Breast Cancer Syndrome Research Articles

When we Fight a Winnable Battle in an Unwinnable War? The Story of a Cancer - A Case Report

Introduction: Breast cancer is the most frequent malignancy in women and is curable in ~70-80% of patients with early-stage detection and without complication. Paraneoplastic neurologic syndrome of breast cancer is one such complication which is often hard to diagnose, severely debilitating, and also challenging to treat. Materials and Methods: A 57-year- old woman with no known co-morbidity presented with sudden onset altered sensorium. She was in status epilepticus when brought to emergency and progressed to super refractory status epilepticus in-spite of our efforts. MRI of the brain with contrast done revealed hyper intense signal in bilateral frontal, parietal, occipital, bilateral thalami, periaqueductal region and dorsal midbrain. Cerebrospinal fluid (CSF) study revealed only increased protein. The comprehensive infective panel of CSF was negative. The vasculitis marker, anti NMO and anti MOG antibody were absent. So, we suspected a possibility of autoimmune aetiology and started methylprednisolone along with intravenous immunoglobulin. Results: Her epileptic discharges settled in an electroencephalogram, and we weaned her off ventilation. We detected a right breast mass on clinical examination. The PET CT scan revealed metastasis in the liver, bones, right axillary lymph nodes, and bone marrow. Conclusion: Our patient, who had the first-time presentation, was diagnosed to have paraneoplastic encephalopathy in the background of breast cancer. The importance of proper clinical examination and whole-body PET CT scan, followed by a trial of immunomodulator therapy, is necessary in all patients with non-infective encephalitis.

Assessment of the frequency of BRCA1/2 mutations detection by means of PCR in State Budgetary Healthcare Institution «Saint-Petersburg clinical scientific and practical center for specialised types of medical care (oncological) named after N.P. Napalkov»

Background.BRCA1/2 germline testing allows us to optimize treatment strategy for patients with breast and ovarian cancer cases,to provide early diagnosis and also prophylactic measures for mutation carriers. Considering absence of large BRCA studies on Russian population, we do not have any clear understanding of approximate BRCA1/2 germline mutation frequency, a whole number of founder mutations and impact of non-founder BRCA1/2 mutations, which are not included in a standard PCR panel. Objective. Assessment of the frequency of BRCA1/2 mutations detection by means of PCR in breast and ovarian cancer patients in real clinical practice in St. Petersburg Clinical Scientific and Practical Center for Specialized Types of Medical Care (oncological) named after N.P. Napalkov. Analysis of a database for BRCA1/2-negative patients on a presence of risk factors associated with a probability of carrying a germline mutation in BRCA1/2 genes. Materials and methods. We retrospectively evaluated 335 ovarian and 1196 breast cancer patients, tested for germline BRCA1/2 by PCR in SPb CSPC(o) named after N.P. Napalkov from 01.01.2019 to 31.12.2021. For analysis was used patient’s blood plasma and a standard PCR panel detecting 8 mutation variants. A database for BRCA1/2-negative patients was retrospectively analyzed on a presence of risk factors associated with a high probability of hereditary cancer: an early onset and family history of cancer (BRCA associated). Statistical analysis was carried out using the SPSS software package (IBM® SPPS® Statistics v. 20), a number of graphs were carried out using Microsoft® Excel® 2016 programs. Results. BRCA1/2 germline mutations were detected in 6,4% (n= 98). Mean frequency of detection was 12,6% (n=45) for ovarian cancer patients, 4,3% (n=53) for breast cancer patients. Analysis of a database for BRCA1/2-negative patients demonstrated that 22,5% (n=346) BC and OC cases had an early onset. Family history of cancer was identified for 13,6% (n=195) patients with breast or ovarian cancer, including 3,8% (n=43) with 2 and more family cases of BRCA associated cancers. Conclusions. The frequency of detected BRCA1/2 germline mutations by PCR for breast and ovarian cancer patients in SPb CSPC(o) named after N.P. Napalkov is lower than the one described in international data. A large part of patients BRCA1/2 negative by PCR test has characteristics of hereditary breast cancer syndrome and requires further NGS.

Influence of family history on penetrance of hereditary cancers in a population setting

We sought to investigate how penetrance of familial cancer syndromes varies with family history using a population-based cohort. We analysed 454,712 UK Biobank participants with exome sequence and clinical data (data collected between March 2006 and June 2021). We identified participants with a self-reported family history of breast or colorectal cancer and a pathogenic/likely pathogenic variant in the major genes responsible for hereditary breast cancer or Lynch syndrome. We calculated survival to cancer diagnosis (controlled for sex, death, recruitment centre, screening and prophylactic surgery). Women with a pathogenic BRCA1 or BRCA2 variant had an increased risk of breast cancer that was higher in those with a first-degree family history (relative hazard 10.3 and 7.8, respectively) than those without (7.2 and 4.7). Penetrance to age 60 was also higher in those with a family history (44.7%, CI 32.2-59.3 and 24.1%, CI 17.5-32.6) versus those without (22.8%, CI 15.9-32.0 and 17.9%, CI 13.8-23.0). A similar pattern was seen in Lynch syndrome: individuals with a pathogenic MLH1, MSH2 or MSH6 variant had an increased risk of colorectal cancer that was significantly higher in those with a family history (relative hazard 35.6, 48.0 and 9.9) than those without (13.0, 15.4 and 7.2). Penetrance to age 60 was also higher for carriers of a pathogenic MLH1 or MSH2 variant in those with a family history (30.9%, CI 18.1-49.3 and 38.3%, CI 21.5-61.8) versus those without (20.5% CI 9.6-40.5 and 8.3% CI 2.1-30.4), but not for MSH6 (6.5% CI 2.7-15.1 with family history versus 8.3%, CI 5.1-13.2). Relative risk increases were also observed both within and across conditions. Individuals with pathogenic cancer syndrome variants may be at a less elevated risk of cancer in the absence of a first-degree family history, so in the context of results return, family history should be considered when counselling patients on the risks and benefits of potential follow-up care. The current work is supported by the MRC (grant no MR/T00200X/1). The MRC had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Impact of non-BRCA genes in the indication of risk-reducing surgery in hereditary breast and ovarian cancer syndrome (HBOC)

Hereditary breast and ovarian cancer syndrome (HBOC) is associated with other genes beyond BRCA. The performance of prophylactic bilateral mastectomy (PBM) and risk-reducing salpingo-oophorectomy (RRSO) are primary prevention measures that can be recommended depending on the type of pathogenic/likely pathogenic (P/LP) variant detected or family history. Descriptive, retrospective, and observational audit. Between the years 2015 to May 2023, a total of 288 families were studied by a multigene panel using NGS. Statistical analysis was performed using IBM SPSS Statistics 22. Non-BRCA P/LP variants were detected in 38 families (84.2% females and 15.8% males); 18 in ATM (44.7 %), 7 in CHEK2 (18.4%), 5 in TP53 (13.2%), 2 in PTEN (5.3%), 2 in PALB2 (5.3%), 1 in RAD51C (2.6%), 1 in BRIP1 (2.6%), 1 in CDH1 (2.6%) and 1 in RAD51D (2.6%). Risk-reducing surgery was recommended in 18 patients (PBM in 18 [46.2 %] and RRSO in 5 [13.2%]). Given the results of our study, we support the recommendations of the guidelines on the use of multigene panels in the study of HBOC. Knowing P/LP variants beyond BRCA1 and 2 has an impact on the follow-up and primary and secondary prevention of affected families.

Can we talk about sex? Universal sexual health screening for cancer survivors and previvors with hereditary breast and ovarian cancer syndromes (2188)

Can we talk about sex? Universal sexual health screening for cancer survivors and previvors with hereditary breast and ovarian cancer syndromes (2188)

Landscape of somatic mutated genes and inherited susceptibility genes in gynecological cancer.

Traditionally, gynecological cancers have been classified based on histology. Since remarkable advancements in next-generation sequencing technology have enabled the exploration of somatic mutations in various cancer types, comprehensive sequencing efforts have revealed the genomic landscapes of some common forms of human cancer. The genomic features of various gynecological malignancies have been reported by several studies of large-scale genomic cohorts, including The Cancer Genome Atlas. Although recent comprehensive genomic profiling tests, which can detect hundreds of genetic mutations at a time from cancer tissues or blood samples, have been increasingly used as diagnostic clinical biomarkers and in therapeutic management decisions, germline pathogenic variants associated with hereditary cancers can also be detected using this test. Gynecological cancers are closely related to genetic factors, with approximately 5% of endometrial cancer cases and 20% of ovarian cancer cases being caused by germline pathogenic variants. Hereditary breast and ovarian cancer syndrome and Lynch syndrome are the two major cancer susceptibility syndromes among gynecological cancers. In addition, several other hereditary syndromes have been reported to be associated with gynecological cancers. In this review, we highlight the genes for somatic mutation and germline pathogenic variants commonly seen in gynecological cancers. We first describe the relationship between clinicopathological attributes and somatic mutated genes. Subsequently, we discuss the characteristics and clinical management of inherited cancer syndromes resulting from pathogenic germline variants in gynecological malignancies.

Hereditary breast and ovarian cancer triggered by occult fallopian tube cancer: a case report

BackgroundAt the time of benign gynecological surgery, a prophylactic salpingo-oophorectomy or salpingectomy is increasingly being performed concurrently to reduce the risk of future ovarian and fallopian tube cancer. We herein describe a case of hereditary breast and ovarian cancer syndrome in which a hysterectomy and bilateral adnexectomy were performed with a preoperative diagnosis of benign tumor. A detailed pathological examination revealed occult fallopian tube cancer, and additional staging surgery provided an accurate pathology diagnosis.Case presentationA 72-year-old Japanese woman with a past history of breast cancer underwent a hysterectomy and bilateral oophoro-salpingectomy for the preoperative diagnosis of uterine myoma and a right para-ovarian cyst. In the detailed pathological examination, high-grade serous carcinoma of the right fallopian tube was detected incidentally, and a subsequent staging laparotomy confirmed single para-aortic lymph node metastasis. Furthermore, a mutation in germline BRCA2 was detected postoperatively, and the patient was finally diagnosed with hereditary breast and ovarian cancer syndrome. She was diagnosed with fallopian tube cancer International Federation of Gynecology and Obstetrics Stage IIIA1(i) and started on adjuvant therapy (six courses of paclitaxel and carboplatin followed by maintenance therapy with olaparib), and 18 months after surgery, she was free of disease.ConclusionThis is a case of fallopian tube cancer that was diagnosed incidentally and then accurately staged with additional advanced staging surgery. Even in the absence of grossly malignant findings, a detailed pathological search of the fallopian tubes and accurate staging surgery are important to make the necessary treatment decisions for the patient.

Combining clinical and molecular characterization of CDH1: a multidisciplinary approach to reclassification of a splicing variant.

Pathogenic germline variants (PGVs) in the CDH1 gene are associated with diffuse gastric and lobular breast cancer syndrome (DGLBC) and can increase the lifetime risk for both diffuse gastric cancer and lobular breast cancer. Given the risk for diffuse gastric cancer among individuals with CDH1 PGVs is up to 30-40%, prophylactic total gastrectomy is often recommended to affected individuals. Therefore, accurate interpretation of CDH1 variants is of the utmost importance for proper clinical decision-making. Herein we present a 45-year-old female, with lobular breast cancer and a father with gastric cancer of unknown pathology at age 48, who was identified to have an intronic variant of uncertain significance in the CDH1 gene, specifically c.833-9C > G. Although the proband did not meet the International Gastric Cancer Linkage Consortium (IGCLC) criteria for gastric surveillance, she elected to pursue an upper endoscopy where non-targeted gastric biopsies identified a focus of signet ring cell carcinoma (SRCC). The proband then underwent a total gastrectomy, revealing numerous SRCC foci, but no invasive diffuse gastric cancer. Simultaneously, a genetic testing laboratory performed RNA sequencing to further analyze the CDH1 intronic variant, identifying an abnormal transcript from a novel acceptor splice site. The RNA analysis in conjunction with the patient's gastric foci of SRCC and family history was sufficient evidence for reclassification of the variant from uncertain significance to likely pathogenic. In conclusion, we report the first case of the CDH1 c.833-9C > G intronic variant being associated with DGLBC and illustrate how collaboration among clinicians, laboratory personnel, and patients is crucial for variant resolution.

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

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

Assessment of medical knowledge toward genetic testing for individuals with hereditary breast and ovarian cancer syndrome in Brazil

Genetic testing has become increasingly used in medical practice to enable genetic cancer risk assessment. In Hereditary Breast and Ovarian Cancer syndrome (HBOC), it can be used to screen pathogenic germline variants. The access to early diagnosis, from the request until the proper interpretation of genetic tests depends on medical knowledge. The aim of this study was to evaluate the knowledge of family physicians, oncologists, geneticists and gynecologists regarding genetic testing for patients with suspected HBOC in Brazil. A cross-sectional survey of physicians was performed using a self-administered questionnaire. One hundred and ninety-two physicians answered the questionnaire (23 were geneticists, 38 gynecologists, 39 family physicians, and 92 oncologists). Only 15.4% of family physicians and 26% of gynecologists feel prepared to order genetic testing for patients with personal and/or family history of breast and/or ovarian cancer. Even though 87% of the oncologists have genetic testing available in their clinical practice, only 51.1% consider they have sufficient knowledge to manage patients after detecting a pathogenic germline variant and 17.4% do not feel comfortable interpreting them. Most oncologists and geneticists are very knowledgeable about recommendations for genetic testing order and management of HBOC patients. On the other hand, gynecologists and family physicians order genetic testing less frequently (28.9% and 7.7%, respectively) and have difficulties interpreting (26.3% and 2.3%, respectively) and managing these patients. These observations raise important issues regarding the implementation of genetic testing in Brazil, including the development of training programs for physicians from different specialties.

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

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

The Evolution of Genetic Testing from Focused Testing to Panel Testing and from Patient Focused to Population Testing: Are We There Yet?

The field of cancer genetics has evolved significantly over the past 30 years. Genetic testing has become less expensive and more comprehensive which has changed practice patterns. It is no longer necessary to restrict testing to those with the highest likelihood of testing positive. In addition, we have learned that the criteria developed to determine who has the highest likelihood of testing positive are neither sensitive nor specific. As a result, the field is moving from testing only the highest risk patients identified based on testing criteria to testing all cancer patients. This requires new service delivery models where testing can be mainstreamed into oncology clinics and posttest genetic counseling can be provided to individuals who test positive and those with concerning personal or family histories who test negative. The use of videos, testing kiosks, chatbots, and genetic counseling assistants have been employed to help facilitate testing at a larger scale and have good patient uptake and satisfaction. While testing is important for cancer patients as it may impact their treatment, future cancer risks, and family member's cancer risks, it is unfortunate that their cancer could not be prevented in the first place. Population testing for all adults would be a strategy to identify individuals with adult-onset diseases before they develop cancer in an attempt to prevent it entirely. A few research studies (Healthy Nevada and MyCode) have offered population testing for the three Centers for Disease Control and Prevention Tier 1 conditions: hereditary breast and ovarian cancer syndrome, Lynch syndrome, and familial hypercholesterolemia finding a prevalence of 1 in 70 individuals in the general population. We anticipate that testing for all cancer patients and the general population will continue to increase over the next 20 years and the genetics community needs to help lead the way to ensure this happens in a responsible manner.

Overview of the Genetic Causes of Hereditary Breast and Ovarian Cancer Syndrome in a Large French Patient Cohort.

The use of multigene panel testing for patients with a predisposition to Hereditary Breast and Ovarian Cancer syndrome (HBOC) is increasing as the identification of mutations is useful for diagnosis and disease management. Here, we conducted a retrospective analysis of BRCA1/2 and non-BRCA gene sequencing in 4630 French HBOC suspected patients. Patients were investigated using a germline cancer panel including the 13 genes defined by The French Genetic and Cancer Group (GGC)-Unicancer. In the patients analyzed, 528 pathogenic and likely pathogenic variants (P/LP) were identified, including BRCA1 (n = 203, 38%), BRCA2 (n = 198, 37%), PALB2 (n = 46, 9%), RAD51C (n = 36, 7%), TP53 (n = 16, 3%), and RAD51D (n = 13, 2%). In addition, 35 novel (P/LP) variants, according to our knowledge, were identified, and double mutations in two distinct genes were found in five patients. Interestingly, retesting a subset of BRCA1/2-negative individuals with an expanded panel produced clinically relevant results in 5% of cases. Additionally, combining in silico (splicing impact prediction tools) and in vitro analyses (RT-PCR and Sanger sequencing) highlighted the deleterious impact of four candidate variants on splicing and translation. Our results present an overview of pathogenic variations of HBOC genes in the southeast of France, emphasizing the clinical relevance of cDNA analysis and the importance of retesting BRCA-negative individuals with an expanded panel.

A comprehensive study on surveillance outcomes of a male population followed at a hereditary breast cancer high-risk consultation at a Portuguese tertiary hospital.

Men born with pathogenic/likely pathogenic variants in genes associated with the Hereditary Breast and Ovarian Cancer Syndrome have a higher risk to develop breast cancer and other cancers (such as prostate cancer) and should undergo adequate surveillance protocols in highly specialized Centers. A retrospective study was conducted to assess these genetic variants' epidemiological and phenotypical manifestations in male carriers, as well as the efficacy of the surveillance protocol and compliance toward it through a survey. During follow-up, a genetic panel for testing was implemented, the starting age for surveillance was delayed, and the six-month screening interval was extended to annual. A total of 104 men from a tertiary hospital's High-Risk Consultation were included, 102 with positive genetic testing for BRCA1 (n = 31), BRCA2 (n = 55), both BRCA2 and another gene (n = 5), CDH1 (n = 2), CHEK2 (n = 4), NF1 (n = 1), RAD51C (n = 4), and an additional two men with no actionable genetic variant identified. The follow-up period ranged from 1 to 13years, and only one man developed cancer. Survey responses from 48 men in active surveillance showed that more than half recognizes their carrier status and consequent surveillance impact on their life, including the risk of transmission to offspring, fear of future cancer, meaningful distress, and feeling of injustice. Biannual surveillance was not actively detecting more cancer disease cases, confirming the adequacy of the currently implemented protocol CONCLUSION: With support of Genetics to fulfill the current gaps in high-risk management, the proposed redefinition of surveillance protocol would adapt it to the population needs and concerns.

Connecting Black families in Houston, Texas, to hereditary cancer genetic counseling, genetic testing, and cascade testing by using a simple cancer genetic risk assessment and telegenetics.

TPS10638 Background: Hereditary breast and colorectal cancers accounts for 5-10% of all cases, but less than half of all eligible patients undergo NCCN guideline-concordant screening. This proportion is even lower among Black patients, who have a higher breast cancer and colorectal incidence and mortality. Recruitment through community organizations has been shown to identify patients who are eligible for genetic testing but have not been offered it by their doctor. Our one-page cancer genetic risk assessment (CGRA) and telegenetics were previously shown to improve adherence to genetic testing guidelines for hereditary breast and ovarian cancer. Our objective is to identify adults eligible for hereditary breast and colorectal cancer syndromes genetic testing using trusted community organizations that serve the Black community as entry points, reach them with our tailored program, and measure impact. Methods: In this prospective single-arm trial, adults of > 18 years old who self-identify as Black or African American are recruited during events put together by community organizations in Houston, Texas. The CGRA was modified to encompass hereditary breast and colorectal cancer syndromes based on NCCN guidelines. To improve convenience, eligible participants can be consented and fill out the CGRA in-person or via QR code link using a smart phone. Study team members attend community events and are also available via phone to help with informed consent, CGRA, etc. Those at high risk for hereditary breast and colorectal cancer syndromes are provided with educational materials and can be sent the saliva-based kit or complete it on-site. When results of genetic testing include a pathogenic mutation (PV) or variant of uncertain significance, individuals receive telegenetic counseling and risk reduction resources, including about cascade genetic testing. Others are notified of negative results. The program includes education for interested community organization members about importance of genetic testing. The program is projected to reach 1,000 participants with 300 completing genetic testing and identification of 11 PV. The study is overseen by a Community Advisory Board. Impact will be evaluated via a multiple methods design using the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) Qualitative Evaluation for Systematic Translation (QuEST) framework six months after program start. Quantitative data will be analyzed using descriptive statistics and standard tests of association. Data collected via semi-structured interviews with participants and program implementers will be audio-recorded, transcribed, double-coded, and analyzed via thematic analysis. Enrollment started December of 2022. 15 participants patients enrolled during two community events. Clinical trial information: NCT05694559 .

Digital cancer genetic risk assessment in a gynecologic oncology clinic.

10612 Background: Population-based screening for hereditary cancer syndromes and referral of those who screen positive for genetic testing is a cost effective, evidence-based national health priority. However, under-recognition of hereditary cancer syndromes remains a critical concern, with fewer than 20% of individuals with Hereditary Breast and Ovarian Cancer Syndrome and Lynch Syndrome identified. Here, we evaluate the Ambry Genetics Comprehensive, Assessment, Risk, and Education (CARE) Program, a risk-stratification tool to assess eligibility for National Comprehensive Cancer Network (NCCN) genetic testing criteria and lifetime risk for breast cancer based on the Tyrer-Cuzick (version 8.0) risk algorithm. Methods: Between November 2022 and February 2023, new patients in a gynecologic oncology clinic were prompted by text message to complete CARE prior to their appointment. Those using CARE then completed a System Usability Scale (SUS), a validated 10-item questionnaire for the assessment of perceived usability. Results: Sixty patients presented for a new patient gynecologic oncology appointment and were prompted to complete CARE. The median patient age was 55 years (interquartile range, 40-68). The patients self-identified as Non-Hispanic White (44, 73%), Non-Hispanic Black (5, 8%), Asian (5, 8%), Hispanic (3, 5%), other (2, 3%), and unknown (1, 2%). All identified as female. Forty-three patients (72%) completed CARE. Among CARE users, 11 (26%) were identified as meeting criteria for genetic testing; of these, 9 (82%) proceeded with point-of-care same day genetic testing. Nine (21%) patients were eligible for enhanced breast cancer screening based on an estimated lifetime breast cancer risk of 20% or greater; of these, 100% were referred for high-risk breast screening. There were no patient demographics associated with completion of CARE. Forty-one patients (72%) completed the SUS survey; the median SUS score was 80 (interquartile range, 60-92.5), which corresponded to 85-89th percentile and a letter grade of A-. Conclusions: Implementation of a digital tool for cancer genetic risk assessment identified a quarter of patients to be eligible for genetic testing, among whom 82% completed same-day genetic testing. Additionally, the tool was reviewed favorably by patient users. Large randomized controlled trials of health information technology tools are needed to move closer to the goal of population-based hereditary cancer risk assessment.

Genetic evaluations and testing rates for hereditary breast and ovarian cancer syndrome in a community oncology setting.

e22533 Background: Several professional medical societies recommend genetic evaluations and testing for individuals with a personal and/or family cancer history. The National Comprehensive Cancer Network (NCCN) outlines germline testing criteria for breast, ovarian, and pancreatic cancer predisposition genes. This study aims to assess the genetic evaluation and testing rates in community oncology centers among patients who qualify based on their personal history of cancer. Methods: A retrospective study assessed patients diagnosed at any Texas Oncology site between 1/01/2017 and 12/31/2019. Using NCCN Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic V1.2020, individuals with the following cancer diagnoses were included: epithelial ovarian, breast < 45 years, triple negative breast < 60 years, metastatic HER2 negative breast, male breast, exocrine pancreatic, or metastatic prostate. Data was obtained from electronic medical records. The project was approved by the Texas Oncology Privacy Board. Results: Of the 10,202 patients included, 6033 (59%) underwent genetic testing. Only 3660 (36%) had a genetic evaluation, and of those, 2720 (74%) were conducted within Texas Oncology. Younger patients were significantly more likely to be tested than those diagnosed at older ages (p = 2.2e-16). Testing rates were significantly higher (p = 8.95e-07) at sites that employ a provider with genetics training; moreover, the rates of evaluation and testing trended upward, the longer those providers had been offering genetics services. Of the patients without test results, most (76%) had neither a genetics referral nor germline test order documented, suggesting an opportunity for provider education. Conclusions: Most patients who met criteria underwent genetic testing, but the rates varied by cancer type. Patients with breast cancer were most likely to have genetic testing. This study proved that having a genetics provider on staff significantly improved testing rates for patients who qualify. However, given that 100% of the cohort qualified and only 59% underwent testing, quality improvement measures are needed to increase the rate of genetic evaluations and testing for these diagnoses. [Table: see text]

Hereditary breast and ovarian cancer syndrome: A misnomer?

10594 Background: Germline pathogenic gene variants (PGV) in homologous recombination deficiency (HRD) genes are traditionally associated with breast, ovarian, pancreatic, prostate and melanoma skin cancer. Recent evidence suggests other cancers may also be associated with these genes. We analyzed the prevalence of somatic HRD mutations in common, traditionally non-hereditary breast and ovarian cancer (HBOC) associated incident cancers in the US. Methods: Data were collected from the American Association for Cancer Research’s (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database version 13.0 via cBioPortal (http://genie.cbioportal.org). This is a publicly available, multi-institutional database of next-generation sequencing (NGS) genomic profiles of tumor samples. The database was queried for all cancers with at least 20,000 incident cases in 2022, as reported by the American Cancer Society, excluding well established HBOC associated cancers – breast, ovarian, prostate, pancreatic, melanoma. Frequencies of somatic PGVs were reported for nine HRD genes currently included in National Comprehensive Cancer Network (NCCN) management guidelines for HBOC: ATM , BARD1, BRCA1, BRCA2, BRIP1, CHEK2, PALB2, RAD51C and RAD51D. Results: A total of 78,285 tumor samples across 12 cancer types were included. At least 1 somatic HRD was found in 6.8% of all included tumors. At least 1 HRD PGV was most common in: Uterine Cancer (694/5,760, 12.1%), Non-Melanoma Skin Cancer (127/1,209, 10.5%), Bladder Cancer (462/4,605, 10.0%), Colorectal Cancer (1306/14,625, 8.9%) Non-Hodgkin’s Lymphoma (5/58, 8.6%), Esophagogastric Cancer (356/4,649, 7.7%), Hepatobiliary Cancer (219/3,325, 6.6%), Lung Cancer (1,480/23,621, 6.3%), Kidney Cancer (113/2,564, 4.4%), Brain Cancer (420/10,206, 4.1%), Thyroid Cancer (89/2,246, 4.0%) and Leukemia (80/5,417, 1.5%). The most common PGVs across all cancer types were BRCA1/2 and ATM (Table). Conclusions: A pan-cancer analysis using NGS data demonstrates a substantial rate of somatic HRD PGVs in common, traditionally non-HBOC associated cancers in the US. These data raise the possibility that germline pathogenic variants in HRD genes could be associated with several more cancers than currently known, underscoring the need for studies evaluating risks of the aforementioned cancers in germline PGV carriers. Additionally, these findings present opportunities for trials evaluating the efficacy of HRD-targeting therapies in these cancers. [Table: see text]

Publication trends in sarcoma research: A bibliometric analysis.

e23530 Background: Sarcomas are rare primary malignant tumors originating from connective tissue, worldwide research trends on this topic are unclear. We conducted a bibliometric analysis of the 100 most influential articles on sarcoma. Methods: We sourced the literature published in academic journals indexed by the Scopus Database. Using the key words “sarcoma,” “soft-tissue tumor,” “bone sarcoma,” “soft-tissue sarcoma,” “connective tissue malignancy.” A list of the 100 most-cited articles were extracted and sorted by number of citations, excluding articles related to Kaposi’s Sarcoma. The papers were checked independently by our authors for accuracy of topic. R was used to extract the publishing journal, year of publication, country of origin, affiliated institutions, authors, and total citations. Results: The total number of citations for 100 articles was 73,483. Citations for individual articles ranged from 453 to 3,064, with a median of 588 (IQR: 341).The United States contributed the most papers (n = 70), followed by France and the United Kingdom (n = 5). Most articles, 67, were published prior to the 21st century and only 3 were in the last 10 years. The most cited study was Malkin et al.’s Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms with 3,064 citations. Of the top 10, 8 were published between 1978 and 1998. Journal of Clinical Oncology made the greatest number of contribution to the research on sarcoma with a total of 18 articles (citations = 12,166), followed by Cancer with 15 (citations = 9,052), and Proceedings of the National Academy of Sciences of the United States with 10 (citations = 8,431). The median Scopus CiteScore for publishing journals was 19.7, the highest being The Lancet (115.3) and The Iowa Orthopaedic Journal with the lowest score (1.5). Conclusions: Within the United States, the institutions producing the most literature were the NCI and Memorial Sloan Kettering Cancer Center. The majority of the 100 most cited studies are cited an average of 735 times, indicating that these sources are providing a substantial foundation for emerging research in the field. This begs the question of the quality and relevance of evidence in the literature, given the amount of citations. The Lancet produced literature with the highest journalistic impact, having a CiteScore of 115.3 based on Scopus metrics. While the majority of the 100 most cited pieces of literature (67%) on sarcomas were published prior the 21st century, a small portion, eight, were produced in the last decade. This information could indicate either a lull in the frequency of research being conducted, or an effort on the part of institutions to create more substantial investigations that provide more valuable contributions to the field of research in sarcomas. We hope to continue seeing the field of sarcoma expand with new advances in its management.

Delivery of soluble ethinylestradiol complex by pH‐responsive core‐shell composite hydrogel capsules

AbstractEthinylestradiol (EE) is a potent estrogen widely used to treat diseases such as breast cancer, prostate cancer, and menopausal syndrome. The poor aqueous solubility of EE leads to erratic oral absorption, resulting in suboptimal plasma levels. Developing a formulation to enhance the solubility of EE in the gastrointestinal tract would be beneficial to increase the bioavailability of EE. Thereafter, we prepare diethylenetriamine‐β‐cyclodextrin/ethinylestradiol (DETA‐β‐CD/EE) complex, aiming to increase the solubility of EE in water, and design and prepare core‐shell composite hydrogel capsules with aldocellulose and hydroxyethyl cellulose as the core and sodium alginate as the shell. The stability, swelling, drug release behavior and biocompatibility of the core‐shell hydrogel capsules are carefully investigated. And the results show that the prepared hydrogel capsules have the controlled and sustained release ability of soluble DETA‐β‐CD/EE, can achieve pH‐responding to intestinal fluid, and are non‐toxic to normal human cells.