGS) is the most important biomarker for PARP inhibitor use and maintenance-targeted therapies. A discrepancy in the detection rates of BRCA1 and BRCA2 PV/LPV was identified among the NGS platforms. The objective of this study was to compare the somatic BRCA results from two distinct platforms using the same cohort and to identify the causes of these differences. Patients with epithelial ovarian cancer who concurrently underwent tumor NGS using two different platforms between January 2022 and June 2023 were included in this study. The two platforms used were in-house tumor NGS (Illumina NextSeq 550Dx, SureSelectXT library kit, and datasets from 1000 Genomes, ESP6500, ExAC, and ClinVar) and GreenPlan homologous recombination deficiency (HRD) test (Illumina NextSeq 550Dx, customized Twist Bioscience library kit, and datasets from COSMIC and OncoKB). The results of somatic mutations in BRCA1 and BRCA2 were compared between the two platforms. Of the 118 patients, 11.9% (n = 14) exhibited a discordant interpretation of BRCA1 or BRCA2 between the two platforms. Eleven patients (9.3%) exhibited negative results in the in-house platform but positive results (eight seven as PV of BRCA1, one as PV of BRCA2, one as LPV of BRCA1, and two as LPV of BRCA2) in the GreenPlan HRD test, while three patients (2.6%) had positive BRCA pathogenic variants (two as PV of BRCA1 [c.3340G > T, c.5152 + 3 A > C], one as LPV of BRCA2 [c.8174G > T], and one as LPV of BRCA1 [c.5017_5019delCAC]) in the in-house platform but a negative result in the GreenPlan HRD test. The discordance rate of somatic BRCA1 or BRCA2 mutations from different platforms was approximately 12%. In the case of the strong implication of BRCA PV/LPV with a negative result with one genetic test, different platforms could be considered in limited cases. Careful interpretation and further studies for the cross-validation of gene analysis platforms are needed. [ABSTRACT FROM AUTHOR]

Growing evidence has demonstrated the role of mutations of tumor biomarkers in diagnosing and treating epithelial ovarian cancer. This review aims to analyze recent literature on the correlation between tumor biomarkers and chemotherapy in nonmucinous ovarian cancer, providing suggestions for personalized treatment approaches. An extensive literature search was conducted to identify relevant studies and trials. BRCA1/2 mutations are central in homologous recombination repair deficiency (HRD) in ovarian cancer, but several other genetic mutations also contribute to varying cancer risks. While the role of MMR testing in ovarian cancer is debated, it is more commonly linked to non-serous ovarian cancer, often associated with Lynch syndrome. A significant proportion of ovarian cancer patients have HRD, affecting treatment decisions in both first-line (especially in advanced stages) and second-line therapy due to HRD's connection with platinum-based therapy and PARP inhibitors' response. However, validated genetic tests to identify HRD have not yet been universally implemented. There is no definitive therapeutic algorithm for advanced ovarian cancer, despite ongoing efforts and multiple proposed tools. Future research should focus on expanding the utility of biomarkers, reducing resistance, and increasing the actionable biomarker pool. [ABSTRACT FROM AUTHOR]

Due to the widespread use of cancer genetic testing in gastrointestinal cancer, the BRCA1/2 genetic mutation has been identified in biliary tract cancer as well as pancreatic cancer. Niraparib is a poly(ADP-ribose) polymerase (PARP) inhibitor, and PARP inhibitors exert their cytotoxicity against cancer cells in the context of homologous recombination deficiency, such as BRCA mutations, via the mechanism of synthetic lethality. The aim of this phase II NIR-B trial is to evaluate the efficacy and safety of niraparib for patients with unresectable advanced or recurrent biliary tract cancer, pancreatic cancer or other gastrointestinal cancers with germline or somatic BRCA1/2 mutations revealed by genetic testing. The primary end point is an investigator-assessed objective response rate in each cohort. Clinical Trial Registration:jRCT2011200023 (ClinicalTrials.gov) Plain Language Summary A clinical study to confirm the efficacy and safety of niraparib for people with advanced biliary tract, pancreatic and other abdominal cancers with the BRCA genetic mutation: the NIR-B trial. BRCA gene is involved in repairing DNA injury and plays an important role in cancer growth. Cells with a mutation in the BRCA gene cannot repair DNA using a method called homologous recombination repair. Niraparib is part of a class of drugs called 'PARP inhibitors' that inhibit enzymes called 'PARP' involved in repairing DNA injury, and has shown efficacy against cancers with BRCA gene mutations. BRCA gene mutations are infrequent but have been found in a variety of cancers. The NIR-B trial is a clinical trial to evaluate the efficacy and safety of niraparib for people with advanced biliary tract, pancreatic and other abdominal cancers with BRCA gene mutations. Executive summary Background Recent comprehensive genomic profiling testing has revealed therapeutic target molecules. It has been proven that the BRCA1/2 genetic mutation has been identified in biliary tract and pancreatic cancer. Niraparib is classified as a poly(ADP-ribose) polymerase (PARP) inhibitor, and PARP inhibitors exert cytotoxicity against cancer cells in the context of homologous recombination deficiency, such as BRCA mutations, by the mechanism of synthetic lethality. Niraparib has been shown to be selective for PARP1/2 as well as more cytotoxic than other PARP inhibitors owing to its PARP-trapping activity. NIR-B trial This NIR-B trial is a multicenter, open-label, single-arm, three-cohort and basket-type phase II study, with the aim to evaluate the efficacy and safety of niraparib for patients with unresectable advanced or recurrent biliary tract cancer, pancreatic cancer and other gastrointestinal cancers with germline or somatic BRCA1/2 mutations observed on genetic testing. Eligible patients will be enrolled at six trial sites in Japan. Patients with a body weight ≥77 kg and platelet count ≥150,000/mm3 will be administered 300 mg of niraparib orally once daily, while patients with a body weight <77 kg or platelet count <150,000/mm3 will be administered 200 mg of niraparib orally once daily. The primary end point is an investigator-assessed objective response rate (ORR) in each cohort with a threshold ORR of 10% and an expected ORR of 35%. The key secondary end points are progression-free survival, overall survival, disease control rate, duration of response and safety. Pretreatment tumor tissue and serial circulating tumor DNA will be collected and analyzed to investigate the resistance mechanisms and to provide a clinically meaningful biomarker that can be used to identify and implement treatment changes. The trial was initiated in January 2021, and enrollment is ongoing. [ABSTRACT FROM AUTHOR]

The BRCA1/2 pathogenic variant (PV) increases the risk of breast and ovarian cancer; thus, risk-reducing salpingo-oophorectomy (RRSO) and mastectomy (RRM) are recommended. We evaluated the effects of the graphical display of cancer risk compared with those of numerical presentation on the decision-making for risk-reducing (RR) surgery. A total of 471 women representing the Korean population were recruited. The lifetime risk of breast/ovarian cancer were given numerically followed by graphically in hypothetical BRCA1/2 PV-positive cases. Subsequently, the study participants were asked for their willingness to undergo RRSO/RRM. When the ovarian cancer risk was shown as 44.0%, the percentage of study participants who chose RRSO was 41.0% after numerical presentation versus 39.9% after graphical display, of which the difference was not significant. When the breast cancer risk was presented as 72.0%, 30.4% of the participants opted for RRM under numerical presentation, whereas this increased to 38.6% under graphical display, of which the difference was significant (p < 0.0075). The average levels of the cancer risk which study participants consider RR surgery were 57.1% for ovarian cancer and 60.6% for breast cancer. This suggests that the impacts of different formats of risk communication on decision about RRSO or RRM may be different by the absolute levels of ovarian or breast cancer. [ABSTRACT FROM AUTHOR]

Background: Management of pathogenic variants in high penetrance genes related to breast cancer (BC), such as BRCA1 and BRCA2, are well established. However, moderate penetrance mutations are understudied. We aim to compare risk reduction decision-making patterns in patients with a moderate penetrance BC-related genetic mutations, without a prior BC diagnosis. Patients and Methods: Female patients aged ≥ 18 years who tested positive for a BRCA1/2, high penetrance, or moderate penetrance mutation related to BC between 1996 and 2023 without a concurrent or prior BC diagnosis were retrospectively identified from a single academic center's database. Groups were stratified by mutation type: BRCA1/2 mutations (BRCA1, BRCA2), high penetrance mutations (HPM; CDH1, PALB2, PTEN, STK11, TP53), or moderate penetrance mutations (MPM; ATM, BARD1, CHEK2, NF1, RAD51C, RAD51D). Demographics and clinical outcomes were compared. Results: A total of 528 patients met the inclusion criteria, with 66% (n = 350) having a BRCA1/2 mutation, 8% (n = 44) having HPM, and 25% (n = 134) having MPM; the median follow-up was 56.0 months. In our cohort, 20.9% of patients with BRCA mutations, 9.1% with HPM, and 7.5% with MPM chose to undergo risk-reducing mastectomies (RRM). Within the moderate penetrance cohort, patients who chose to undergo RRM were younger at the time of genetic testing (39.4 vs. 47.5 years, p = 0.03) and had a higher number of family members with BC (2 vs. 1, p = 0.05). Conclusions: Our findings provide insights into the demographic characteristics and family history of patients with moderate penetrance mutations and those who pursue risk-reducing surgery. [ABSTRACT FROM AUTHOR]

The singular BRCA1/2 mutational landscape of Asturias is updated 10 years after the first study. We analyzed BRCA1 and BRCA2 pathogenic variants in 1653 index cases. In total, 238 families were identified to carry a pathogenic variant, 163 families in BRCA1 and 75 families in BRCA2. This yielded a prevalence rate of 14.4%. Seven recurrent variants were found accounting for 55% of the cases. Among them, three are widely distributed (BRCA1 c.211A>G, c.470_471del and c.3331_3334del) and four had been reported as novel in Asturias: two in BRCA1 (c.1674del and c.2901_2902dup) and two in BRCA2 (c.2095C>T and c.4040_4035delinsC). A common haplotype was established for all recurrent variants indicating a shared ancestral origin. Three splicing analyses are shown: BRCA1:c.5152+3A>C and BRCA1:c.5333‐3T>G that lead to skipping of exon 18, and 22 respectively, and BRCA1:c.5278‐1G>T giving rise to two transcripts, one lacking exon 21 (p.Ille1760Glyfs*60) and one lacking the first 8 nucleotides of exon 21 (p.Phe1761Asnfs*14), supporting pathogenicity for these variants. [ABSTRACT FROM AUTHOR]

Whether or not women who harbor a germline pathogenic variant ('mutation') in the BRCA1 or BRCA2 genes are at elevated risk of developing endometrial cancer is yet to be determined. We conducted a prospective analysis of 4959 BRCA mutation carriers with no prior history of cancer (except for breast or melanoma) and an intact uterus. After a mean of 6.7 years of follow-up there were 38 incident cases of endometrial cancer diagnosed; 30 among BRCA1 carriers and eight among BRCA2 carriers. The mean age at diagnosis was 58.4 years (range 46.8–76.1). The majority were of the endometrioid subtype (n = 16), followed by mixed endometroid and serous (n = 4), serous (n = 3) or clear cell (n = 1) (missing = 13). The cumulative incidence from age 40 to age 70 was 3.4% for BRCA1 carriers and was 1.6% for BRCA2 mutation carriers. Prior tamoxifen use was associated with a significant two–fold increased risk (HR = 2.24; 95% CI 1.10–4.55). There was no significant association between exogenous hormone use, oophorectomy, smoking or BMI at age 40 and risk (P ≥ 0.32). Compared to the general population, we observed higher rates of endometrial cancer among young BRCA1 mutation carriers; however, lifetime risks were similar. Women with prior tamoxifen exposure were at a significantly increased risk. These findings were based. on a small number of incident cases and require confirmation with additional follow-up of our aging cohort. • We prospectively evaluated whether endometrial cancer is part of the BRCA - spectrum. • Cumulative incidence was 3.4% for BRCA1 and 1.6% for BRCA2 mutation carriers. • Tamoxifen use was a significant risk factor BRCA -endometrial cancer. • With few incident cases, we are not able to conclusively confirm an increased risk. • Hysterectomy at the time of preventive ophorectomy should be individualized. [ABSTRACT FROM AUTHOR]

To describe extension of ovarian tissue beyond visible and National Comprehensive Cancer Network recommended margins among patients with BRCA mutations undergoing minimally invasive risk-reducing salpingo-oophorectomy. A prospective study of patients with BRCA mutations who underwent minimally invasive risk-reducing bilateral salpingo-oophorectomy was conducted. Patient enrollment occurred between October 2021 and 2023. Tissue specimens were analyzed according to the Sectioning and Extensively Examining the Fimbriated End protocol. Twenty women with BRCA mutations were prospectively enrolled. All patients underwent minimally invasive surgery with 70% undergoing concurrent hysterectomy (n = 14). Approximately half of these procedures were performed with robotic assistance (n = 9, 45%). One patient was admitted overnight (5%); the other nineteen were discharged on the day of surgery (95%). One patient experienced a major complication and required readmission (5%). Extension of ovarian tissue beyond the visible ovary was noted on pathologic examination of six specimens (30%). In one patient this was observed on the left (17%), in three on the right (50%), and in two bilateral extension (33%) was noted. The distance ovarian stroma extended microscopically beyond the visible ovary was between 2 and 14 mm, with a median of 5 mm. Among patients with microscopic extension of ovarian tissue, the majority (n = 5, 83%) had a BRCA2 mutation. In women with BRCA mutations undergoing risk-reducing minimally invasive surgery, approximately one third had microscopic extension of ovarian stroma beyond the visible ovary. Current guidelines which recommend resection of at least 20 mm of tissue beyond the visible ovary are likely adequate in this population. • In women with BRCA undergoing risk-reducing minimally invasive surgery, one third had ovarian stroma beyond the visible ovary • Distance ovarian stroma extended microscopically beyond the visible ovary was between 2 and 14 mm, with a median of 5 mm • Current guidelines which recommend resection of 20 mm of tissue beyond the visible ovary are adequate in this population [ABSTRACT FROM AUTHOR]

Purpose: We evaluated the prevalence of homologous recombination deficiencies (HRD) to determine the efficacy of different techniques and clinical characteristics of patients. Methods: This retrospective study included patients with metastatic prostate cancer who underwent molecular testing at our hospital between 2016 and 2022. We used tumor tissue, ctDNA, and lymphocytes for somatic or germline testing. We analyzed the clinical characteristics and survival outcomes. Results: 144 patients were tested (113 somatic, 21 germline, and 10 both). Technical issues prevented the analysis of 23 prostatic samples (18.7%). 12 (8.3%) patients had HRD. BRCA2 was the most frequent mutation (66.7%). Patients with HRD were younger (57.5 years). Patients with BRCA mutations had poorer survival (31.9 vs 56.3 months, p = 0.048). Conclusion: In our institution, 8.3% of the patients had HRD. Tumor tissue analysis failed in 18.7% of tests. ctDNA analysis is an alternative detection method. BRCA mutations are correlated with poor prognosis. [ABSTRACT FROM AUTHOR]

Background: Determining the status of breast cancer susceptibility genes (BRCA) is crucial for guiding breast cancer treatment. Nevertheless, the need for BRCA genetic testing among breast cancer patients remains unmet due to high costs and limited resources. This study aimed to develop a Bi-directional Self-Attention Multiple Instance Learning (BiAMIL) algorithm to detect BRCA status from hematoxylin and eosin (H&E) pathological images. Methods: A total of 319 histopathological slides from 254 breast cancer patients were included, comprising two dependent cohorts. Following image pre-processing, 633,484 tumor tiles from the training dataset were employed to train the self-developed deep-learning model. The performance of the network was evaluated in the internal and external test sets. Results: BiAMIL achieved AUC values of 0.819 (95% CI [0.673–0.965]) in the internal test set, and 0.817 (95% CI [0.712–0.923]) in the external test set. To explore the relationship between BRCA status and interpretable morphological features in pathological images, we utilized Class Activation Mapping (CAM) technique and cluster analysis to investigate the connections between BRCA gene mutation status and tissue and cell features. Significantly, we observed that tumor-infiltrating lymphocytes and the morphological characteristics of tumor cells appeared to be potential features associated with BRCA status. Conclusions: An interpretable deep neural network model based on the attention mechanism was developed to predict the BRCA status in breast cancer. Keywords: Breast cancer, BRCA, deep learning, self-attention, interpretability. [ABSTRACT FROM AUTHOR]

Background Increased access to and indications for genetic testing will lead to more women undergoing risk-reducing salpingo-oophorectomy (RRSO), with a potential impact on sexual function. Aim Our objective was to prospectively investigate (1) sexual function in women with pathogenic variant (PV) in BRCA1/2 genes, before and 1 year after RRSO, and to compare with a healthy age-matched control group and (2) to study if testosterone levels correlate with sexual functioning after RRSO. Methods A prospective observational follow-up study of 43 BRCA1/2 -PV carriers planned for RRSO and 73 healthy-age matched controls. Data including personal medical history, the Female Sexual Function Index (FSFI) and blood samples for analysis of testosterone by tandem mass spectrometry and free androgen index (FAI) were collected before and 1 year after surgery or at inclusion (controls). Outcomes Sexual function and testosterone levels following RRSO. Results Median age in the RRSO group was 42 years at baseline, 55.8% were premenopausal and 53.5% had a history of breast cancer. The RRSO group had significantly lower median FSFI total score (P  < .001), lower scores of all 6 FSFI domains (P  < .001), as well as a higher proportion of female sexual dysfunction (FSD) (P  < .001) compared to the control group at 1 year after surgery. In the RRSO group, users of menopausal hormone therapy (MHT) had a significantly higher median FSFI total score compared with the nonusers both at baseline (P  = .023) and follow-up (P  = .010). The proportion of FSD was significantly higher in the non-MHT group at both baseline (P  = .041) and follow-up (P  = .009). FAI was significantly lower in the RRSO group when compared to the controls at 1-year follow-up (P  = .041); however, no significant correlations between testosterone levels and FSFI scores were found. Clinical implications The results highlight the need to counsel BRCA1/2 -PV carriers before RRSO and offer a structured follow-up and support addressing sexual function and impact of MHT use. Strengths and Limitations The main strength of this study is its prospective design with age-matched controls. Limitation is a small sample size. Conclusion Our findings show that sexual function deteriorated 1 year after RRSO independent of testosterone levels, and the proportion with impaired sexual function was higher compared to healthy age-matched controls. [ABSTRACT FROM AUTHOR]