Hereditary Breast-ovarian Cancer Research Articles

Abstract PO5-08-08: Tumor Registry Guided Genetic Testing: Opportunities Unlocked

Abstract Introduction With the expansion of guidelines for germline genetic testing, more patients are eligible for testing. Unfortunately, many remain untested. Testing is critical, as patients with pathogenic variants (and their families) can benefit from more aggressive screening and preventative strategies, as well as targeted therapies (e.g., poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors) if cancer does occur. Objectives To study the prevalence of Hereditary Breast Ovarian Cancer (HBOC) genetic testing eligibility and uptake among cancer patients from the tumor registry at the Medical University of South Carolina (MUSC) in order to identify a group of living patients who require testing now. Methods This Quality Improvement study included patients 18 years of age or older diagnosed with breast, ovarian/fallopian/primary peritoneal, pancreas and prostate cancers between 1991 and 2021 as reported to the MUSC Tumor Registry. Each patient was evaluated using the latest National Comprehensive Cancer Network (NCCN) criteria for breast-ovarian genetic testing (Excluding family history criteria, which were not available in the tumor registry). Using our genetic testing database, we also determined which had had testing. We describe the prevalence of genetic testing performed vs the number of patients that would benefit from testing under the newest guidelines. Results Patients identified as eligible for testing included 399 breast cancer patients, all 544 ovarian/fallopian/primary peritoneal cancer patients, all 1534 pancreas cancer patients and 872 prostate cancer patients. Reported testing of eligible patients was low (breast: 35%, Ovarian: 33%, pancreas: 4%, and prostate cancer: 6%). Of eligible patients not tested, 310 patients with breast cancer, 343 patients with ovarian/fallopian/primary peritoneal cancer, 717 patients with pancreas cancer and 763 patients with prostate cancer, are alive and eligible for testing (2133 patients) Discussion Using Tumor Registry data plus genetic testing data allowed us to detect a large number of living patients with cancer that would be eligible for HBOC genetic testing. This is despite the fact that this approach underestimates the number of patients that would benefit from further testing as it does not include family history and other factors. A similar approach for colorectal or other cancers will yield additional patients. Conclusion Most cancer patients eligible for breast ovarian genetic testing have not been tested. There is an opportunity to use Tumor Registry and genetic testing data to identify a large number of living patients who can be approached for testing. As we showed in our study, by adopting updated cancer genetic testing guidelines, there is increased opportunity to detect more patients that would benefit from such testing. In our study this benefit is shown especially in the prostate and pancreas cancer groups. Next steps will be to determine how best to notify and make testing available to these patients. Table 1. Testing Status Comparison Assessing Genetic Testing Rates Using Tumor Registry Among Eligible Patients with Breast, Ovarian/Fallopian/Primary Peritoneum, Pancreas and Prostate cancer as per the New Testing Guidelines Citation Format: Kevin Hughes, Antoine Finianos, Kiersten Meeder. Tumor Registry Guided Genetic Testing: Opportunities Unlocked [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 PO5-08-08.

Cascade screening in HBOC and Lynch syndrome: guidelines and procedures in a UK centre.

In the 33years since the first diagnostic cancer predisposition gene (CPG) tests in the Manchester Centre for Genomic Medicine, there has been substantial changes in the identification of index cases and cascade testing for at-risk family members. National guidelines in England and Wales are usually determined from the National Institute of healthcare Evidence and these have impacted on the thresholds for testing BRCA1/2 in Hereditary Breast Ovarian Cancer (HBOC) and in determining that all cases of colorectal and endometrial cancer should undergo screening for Lynch syndrome. Gaps for testing other CPGs relevant to HBOC have been filled by the UK Cancer Genetics Group and CanGene-CanVar project (web ref. https://www.cangene-canvaruk.org/ ). We present time trends (1990-2020) of identification of index cases with germline CPG variants and numbers of subsequent cascade tests, for BRCA1, BRCA2, and the Lynch genes (MLH1, MSH2, MSH6 and PMS2). For BRCA1/2 there was a definite increase in the proportion of index cases with ovarian cancer only and pre-symptomatic index tests both doubling from 16 to 32% and 3.2 to > 8% respectively. A mean of 1.73-1.74 additional family tests were generated for each BRCA1/2 index case within 2 years. Overall close to one positive cascade test was generated per index case resulting in > 1000 risk reducing surgery operations. In Lynch syndrome slightly more cascade tests were performed in the first two years potentially reflecting the increased actionability in males with 42.2% of pre-symptomatic tests in males compared to 25.8% in BRCA1/2 (p < 0.0001).

Hereditary breast ovarian cancer syndrome

Hereditary breast ovarian cancer syndrome

Germline mutations of 4567 patients with hereditary breast-ovarian cancer spectrum in Thailand

Multi-gene panel testing has led to the detection of pathogenic/likely pathogenic (P/LP) variants in many cancer susceptibility genes in patients with breast-ovarian cancer spectrum. However, the clinical and genomic data of Asian populations, including Thai cancer patients, was underrepresented, and the clinical significance of multi-gene panel testing in Thailand remains undetermined. In this study, we collected the clinical and genetic data from 4567 Thai patients with cancer in the hereditary breast-ovarian cancer (HBOC) spectrum who underwent multi-gene panel testing. Six hundred and ten individuals (13.4%) had germline P/LP variants. Detection rates of germline P/LP variants in breast, ovarian, pancreatic, and prostate cancer were 11.8%, 19.8%, 14.0%, and 7.1%, respectively. Non-BRCA gene mutations accounted for 35% of patients with germline P/LP variants. ATM was the most common non-BRCA gene mutation. Four hundred and thirty-two breast cancer patients with germline P/LP variants (80.4%) met the current NCCN genetic testing criteria. The most common indication was early-onset breast cancer. Ten patients harbored double pathogenic variants in this cohort. Our result showed that a significant proportion of non-BRCA P/LP variants were identified in patients with HBOC-related cancers. These findings support the benefit of multi-gene panel testing for inherited cancer susceptibility among Thai HBOC patients. Some modifications of the testing policy may be appropriate for implementation in diverse populations.

&lt;I&gt;BRCA1/2&lt;/I&gt; mutation spectrum in Armenian patients with breast and ovarian cancers

The aim of the study was to compare the spectra of pathogenic BRCA1 and BRCA2 variants in patients with hereditary breast cancer (BC) and ovarian cancer (OC) from two groups of ethnic Armenians: Yerevan and cities of southern Russia.Material and Methods. 106 BC patients from the V.A. Fanardjian National Centre of Oncology (Yerevan, Republic of Armenia) and 117 BC and OC patients of Armenian origin who were referred to the Petrov National Medical Centre of Oncology (St. Petersburg, Russia) from several cancer centers of Russia (Krasnodar, Sochi, Pyatigorsk) were included into the study. The coding sequences of BRCA1 and BRCA2 genes were analyzed by the method of targeted high-throughput sequencing.Results. Pathogenic variants of BCRA1 and BCRA2 genes were detected in 16/106 (BRCA1: n=9, BRCA2: n=7; 15%) BC patients from Yerevan. The only recurrent mutation was the BRCA1 nonsense variant c.5444G&gt;A [W1815X], accounting for 44% of all pathogenic alleles identified. In patients of Armenian origin from Russia, pathogenic BRCA1/2 variants were detected in 16/117 (14%) individuals (BRCA1: n=6, BRCA2: n=10). The proportion of samples with mutations was 13% in the group of BC patients and 19% in the group of OC patients. 75% of pathogenic alleles were represented by five recurrent mutations: BRCA1 c.2649_2650insGGCA, BRCA2 c.2808_2808_2811delACAA, BRCA1 c.4065_4068delTCAA, BRCA2 c.9027delT and BRCA2 c.8437G&gt;T [G2813X]. The independent origin of the pathogenic BRCA2 c.2808_2808_2811delACAA variant in Armenian and non-Armenian patients was shown.Conclusion. A significant difference in the spectrum of BRCA1/2 mutations between Armenian patients from Yerevan and patients from southern regions of Russia was found. This should be taken into account when developing diagnostic programs.

Results of a randomized controlled trial of a decision support intervention for disclosing maternal BRCA genetic test results to children and adolescents.

Evaluate the impact of a targeted family communication intervention for mothers undergoing genetic counseling and testing (GCT) for BRCA gene alterations. Following BRCA GCT, mothers (N = 204; M age = 45 y) were randomized to either a control condition (self-help print materials) or intervention (printed decision support guide, based on behavioral decision making theory in health care) for supporting choices about disclosing maternal genetic test results to children and adolescents. Behavioral assessments were administered prior to maternal GCT and after receipt of results: primary outcomes were maternal disclosure to children and parent-child communication quality. Mothers in the intervention were > 2x likely to disclose their BRCA test results to their children compared to those in the control condition (odds ratio [OR] = 2.33, 95% confidence interval [CI] = 1.06, 5.10; p = .04). This effect was moderated by children's ages: mothers of preteens (<13 y) assigned to the intervention were >3x likely to disclose their results (OR = 3.74, 95% CI = 1.49, 9.41; p = .005). In adjusted models, intervention was also associated with favorable changes in the quality of parent-child communication (95% CI = 0.30, 9.00; p < .05). Decision support improves parent-child communication outcomes about GCT for hereditary breast-ovarian cancer. This trial is among the first to empirically evaluate the outcomes of a behavioral intervention to support family communication of maternal BRCA risk information to children.

Cascade testing in Italian Hereditary Breast Ovarian Cancer families: a missed opportunity for cancer prevention?

Cascade testing in Italian Hereditary Breast Ovarian Cancer families: a missed opportunity for cancer prevention?

Abstract 14175: Risk of Cardiovascular Disease in Women Who Underwent Salpingo-Oophorectomy to Prevent Hereditary Breast Ovarian Cancer: A Systematic Review and Meta-Analysis

Introduction: Hereditary breast and ovarian cancer (HBOC) syndrome is defined by family history and identification of germline pathogenic variants (PVs). In particular, the mutations in BRCA1/2 (BRCAm) increased approximately 44% and 17% risk of ovarian cancer or fallopian tube cancer and 72% and 69% risk of breast cancer. Risk-reducing salpingo-oophorectomy (RRSO), the physiologic removal of the ovaries and fallopian tubes, effectively reduces the risk of ovarian cancer by 80-95% in women with HBOC. Hypothesis: Is performing a RRSO in women with HBOC or BRCAm associated with the development of cardiac and metabolic diseases? Aims: To assess the risk of myocardial infarction (MI)/coronary artery disease (CAD), hypertension, diabetes mellitus (DM), and hypercholesterolemia/dyslipidemia among women with HBOC or BRCA1/2 mutation after performing RRSO. Methods: We searched in PubMed, Scopus, and Web of Science databases for studies that assessed cardiovascular and metabolic events following RRSO in women with HBOC or BRCAm. Statistical analysis was performed using RStudio v4.4.2 using the DerSimonian and Laird random-effects model. Heterogeneity was examined using the Cochran Q test and I 2 statistics. Significance for heterogeneity was set at a p-value&lt;0.01. Results: Five studies were included with a total of 1320 patients. Among them, 956/1320 (72.4%) had BRCAm: 469 (35.5%) had BRCA1 and 400 (30.3%) had BRCA2. The majority of patients (928;69.3%) had RRSO&lt;50 years, and the mean age of the study sample was 54.3 years (41.45-57, 2.35). The incidence of MI events was reported in 18/1126 patients (1.4%, 95% Cl, 5-2.3%; I 2 =40.15%). Most common metabolic comorbidities were hypercholesterolemia. Observed in 170/994 women (19.6%, 95% Cl, 4.6-34.6%; I 2 =97.88%), hypertension, in 125/994 women (12.9%, 95% Cl, 4-21.8%; I 2 =96.93%), and DM, reported in 46/1320 patients (3%, 95% Cl, 1.2-4.7%; I 2 =75.41%). Conclusions: This meta-analysis provides evidence to support that patients with HBOC or BRCAm who undergo RRSO have an increased risk of developing heart and metabolic diseases. Larger studies with longer follow-up are required to further explore these associations.

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

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

Germline BRCA 1 Positive Breast Ovarian Cancer Syndrome

Background: BRCA1 (Beast Cancer gene 1) and BRCA2 (Breast Cancer gene 2) are genes that produce proteins that help repair damaged DNA. Mutations in these genes predispose the person to a substantiable risk of developing breast and ovarian cancers among others. Approximately 10 to 15% of all cases of epithelial ovarian cancer and les than 10 % of Breast cancers are caused by a mutation in the BRCA1 or BRCA2 genes, which when occurs together results in hereditary breast ovarian cancer syndrome. Case Presentation: This case report presents the clinical course of a 57-year-old female patient who presented with a mass in her right breast in June 2022. The patient’s past medical history is significant with a diagnosis of triple-negative non-metastatic left breast cancer that was treated with surgery followed by adjuvant chemotherapy containing Doxorubicin and Taxanes with loco-regional radiotherapy in May 2009. On June 2022 (later after 13 years) patient noticed a Rt breast mass and was evaluated further. A mammography showed an ill-defined micro lobulated lesion 4 cm from the nipple, measuring 43 x 27 mm with a few microcalcifications. Later, an ultrasound right breast confirmed the presence of an ill-defined lesion in her right breast with no significant axillary nodes, True-cut biopsy performed on October 26th, 2022 revealed invasive triple negative ductal carcinoma. Staging work up with Positron Emission tomography and computerized tomography scan showed in addition to the right breast mass, an ovarian mass with peritoneal deposits. This prompted a peritoneal biopsy which confirmed a high grade primary serous carcinoma of ovary. Additionally, BRCA1/2 germline testing showed a positive BRCA1 germline mutation. Following this, the patient was started on neoadjuvant keynote 522 protocol specifically with Epirubicin, Cyclophosphamide, Paclitaxel carboplatin with pembrolizumab. As of the date of reporting she has completed CARBOPLATIN-TAXOL and is now on the third ........

Healthcare utilization among individuals diagnosed with hereditary breast-ovarian cancer syndrome through a universal germline genetic testing program.

10604 Background: Most individuals with Hereditary Breast-Ovarian Cancer Syndrome (HBOC) are unaware of their risk. Criteria-based testing will not close this gap as it fails to identify ~50% of mutation carriers. Universal germline testing (GT) in oncology stands to identify more mutation carriers and advance cancer control. However, the clinical utility of universal germline testing is unknown. Methods: The City of Hope INSPIRE study offers all consented patients GT for cancer susceptibility (155 genes) and actionable disorders (59 genes). We used an informatics approach to evaluate healthcare utilization for patients found to have BRCA1/ BRCA2 mutations. We queried codified data in our electronic data warehouse before and after GT (post testing interval: 1-29 months). We binned care as possibly related/ not related to HBOC based on NCCN guidelines. Results: Of 10,814 patients who had GT, 217 (2%) had a pathogenic/ likely pathogenic mutation in either BRCA1 or BRCA 2. The demographic distribution of mutation carriers was: white (n = 162, 75%), Asian (n = 28, 13%), Hispanic (n = 65, 30%); female (n = 184, 85%); the mean age was 54 yrs. Eighty-four percent (n = 182) had cancer, including 64% with cancers associated with HBOC (breast 40%, ovarian 13%, pancreatic 3%, 5% prostate, and 0.5% melanoma) and 18% with cancers that are not associated with HBOC. Eighty-three percent of patients had procedures, imaging, and/or therapy potentially related to the BRCA mutation. Eighty-six percent of cancer patients had potentially related care. As expected, use of breast MRI, mammography, MRCP, mastectomy, and bilateral salpingo-oophorectomy (BSO) occurred both before and after testing, with most utilization occurring prior to GT and likely related to cancer staging and treatment. The exception was MRCP which occurred more often following GT (0.6% before vs 1.2% after). Fifty-one (28%) cancer patients received PARP inhibitors. In the unaffected cohort, 67% of patients received possibly related care. Use of mammography was higher prior to GT (7% vs 2%). Consistent with the fact that some unaffected patients were likely known mutation carriers prior to consent, mastectomy was higher prior to GT (5% vs 0%) and BSO was equivalent before and after GT (1.8%). Use of breast MRI (9% vs 15%), MRCP (1.8% vs 3%) and transvaginal US (5% vs 7%) were all higher after GT. Conclusions: We found high levels of relevant healthcare utilization for BRCA mutation carriers in the context of universal GT. However, this initial informatics approach is limited because key information on prior GT and motivations for surgery (e.g., therapeutic vs prophylactic mastectomy) are not adequately captured in codified data. Codified EHR queries will need to be augmented by text mining and/or manual chart review to fully capture care and assess the clinical utility of system-wide genetic care delivery interventions.

Assessment of Knowledge and Attitude of Breast and Ovarian Cancer Patients Regarding Hereditary Breast-Ovarian Cancer Syndrome at a Tertiary Cancer Institute: A Cross-Sectional Observational Study

Abstract Introduction Hereditary breast and ovarian cancer (HBOC) syndrome affects a significant proportion of our breast and ovarian cancer patients. Mutations in genes, for example, BRCA1 and 2, confer a high risk of acquiring certain malignancies, including breast cancer in both men and women, and ovarian cancer in women. Mutation carriers provide a unique opportunity for healthcare professionals to intensively screen and detect malignancy at an early and curable stage. But, patient awareness and acceptance are the keys to the success of these strategies. Objective There is a need to assess the awareness of the patients in this field as the patients come from varied backgrounds, and differ in their socioeconomic profiles, educational backdrop, and cultures. In this study, done prior to establishing our cancer genetics clinic, we evaluated the knowledge and attitude toward HBOC in patients with breast cancer and ovarian cancer. Materials and Methods This cross-sectional observational study was conducted on patients registered in IRCH-AIIMS, who has a diagnosis of breast cancer or ovarian cancer using a self-administered questionnaire based on knowledge and attitude. The sample population included 84 women aged between 25 and 80 years. A binary response was given to knowledge questions, whereas a categorical response was given to attitude questions. The overall data was computed using STATA v13 software. Results According to the findings of the study, 39.3% (5.11/13) of the patients were aware of hereditary cancer. Knowledge among the targeted population was poor, but 72.1% (37.5/52) of the population had a neutral attitude toward learning more about hereditary cancer tests. Only 23/84 (27%) people had heard of genetic counseling. Seventy of eighty-four (83%) patients agreed that they would opt for a genetic test if indicated. While 60/84 (72%) of the population wanted to interact with a counselor over a telephonic call, only 41/84 (49%) wanted to interact in person. Conclusion We concluded from the study that breast and ovarian cancer patients in our clinic have little understanding of HBOC syndrome but have a neutral attitude toward learning more about it.

Hereditary cancer syndromes.

Hereditary cancer syndromes (HCSs) are arguably the most frequent category of Mendelian genetic diseases, as at least 2% of presumably healthy subjects carry highly-penetrant tumor-predisposing pathogenic variants (PVs). Hereditary breast-ovarian cancer and Lynch syndrome make the highest contribution to cancer morbidity; in addition, there are several dozen less frequent types of familial tumors. The development of the majority albeit not all hereditary malignancies involves two-hit mechanism, i.e. the somatic inactivation of the remaining copy of the affected gene. Earlier studies on cancer families suggested nearly fatal penetrance for the majority of HCS genes; however, population-based investigations and especially large-scale next-generation sequencing data sets demonstrate that the presence of some highly-penetrant PVs is often compatible with healthy status. Hereditary cancer research initially focused mainly on cancer detection and prevention. Recent studies identified multiple HCS-specific drug vulnerabilities, which translated into the development of highly efficient therapeutic options.

Cancer prevention in cancer predisposition syndromes: A protocol for testing the feasibility of building a hereditary cancer research registry and nurse navigator follow up model.

Monogenic, high penetrance syndromes, conferring an increased risk of malignancies in multiple organs, are important contributors to the hereditary burden of cancer. Early detection and risk reduction strategies in patients with a cancer predisposition syndrome can save their lives. However, despite evidence supporting the benefits of early detection and risk reduction strategies, most Canadian jurisdictions have not implemented programmatic follow up of these patients. In our study site in the province of Newfoundland and Labrador (NL), Canada, there is no centralized, provincial registry of high-risk individuals. There is no continuity or coordination of care providing cancer genetics expertise and no process to ensure that patients are referred to the appropriate specialists or risk management interventions. This paper describes a study protocol to test the feasibility of obtaining and analyzing patient risk management data, specifically patients affected by hereditary breast ovarian cancer syndrome (HBOC; BRCA 1 and BRCA 2 genes) and Lynch syndrome (LS; MLH1, MSH2, MSH6, and PMS2 genes). Through a retrospective cohort study, we will describe these patients' adherence to risk management guidelines and test its relationship to health outcomes, including cancer incidence and stage. Through a qualitative interviews, we will determine the priorities and preferences of patients with any inherited cancer mutation for a follow up navigation model of risk management. Study data will inform a subsequent funding application focused on creating and evaluating a research registry and follow up nurse navigation model. It is not currently known what proportion of cancer mutation carriers are receiving care according to guidelines. Data collected in this study will provide clinical uptake and health outcome information so gaps in care can be identified. Data will also provide patient preference information to inform ongoing and planned research with cancer mutation carriers.

Molecular classification and clinicopathological features of endometrial carcinoma

Objective: To investigate the molecular classification and clinicopathological features of endometrial carcinoma(EC). Methods: One hundred cases of EC diagnosed in the Department of Pathology, Tianjin Central Hospital of Gynecology and Obstetrics from November 2020 to November 2021 were selected. Sanger sequencing and immunohistochemical staining were used for molecular classification according to the 5th WHO classification. The clinicopathological characteristics of each molecular subtype was analyzed. Results: The 100 EC patients had a mean age of 53 years (range 26 to 72 years). There were 10 cases of POLE mutation (POLE mut), including two cases (2/10) of "binary-classifier" EC, two cases (2/10) of FIGO Grade 3 endometrioid endometrial carcinoma (G3-EEC), and three cases (3/10) of other high-grade subtypes. There were 38 cases of mismatch repair deficiency (dMMR), including one case (1/38, 2.6%) of "binary-classifier" EC and 36 cases (36/38, 94.7%) were EEC. Twenty-one cases (21/38, 55.3%) showed simultaneous loss of expression of MLH1 and PMS2, and 20 cases (20/21, 95.2%) were positive for MLH1 methylation, indicating that they were sporadic EC. Six patients (6/38, 15.8%) were tested for germline detection of Lynch syndrome (LS) related genes, and one patient was LS-related EC. There were 44 cases of non-specific molecular profile (NSMP), including 34 cases (34/44, 77.3%) of G1-2 EEC and seven cases (7/44, 15.9%) of G3-EEC. There were eight cases of p53 abnormality (p53 abn), including four cases (4/8) of G3-EEC, two cases (2/8) of other high-grade subtypes, and one patient had hereditary breast cancer and ovarian cancer syndrome. Conclusions: Correct interpretation of POLE mutation, MMR and p53 immunohistochemistry is the key of molecular classification. The interpretation must strictly follow standard diagnostic procedures and specifications to ensure the accuracy of molecular classification.

The Identification by Exome Sequencing of Candidate Genes in BRCA-Negative Tunisian Patients at a High Risk of Hereditary Breast/Ovarian Cancer.

(1) Background: Germline variants in BRCA1/BRCA2 genes explain about 20% of hereditary breast/ovarian cancer (HBOC) cases. In the present paper, we aim to identify genetic determinants in BRCA-negative families from the South of Tunisia. (2) Methods: Exome Sequencing (ES) was performed on the lymphocyte DNA of patients negative for BRCA mutations from each Tunisian family with a high risk of HBOC. (3) Results: We focus on the canonical genes associated with HBOC and identified missense variants in DNA damage response genes, such as ATM, RAD52, and RAD54; however, no variants in PALB2, Chek2, and TP53 genes were found. To identify novel candidate genes, we selected variants harboring a loss of function and identified 17 stop-gain and 11 frameshift variants in genes not commonly known to be predisposed to HBOC. Then, we focus on rare and high-impact genes shared by at least 3 unrelated patients from each family and selected 16 gene variants. Through combined data analysis from MCODE with gene ontology and KEGG pathways, a short list of eight candidate genes (ATM, EP300, LAMA1, LAMC2, TNNI3, MYLK, COL11A2, and LAMB3) was created. The impact of the 24 selected genes on survival was analyzed using the TCGA data resulting in a selection of five candidate genes (EP300, KMT2C, RHPN2, HSPG2, and CCR3) that showed a significant association with survival. (4) Conclusions: We identify novel candidate genes predisposed to HBOC that need to be validated in larger cohorts and investigated by analyzing the co-segregation of selected variants in affected families and the locus-specific loss of heterozygosity to highlight their relevance for HBOC risk.

PSY8-3 PARP inhibitors for hereditary breast cancer with germline BRCA mutation

BRCA1 and BRCA2 mutations (mt) are responsible genes which give an autosomal-dominant inherited trait predisposing women to hereditary breast cancer and ovarian cancer(HBOC). BRCA-mt cancer cells have abnormal homologous recombination (HR) repair of DNA. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) are effective in causing cell death in BRCA-mt cells while sparing normal cells-a concept called synthetic lethality. PARPi are the first cancer therapy designed to exploit synthetic lethality.

Outcomes of Hereditary Breast-Ovarian Cancer Syndrome: A single center experience

Aim: To assess the survival and progression patterns of Hereditary Breast and Ovarian Cancer (HBOC) at our hospital. Methods: We did retrospective cohort study of thirty patients presenting with hereditary breast ovarian and cancer diagnosed and treated at Shaukat Khanum Memorial Cancer Hospital and Research Center (SKMCH&amp;RC), Lahore, Pakistan from 1994 to 2012. Patient’s demographics, clinical and histopathology data was obtained from cancer registry department of SKMCH&amp;RC hospital. Chi-square test and independent sample T-test were used to analyze the data to find the association between variables i.e. age, comorbidities, BMI and progression free survival. Result: All patients except two received chemotherapy and surgery as per guidelines. Of the thirty patients, thirteen patients had shown progression free survival (PFS) out of which one patient died whereas progression of disease was observed in seventeen patients of HBOC out of which six patients were expired. Comorbidities and family history of cancer did not show statistically significant results for the mortality (P &gt; 0.05). Metastasis and presence of ascites indicated statistically significant influence on PFS having P value &lt; 0.05. CA-125 at presentation, chemotherapy usage and adjuvant therapy did not show significant impact on PFS (P &gt; 0.05). Conclusion: Seven cases of diagnosed HBOC died. We identified that there were 43.33% cases of diagnosed HOBC who met progression free survival and rest developed the progression. Metastasis and presence of ascites showed significant impact for the progression of disease. Keywords: Progression free survival (PFS), BRCA mutation; Hereditary Breast and Ovarian cancer (HBOC).

PALB2 germline mutations in a multi-gene panel testing cohort of 1905 breast-ovarian cancer patients in Argentina

PALB2 variants have been scarcely described in Argentinian and Latin-American reports. In this study, we describe molecular and clinical characteristics of PALB2 mutations found in multi-gene panels (MP) from breast-ovarian cancer (BOC) families in different institutions from Argentina. We retrospectively identified PALB2 pathogenic (PV) and likely pathogenic (LPV) variants from a cohort of 1905 MP results, provided by one local lab (Heritas) and SITHER (Hereditary Tumor Information System) public database. All patients met hereditary BOC clinical criteria for testing, according to current guidelines. The frequency of PALB2 mutations is 2.78% (53/1905). Forty-eight (90.5%) are PV and five (9.5%) are LPV. Most of the 18 different mutations (89%) are nonsense and frameshift types and 2 variants are novel. One high-rate recurrent PV (Y551*) is present in 43% (23/53) of the unrelated index cases. From the 53 affected carriers, 94% have BC diagnosis with 14% of bilateral cases. BC phenotype is mainly invasive ductal (78%) with 62% of hormone-receptor positive and 22% of triple negative tumors. Self-reported ethnic background of the cohort is West European (66%) and native Latin-American (20%) which is representative of Buenos Aires and other big urban areas of the country. This is the first report describing molecular and clinical characteristics of PALB2 carriers in Argentina. Frequency of PALB2 PV in Argentinian HBOC families is higher than in other reported populations. Y551* is a recurrent mutation that seems to be responsible for almost 50% of PALB2 cases.

Assessing Breast Cancer Risks to Improve Care for an Increased-Risk Population within Eastern North Carolina.

BACKGROUND The average lifetime risk of breast cancer for an American woman is 12.5%, but individual risks vary significantly. Risk modeling is a standard of care for breast cancer screening and prevention with recommended tools to stratify individual risks based on age, family history, breast density, and a host of other known risk factors. Because of a lack of resources rurally, we have not consistently met this standard of care within all of North Carolina.METHODS We implemented a quality improvement project to assess the risk for breast cancer by gathering data on community risks. We implemented an evidence-based tool (Tyrer-Cuzick) for quantifying risk within a mostly rural population of Eastern North Carolina and developed customized services for women meeting elevated-risk definition. These services included additional imaging for elevated-risk women and a risk-reduction program. We also assessed genetic risks for hereditary breast and ovarian cancer in our at-risk population using National Comprehensive Cancer Network (NCCN) guidelines based on family history and added local genetics extenders to help test more women. We analyzed data regularly using Plan-Do-Study-Act methods to improve outcomes over 1 year.RESULTS We screened a population of 4500 women at a community hospital over a 1-year period for their individual lifetime cancer risk and genetic risk. Breast cancer risk was quantitated at the time of mammography, and women were stratified into 3 groups for risk management. Within our screening population, 6.3% of women were at high risk (defined by a lifetime breast cancer risk greater than or equal to 20%) and another 8.1% were above-average risk (defined by a lifetime breast cancer risk of 15%-20%). These women (14.4%) could potentially benefit from additional risk-management strategies. Additionally, 20% of all unaffected women within a typical screening population of Eastern North Carolina met NCCN guidelines for hereditary breast cancer and ovarian cancer testing independent of their cancer risk score. Using a model of targeted intervention within a population with elevated risks can be helpful in improving outcomes.LIMITATIONS This population within Eastern North Carolina is mostly rural and represents a potentially biased population, as it involves older women undergoing annual mammography. It may not be broadly applicable to the entire population based on age, geography, and other risks.CONCLUSIONS This model for improving cancer risk assessment and testing at a small community hospital in Eastern North Carolina was successful and addressed a community need. We discovered a high rate of increased-risk women who can benefit from individualized risk management, and a higher percentage of women who potentially benefit from genetic testing. These higher cumulative risks may in part explain some of the disparities seen for breast-cancer-specific outcomes in some parts of the state.