Genetic Counseling Recommendations Research Articles

Access for adolescents and young adults with hard-to-cure cancer to PROFYLE: The pan-Canadian precision oncology pipeline.

10012 Background: Cancer is the most common cause of disease-related death in children, adolescents and young adults (CAYA). Approximately, 1.5% of patients with cancer in Canada are adolescents and young adults (AYAs) (age 15-29). AYAs often present with advanced disease and limited access to clinical trials including genomic testing. The PRecision Oncology For Young peopLE (PROFYLE) national, collaborative program, was created to provide equitable access to molecular profiling to identify novel targeted treatment options for CAYA with hard-to-cure cancers. The AYA node of PROFYLE aims to enhance the inclusion of AYAs across Canada at pediatric and adult centers while raising awareness of improving cancer outcomes of this underserved population. Methods: Building upon 3 pre-existing regional precision oncology programs, PROFYLE was implemented as the first pan-Canadian precision oncology pipeline. The PROFYLE study is multi-centred, non-randomized, interventional, and qualitative. Inclusion criteria: ≤29y; treatment at a Canadian center; diagnosis of a hard-to-cure cancer. It includes genomic and transcriptomic sequencing of paired germline and cancer fresh/frozen samples. Actionable findings, potential targeted therapy options including available clinical trials, clarification of diagnosis, and genetic counseling recommendations are provided to the clinical care team. Results: To date, > 1,200 CAYA are included from all provinces. Of these, 33% were AYAs. Cancer diagnoses included: 47% sarcoma, 15% leukemia/lymphoma, 13% CNS tumor, 25% other. Of the AYAs enrolled, 53% had ≥1 significant tumour profiling finding (48% specific mutations/fusions; 6% DNA repair defect signature, hypermutation, microsatellite instability, chromosomal instability; 3% predictors of therapeutic resistance; 5% outliers in gene expression). 71% had potentially useful findings (15% diagnostic; 9% prognostic; 59% therapeutic; 2% etiologic; 15% cancer predisposition; 2% secondary germline; 0.5% pharmacogenetic). 23% had a pathogenic/likely pathogenic germline variant. 60% had ≥1 potentially actionable somatic alteration. 64% of clinicians indicated that molecular findings impacted clinical management (12% diagnostic; 6% prognostic, 60% therapeutic; 16% germline genetic). 24% indicated a change in treatment planning in response to these findings. Conclusions: The goal of developing a national precision oncology pipeline that provides equitable access to molecular profiling in a clinically relevant timeframe has been realized through the establishment of PROFYLE. Findings demonstrate that the sequencing platform provided medically informative results in the majority of enrolled AYAs. The success of PROFYLE underscores the importance of the continuing efforts to increase the access to this precision oncology initiative for all AYAs with cancer in Canada.

Abstract 792: Continuous, probabilistic variant interpretation with Bayesian graphical models

Abstract Introduction: Current variant classification (VC) frameworks rely on rules-based approaches that use heuristic weighting of various types of evidence, resulting in > 50% of variants being classified as variants of uncertain significance (VUS), and leaving many patients with uncertainty about their disease risk or diagnosis. We propose a probabilistic and scalable Bayesian approach to model the causal relationships between various types of evidence. A fully quantitative system maximizes the utility and integration of various evidence types, empowering clinicians to make more nuanced management decisions. Methods: Probabilistic graphical models (PGMs) are uniquely suited to the needs of clinical VC. Two different component PGMs were developed to model two of the evidence categories that will ultimately be used in a comprehensive VC system: population allele frequency (Population PGM) and reported phenotype observations (Reported Phenotype PGM). Results: The Population PGM treats population allele frequency observations as a binomial process. By conditioning the model on partial observations, the probabilistic relationships between pathogenicity and allele frequencies can be estimated while stochastic variational inference allows uncertainty to be efficiently propagated. The resulting model performs well across a large number of genes at inferring pathogenicity of a variant from its allele frequency, with an average precision of >99% for benign variants. In the Reported Phenotype PGM, phenotypic features characteristic of a disorder are learned from patients expected to be affected based on genotype. Patient-level predictions are in turn combined at the variant level to derive variant pathogenicity likelihoods. To date, models representing at least 102 inherited conditions and 259 genes have demonstrated high predictive performance (>0.8 AUROC) for both patient-level and variant-level predictions. Finally, as a proof-of-concept, we demonstrate how each component PGM can be combined into a probabilistic Bayesian VC framework that also includes protein structure and stability, evolutionary conservation, and sequence context. This framework has high concordance with known, well-accepted pathogenic and benign variants classified with rules-based systems, and could make high-confidence predictions for many variants currently classified as VUS. Conclusion: We present a Bayesian approach that can integrate diverse types of evidence to achieve high VC accuracy while quantifying uncertainty. Future expansion of this Bayesian framework to all evidence types relevant to VC may allow for more accurate risk management guidelines and further inform medical and genetic counseling recommendations. Citation Format: Wolfgang Michael Korn, Yuya Kobayashi, Flavia M. Facio, Arun Nampally, Keith Nykamp, Robert Nussbaum, Alexandre Colavin, Britt Johnson, Toby Manders. Continuous, probabilistic variant interpretation with Bayesian graphical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 792.

Project Inclusive Genetics: Protecting reproductive autonomy from bias via prenatal patient-centered counseling

Clinician bias negatively impacts the healthcare received by marginalized communities. In this study, we explored factors that influence clinician and trainee bias against individuals with intellectual disabilities and its impact on clinical judgment in prenatal genetic testing settings. Specifically, we examined bias toward a fetus with a higher chance of developing a disability. We compared genetics specialists with their non-expert counterparts. This web-based study included clinical vignettes, implicit association tests (IATs), and an educational module. 595 participants were recruited via their institution or professional society. We conducted statistical analyses, including regression models controlling for key demographic characteristics, to analyze recommendation patterns and degree of change after the module. Genetics expertise strongly correlated with appropriate testing recommendation when the patient would not consider pregnancy termination (r= 1.784 pre-module, r= 1.502 post-module, p<0.01). Factors that influenced pre-module recommendation to test include increased age (r= -0.029, p<0.05), high religiosity (r= 0.525, p<0.05), and participant personal preference against testing (r= 1.112, p<0.01). Responses among participants without genetics expertise improved after the educational module (Z= -4.435, p<0.01). 42% of non-experts who answered inappropriately changed their answer to match guidelines after the module. Individual bias, along with structural and institutional bias, permeates family planning encounters and significantly decreases quality of care. We demonstrate here that anti-bias training is effective, particularly for non-expert providers, and it can improve the care provided to individuals with intellectual disability. Evidence-based training such as this one can help providers make appropriate genetic counseling recommendations.

Evaluating interventions to increase the uptake of NCCN genetic counseling recommendations.

10599 Background: Genetic counseling for hereditary breast cancer remains underutilized despite increased access. The lack of identification and/or referral of high-risk women for genetic counseling is the major contributor to the poor uptake. A cancer risk assessment program (CRA) utilizing NCCN guidelines was implemented in our breast imaging department to identify women at increased risk for breast cancer. We analyzed the impact of informing all women who get a screening mammogram of their genetic mutation risk and the effect of nurse navigation on increasing the subsequent uptake of genetic counseling. Methods: To assess the effectiveness of these interventions, data from July 2021 to January 2022 was extracted from the EMR and grouped into cohorts based on nurse navigation contact and the completion of genetic counseling. A chi-squared analysis was performed to determine the significance of the results. Results: A total of 22,915 patients participated in the CRA program during the study period. 2,671 (11.7%) patients qualified for genetic counseling based on NCCN guidelines. 414 (15.5%) of these patients completed a genetic counseling appointment. 298 of these patients received genetic testing (72%) and 18 (4.3%) had a pathogenic mutation found. The nurse navigator was able to reach 1,288 (48%) of the 2,671 patients (Cohort A). Of these patients, 324 (25.2%) completed genetic counseling appointments compared to 90 of the 1,383 (6.5%) patients who were not contacted by the nurse navigator (Cohort B). Statistical analysis determined there was a significant difference in uptake of genetic counseling between Cohort A and Cohort B (p&lt;.0001). Conclusions: The implementation of the CRA program at the breast imaging center uncovered many patients who qualified for genetic counseling and testing based on NCCN guidelines. Genetic counseling uptake is significantly increased in patients who are reached by a Nurse Navigator. These interventions allowed for the discovery of unsuspected deleterious genetic mutations which require more aggressive screening to allow for the early detection of breast cancer and better overall prognosis. [Table: see text]

Abstract 5224: The PRecision Oncology For Young peopLE (PROFYLE) Program: A national precision oncology program for children, adolescents and young adults with hard-to-cure cancer in Canada

Abstract Background: Over 4,300 children, adolescents, and young adults (CAYA) are diagnosed with cancer each year in Canada, 1/3 of whom have refractory/metastatic disease or will relapse. A national collaborative program, PRecision Oncology For Young peopLE (PROFYLE), was created with the goal to develop and implement a pipeline providing access to tumor molecular profiling to identify novel targeted treatment options in a clinically relevant timeframe for CAYA with hard-to-cure cancers. Design: PROFYLE includes more than 20 institutions, building upon 3 pre-existing regional precision oncology programs (Personalized Oncogenomics (POG), SickKids Cancer Sequencing (KiCS), and Personalized Targeted Therapy in Refractory or Relapsed Cancer in Childhood (TRICEPS)). PROFYLE has united an interdisciplinary team of experts, leaders, research team, end-users and advocates from across Canada to form 14 domain specific nodes unified by a shared governance structure. PROFYLE includes genomic and transcriptomic sequencing of paired germline/cancer fresh/frozen samples. Inclusion criteria: ≤29y; treatment at a Canadian center; diagnosis of a hard-to-cure cancer. Profiling results are reviewed by multidisciplinary Molecular Tumor Boards. A report including a results/recommendations summary of actionable findings (therapeutic, diagnostic, prognostic, cancer predisposition), potential targeted therapy options including available clinical trials, clarification of diagnosis, and genetic counseling recommendations is provided to the treating oncologist. Results: To date, &amp;gt;900 CAYA are enrolled. Cancer diagnoses: 36% sarcoma, 16% leukemia/lymphoma, 16% CNS tumor, 13% neuroblastoma, 19% other. At study entry, 44% of participants had not relapsed, 40% had 1 relapse, 9% 2 relapses, 4% 3+ relapses. 17% had a cancer-predisposing pathogenic/likely pathogenic germline variant, 40% had ≥1 potentially actionable somatic alteration, 9.7% had a therapeutically targetable somatic alteration. The most frequent classes of therapeutic alterations were cell cycle (15%), RAS/MAPK (14%), epigenetic (13%), RTK (12%), PI3K/AKT/mTOR (10%), DNA repair (9%), immune checkpoint (8%). Of clinicians who reported the utility of results, 56% indicated the findings were useful for clinical management. Future Directions: With a comprehensive molecular view of cancer, PROFYLE will transform our understanding of underlying disease mechanisms, facilitate and improve diagnostic and prognostic indicators, and identify new therapeutic strategies and targets. Data from this interdisciplinary, multi-institutional research program will inform the development of a framework to innovatively link research, clinical and system considerations with Canadian values relevant to genomic profiling and drug access for CAYA in Canada. Citation Format: Stephanie A. Grover, Lesleigh Abbott, Jason N. Berman, Jennifer A. Chan, Avram E. Denburg, Rebecca J. Deyell, Conrad V. Fernandez, Cynthia Hawkins, Jan-Willem Henning, Meredith S. Irwin, Nada Jabado, Steven J. Jones, Philipp F. Lange, Michael F. Moran, Daniel A. Morgenstern, Antonia Palmer, Shahrad R. Rassekh, Donna L. Senger, Adam Shlien, Daniel Sinnett, Caron Strahlendorf, Patrick J. Sullivan, Michael D. Taylor, Suzanne Vercauteren, Anita Villani, James A. Whitlock, David Malkin, on behalf of the Terry Fox PROFYLE Consortium. The PRecision Oncology For Young peopLE (PROFYLE) Program: A national precision oncology program for children, adolescents and young adults with hard-to-cure cancer in Canada [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5224.

Abstract P159: Molecular tumor board impact at two large health systems

Abstract Background: Molecular tumor boards (MTB) are a key component of most precision oncology programs, designed to provide a structured multidisciplinary approach to evaluating cancer patients (pts) for therapy (Tx), clinical trial (CT) enrollment, and genetic counseling (GC) services. Two health systems separately instituted MTB in 2017, and through a bio-informatics platform have been tracking the impact of these on pt care. We describe the collective experience in tracking MTB impact. Methods: This is a retrospective cohort study of pts reviewed for the first time by MTB between September 1, 2017 and September 30, 2020 at either of the two health systems (HS). Follow up data were obtained by a certified tumor registrar at a median time of 109 days after presentation. Demographics and clinical characteristics of MTB pts were obtained. Pts were identified for whom Tx or CTs were recommended and subsequently administered after MTB review, along with pts for whom GC was recommended and subsequently had genetic testing performed. Results: 351 pts were evaluated. Pt demographics included: median age of 65 years; 61% female; 83% White, 13% Black, 3% Asian, with 2% of Hispanic/Latino ethnicity. The most common primary sites observed were lung (75 pts; 21%), breast (44 pts; 13%) and central nervous system (26 pts, 7%). 334 pts (95%) had data regarding Tx and CT recommendations. 124 pts (37%) received a Tx recommendation and 36 (29%) of these received Tx. 73 pts (22%) received a CT recommendation and 4 (6%) of these pts were enrolled on CTs. 340 pts (97%) had data regarding GC recommendations. 94 pts (28%) received a GC referral and 28 (30%) of these received GC. 25 (89%) of these received a molecular test for germline cancer risk, and 10 (40%) of these had a risk mutation identified in one of the following: ATM (4), BRCA2 (2), BARD1 (1), CHEK2 (1), RAD51C (1), and RET (1). Conclusions: MTB was successful in matching pts to Tx and CT, and in providing appropriate referrals to GC and identifying germline risk mutations. The bio-informatics platform provided a uniform format and structure to collate and analyze data between programs. These parameters will serve as a baseline to monitor future MTB impact and trends as these precision oncology programs continue to grow. The relatively low percentage of patients of color whose cases were reviewed in this MTB analysis merits further understanding. Citation Format: Igor I. Rybkin, Michael A. Thompson, Frank M. Wolf, Kristen Collins, Louisa Laidlaw, Tom Mikkelsen, Jennifer Godden, Mary Walters, James L. Weese, Ronda Broome, Joe Burkhart, Veronica Jones, Chenan Zhang, Thomas D. Brown, Anna Berry. Molecular tumor board impact at two large health systems [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P159.

Planting the seed of doubt: the diagnosis and management of mosaic embryos

This month's Views and Reviews focuses on different aspects of the diagnosis of mosaicism. The first piece was written by Treff and Marin, who discuss the methodologic challenges of preimplantation genetic testing for aneuploidies and how the diagnosis of "mosaic" has led to a significant reduction in the accuracy of such testing. The second article by Viotti etal. provides an excellent overview of outcome data from >1,000 mosaic embryo transfers. The investigators make a strong case for three categorizations of embryos: euploid, aneuploid, and mosaic, and that use of mosaic embryos will prevent the discard of embryos that may lead to live birth. The final piece in this series was written by Besser etal., who discussed the various society recommendations for genetic counseling and prenatal diagnostic testing after mosaic embryo transfer and question whether these are truly data-driven. This collection of pieces will give the reader a deeper understanding of the controversy and management of mosaic embryo transfer.

Impact of Molecular Tumor Board (MTB) on precision oncology in a community setting

<h3>Objectives:</h3> Many cancer types, including gynecologic malignancies, have seen a surge of treatment and trial opportunities based on molecular profiling. We sought to evaluate the impact of a molecular tumor board (MTB) in a community setting on treatment decisions and outcomes. <h3>Methods:</h3> A systematic program of comphrensive genomic profiling (CGP) was initiated in December 2014. We performed a retrospective analysis of patients with MTB recommendations at a community-based oncology practice January 2015 to December 2018; exclusions were lack of follow-up or death within 60 days of the MTB and/or no metastatic disease. Potentially actionable genomic alterations from CGP (immunohistochemistry, in-situ hybridization, next-generation sequencing) were reviewed bi-weekly by MTB practice experts, pathologists, genetic counselors, and other support staff, and clinical care recommendations were provided. MTB recommendations by category (Figure 1) and number of recommendations followed by the treating physician were collated and analyzed for all cases presented at the MTB. <h3>Results:</h3> During the study period, 4,438 tests were ordered and 837 patients were presented at 87 MTBs Of these, 613/4,438 (14%) were evaluated. The median time between CGP result availability and MTB presentation was 12 days. The most common cancers were lung (23%), breast (19%), and colorectal (17%); others included ovarian, endometrial, bladder, and melanoma. Patients received 837 actionable recommendations: standard therapy (37%), clinical trial (31%), germline testing and genetic counseling (17%), off-label therapy (10%), subspecialty multidisciplinary tumor board review (2%), and advice for classifying tumor of unknown origin (2%). Of these recommendations, 36% to 78% were followed by the treating physician. Clinical trial recommendations were made for immediate enrollment, or for enrollment upon progression after standard of care therapy. Immediate trial recommendation was followed in 93 (56%) and 20 (12%) enrolled in a trial. For progression recommendations, 57 (60%) were followed and 15 (16%) enrolled on a clinical trial. MTB recommendations for standard therapy and off-label therapy were followed by the treating physician in 78% (n=244) and 37% (n=31) of cases, respectively. Germline testing and genetic counseling recommendations were followed in 36% (<i>n</i>=52) of cases. Of those who received testing, 39% (15/43) were positive for a germline mutation. <h3>Conclusions:</h3> The MTB was implemented to provide recommendations on clinical care, increase clinical trial participation, and improve awareness of standard or potential targeted therapies. We found MTB recommendations to be particularly useful in identifying clinical trial candidates. A community oncology-based comprehensive and high-throughput MTB provided useful clinical guidance in various treatment domains within an acceptable timeframe for patients with cancer in a large community setting.

Congenital Hypothyroidism: A Review of 2020 European Society for Pediatric Endocrinology and the European Society for Endocrinology Consensus Guidelines

Congenital Hypothyroidism: A Review of 2020 European Society for Pediatric Endocrinology and the European Society for Endocrinology Consensus Guidelines

Precision medicine, genetics and genomics in a community cancer clinic.

e13511 Background: With advances in technology and the decreasing cost of next generation sequencing (NGS) to identify both germline and somatic pathogenic variants, there is a critical need for curation and interpretation of these results. Clinicians often order the tests simultaneously. Our objective was to analyze results of NGS testing in a community cancer care clinic setting with a coordinated precision medicine program. Methods: In a retrospective review, we analyzed the germline NGS results from patients who were seen by the Hereditary Cancer Program (HCP) at Hoag Family Cancer Institute since 2001. Additionally, we compared those who had both positive genetic testing results and had tumor molecular profiling. Results: A total of 8,239 patients were seen by HCP, 6,100 had germline testing done, approximately 50% had multi gene panel testing (MGPT). 15% of the patients with germline testing had a pathogenic or likely pathogenic mutation. Of those with the positive results, 71% were breast and ovarian cancer and 29% were other cancer types. We also analyzed NGS results for 713 tumors tested through a commercial laboratory in one year. All cases were subjected to our secondary annotation, resulting in additional recommendations in 40% of cases, beyond what was in the commercial report and additional clinical trial options in 30%. Based on a new initiative in the past year, we examined tumor profiling results for indications of possible germline mutations. By analyzing those results, we made recommendations for genetic counseling in 91 (12.8%) cases. Conclusions: The data show the importance of genetic counseling and MGPT in a community setting in patients with personal and/or family history of cancer. Adoption of somatic and germline testing is increasing at our cancer center due to demonstrated benefit to patients and increased physician understanding of the clinical utility of molecular testing.

Genetic Counseling and Genome Sequencing in Pediatric Rare Disease.

Both genome sequencing (GS) and exome sequencing (ES) have proven to be revolutionary in the diagnosis of pediatric rare disease. The diagnostic potential and increasing affordability make GS and ES more accessible as a routine clinical test in some centers. Herein, I review aspects of rare disease in pediatrics associated with the use of genomic technologies with an emphasis on the benefits and limitations of both ES and GS, complexities of variant classification, and the importance of genetic counseling. Indications for testing, the role of genetic counselors in genomic test selection, and the diagnostic potential of ES and GS in various pediatric multisystem disorders are discussed. The neonatal population represents an important cohort in pediatric rare disease. Rapid ES and GS in critically ill neonates can have an immediate impact on medical management and present unique genetic counseling challenges. This work includes reviews of recommendations for genetic counseling for families considering genome-wide sequencing, and issues of access to genetic counseling that affect clinical use and will necessitate implementation of innovative methods such as online decision aids. Finally, this work will also review the challenges of having a child with a rare disease, the impact of results from ES and GS on these families, and the role of various support agencies.

An update on risk assessment for familial and hereditary colorectal cancer.

Family history risk assessment can identify individuals at increased risk of colorectal cancer (CRC) who would benefit from earlier or more frequent CRC screening. Clinicians should evaluate the patient's family history as well as personal history to identify red flags and patterns that may suggest predisposition to CRC and then use that information to stratify risk into average, increased, and high risk categories to inform genetic counseling recommendations and personalized management.

The current state of sickle cell trait: implications for reproductive and genetic counseling.

Sickle cell trait (SCT) is unique among the carrier states that are identified during newborn screening. Unlike other heterozygous states for rare recessive diseases, SCT is exceedingly prevalent throughout regions of the world, making sickle cell disease one of the most common monogenetic diseases worldwide. Because of this high frequency, reproductive counseling is of paramount importance. In addition, unlike other carrier states, SCT seems to be a risk factor for several clinical complications, such as extreme exertional injury, chronic kidney disease, and venous thromboembolism. Increasing knowledge about these clinical outcomes can help inform genetic counseling recommendations. Expanding research and clinical efforts are needed to ensure that the promises of modern and precision medicine can be delivered to the millions of SCT carriers and their children.

6. Human ring chromosome registry: Developing an interactive web resource for constitutional and cancer cytogenomic diagnosis

Constitutional ring chromosomes causing developmental disorders and somatic ring chromosomes in the form of double minutes, ring and marker chromosomes in various types of tumors have been documented. However, there are no organized efforts to compile and curate cytogenomic and clinical findings from ring chromosome cases. We have developed a web-based interactive Human Ring Chromosome Registry (HRCR) using a Microsoft Access based relational database to present cytogenomic and clinical findings from ring chromosome cases (http://web.gxmu.edu.cn/shengwu/HRC/home.asp). To validate the functional modules in this registry, constitutional ring chromosome cases reported in Chinese patients were compiled as a testing data set. From a total of 113 cases, relative frequencies, cytogenomic findings, and clinical features were summarized. An initial effort, focused on constitutional ring chromosome 21, classified the patients into three groups based on the cytogenomic findings and provided specific recommendations for prenatal and postnatal genetic counseling of ring chromosome 21. Furthermore, cytogenomic and genomic sequencing results from supernumerary ring chromosomes and derived giant marker chromosomes identified in liposarcoma were summarized to reveal the gene content of genomic imbalances, underlying mechanisms of ring formation, and implications for tumor classification and treatment. The development of HRCR has provided an interactive platform to compile and curate cytogenomic and clinical findings for constitutional and somatic ring chromosome cases. We propose a collaborative effort of clinical cytogeneticists and molecular geneticists to contribute to this online ring chromosome resource for establishing genotype-phenotype correlation and developing diagnostic guidelines and recommendations for genetic counseling and precise treatment.

Abstract P4-10-13: Analyses of racial disparities in genetic testing and surgical management of patients with triple-negative breast cancer in the era of multigene panel testing

Abstract Background Under-utilization of genetic counseling and testing among African-American (AA) women with breast cancer (BC) has been reported in previous studies, and there are concerns that disparities may widen with further genomic advances. Our objective was to compare AA and Caucasian (CC) patients with triple-negative breast cancer (TNBC) with regards to referral for genetic counseling, patterns of genetic testing, and patient-compliance with genetic counseling recommendations. We chose TNBC since a majority of these patients would qualify for genetic counseling ± testing. We also analyzed for differences between the two races in prevalence of deleterious BC-associated mutations, stage of BC on presentation, and surgical choices. Methods In this retrospective medical records-based observational study, we included all patients in our tumor registry with TNBC diagnosed between 09/01/2013 and 02/28/2017. Race, clinical characteristics and details pertaining to genetic counseling and testing were recorded. X2 test was used to compare categorical variables. A p-value &amp;lt; 0.05 was considered significant. Results 477 patients -358 CC and 96 AA- with TNBC were included. Mean age was 60.3 years. 331 patients met National Comprehensive Cancer Network (NCCN) criteria for genetic counseling - of these, 85.5% had genetic consult order placed, 72.8% attended counseling, and 71.9% underwent genetic testing (multigene panel testing 55.0%, BRCA 1/2 testing 39.9%, single-site testing 2.5%, and multisite-3 testing 2.5%). Between CC and AA, no significant differences were found in the proportion of qualifying patients who had referral for genetic counseling (84.7 vs 87.7%, p=0.562), attended counseling (72.2% vs 73.7%, p=0.816), or underwent genetic testing (72.1% vs 70.1%, p=0.764). The choices of type of genetic tests were also not significantly different between the two groups (p=0.349). Though the prevalence of highly penetrant mutations in breast cancer-associated genes trended to be higher among CC than AA (14.1% vs 9.5%), this difference did not reach statistical significance (p=0.429). In our population, stage of TNBC at presentation was comparable between the two races – 80.4% of CC presented with stage I or II disease compared to 80.2% of AA (p=0.931). The two groups were also comparable with regards to the choices of breast surgery and reconstruction, as shown in the table. CaucasiansAfrican-Americansp-valueSurgery TypePartial Mastectomy154(47.4%)38(44.7%)0.317 Unilateral Mastectomy101(31.1%)35(41.2%) Bilateral Mastectomy70(21.5%)12(14.1%)ReconstructionYes96(56.1%)24(51.1%)0.535 No75(43.9%)23(48.9%)Reconstruction TypeImplant87(90.6%)19(79.2%)0.118 Tissue Flap9(9.4%)5(20.8%) Conclusions Contrary to previous reports, in this cohort of TNBC patients, we did not identify significant disparities between AA and CC in patterns of referral for genetic counseling, in patient compliance with testing or in type of testing performed. Also, no significant differences were found between the two races in choices of breast surgery or reconstruction. As a caveat, with an overall insured rate of ˜97% across our network, the uninsured population may have been under-represented by our cohort. Citation Format: Gopalakrishnan D, Yanda C, Abbas H, Kline M, Stephens M, Grobmyer SR, Pederson HJ. Analyses of racial disparities in genetic testing and surgical management of patients with triple-negative breast cancer in the era of multigene panel testing [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-10-13.

The Laws of the Ring: Governing Mechanisms, Diagnostic Standards, and Therapeutic Potentials for Human Constitutional Ring Chromosomes

Human constitutional ring chromosomes are a rare type of chromosome structural abnormalities. The cytogenomic analysis of ring chromosome cases revealed different genomic imbalances and ring structures, variable levels of dynamic mosaicism, and selective karyotype evolution in different tissues. This cytogenomic heterogeneity is likely correlated with variable clinical manifestations of generalized features of ‘ring chromosome syndrome’, chromosome-specific and segmental aneuploidy related phenotypes, and risks of infertility and various types of cancers. Better understanding of the ‘biologic law’ governing ring chromosome formation and its mitotic segregation can contribute to the ‘diagnostic law’ guiding toward best practice in genetic analyses and the ‘therapeutic law’ for evidence-based treatment and management of ring chromosome disorders. Collaborative efforts are needed to study the biological processes involving ring chromosome formation, mitotic segregation and cell-autonomous correction, to develop cytogenomic diagnostic standards, and to generate registry of ring chromosome cases with defined genomic structures and dynamic mosaicism and detailed clinical manifestations. These efforts could provide more reliable karyotype-phenotype correlations for developing chromosome-specific guidelines and recommendations for genetic counseling and clinical treatment.

Clinical Aspects of SDHA-Related Pheochromocytoma and Paraganglioma: A Nationwide Study.

Paraganglioma (PGL) has the highest degree of heritability among human neoplasms. Current clinical understanding of germline SDHA mutation carriers is limited. To estimate the contribution of SDHA mutations in PGL and to assess clinical manifestations and age-related penetrance. Nationwide retrospective cohort study. Tertiary referral centers in the Netherlands (multicenter). Germline SDHA analysis was performed in 393 patients with genetically unexplained PGL. Subsequently, 30 index SDHA mutation carriers and 56 nonindex carriers were studied. SDHA mutation detection yield, clinical manifestations, and SDHA-related disease penetrance. Pathogenic germline SDHA variants were identified in 30 of the 393 referred patients with PGL (7.6%), who had head and neck PGL (21 of 174 [12%]), pheochromocytoma (4 of 191 [2%]), or sympathetic PGL (5 of 28 [18%]). The median age at diagnosis was 43 years (range, 17 to 81 years) in index SDHA mutation carriers compared with 52 years (range, 7 to 90 years) in nonmutation carriers (P = 0.002). The estimated penetrance of any SDHA-related manifestation was 10% at age 70 years (95% confidence interval, 0% to 21%) in nonindex mutation carriers. Germline SDHA mutations are relatively common (7.6%) in patients with genetically unexplained PGL. Most index patients presented with apparently sporadic PGL. In this SDHA series, the largest assembled so far, we found the lowest penetrance of all major PGL predisposition genes. This suggests that recommendations for genetic counseling of at-risk relatives and stringency of surveillance for SDHA mutation carriers might need to be reassessed.

Integrating a Geneticist in a Multidisciplinary Clinic for Down Syndrome Increases Commitment to Genetic Counseling

Although most physicians and genetic professionals are familiar with Down syndrome, many families do not have experience with Down syndrome before having a child diagnosed. The American Academy of Pediatrics has specific recommendations for genetic counseling and chromosome analysis for Down syndrome. The literature indicates that adherence to completion of appropriately timed genetic counseling is low at 31%. This study was initiated to determine our adherence rates and to improve if needed. In the Down syndrome clinic at Nationwide Children's Hospital, a subspecialty clinic in the Division of Developmental and Behavioral Pediatrics, a genetic counselor was on-call but did not routinely attend. The intervention consisted of multidisciplinary care with the presence of a clinical geneticist. Statistical Process Control Charts and Fisher's exact test were used to determine the impact of the intervention. Our baseline rate of adherence to genetic counseling was similar to previous publications. Direct genetics involvement in the Down syndrome clinic in place of an on-call genetic counselor led to significant improvement in adherence to genetic counseling recommendations over a 6-month period from 35% to 62%, P < 0.001 and sustained for 6 months. Postclinic adherence rates and subanalyses by age showed similar results. The final postvisit adherence rate of 89% in February 2017 demonstrates continued improvement. Geneticist involvement allowed chromosome reports uploading and karyotype listing in electronic medical records. Genetic counseling in newborns with Down syndrome is important, yet was often not received at Nationwide Children's Hospital before this study. Integrating a geneticist resulted in improvement. Implementing similar models at other institutions can ensure that the correct genetic testing is completed, results documented and families counseled appropriately.

Bicuspid Aortic Valve: a Review with Recommendations for Genetic Counseling.

Bicuspid aortic valve (BAV) is the most common congenital heart defect and falls in the spectrum of left-sided heart defects, also known as left ventricular outflow tract obstructive (LVOTO) defects. BAV is often identified in otherwise healthy, asymptomatic individuals, but it is associated with serious long term health risks including progressive aortic valve disease (stenosis or regurgitation) and thoracic aortic aneurysm and dissection. BAV and other LVOTO defects have high heritability. Although recommendations for cardiac screening of BAV in at-risk relatives exist, there are no standard guidelines for providing genetic counseling to patients and families with BAV. This review describes current knowledge of BAV and associated aortopathy and provides guidance to genetic counselors involved in the care of patients and families with these malformations. The heritability of BAV and recommendations for screening are highlighted. While this review focuses specifically on BAV, the principles are applicable to counseling needs for other LVOTO defects.

Abstract P1-11-04: Implementation of cancer risk assessment and genetic testing in underserved patients

Abstract PURPOSE: There is great disparity in genetic testing for breast cancer. Hispanic/Latina women with breast cancer are more likely to have adverse clinical features and have a high prevalence of BRCA mutations. We propose that Academic-Community clinic partnerships offer great potential to provide access to genetic cancer risk assessment (GCRA) for underserved communities, including Hispanic/Latina women. The study also evaluated the willingness of these patients to participate in biospecimen collection. METHODS: This study assessed the implementation of a limited GRCA and testing service at a safety net institution from July 1, 2011 to December 31, 2013. In the 10 years prior, only two breast cancer patients had undergone genetic testing and both were insured. The inability to perform GCRA was recognized as a critical area of need. Therefore, a breast surgical oncologist received training with City of Hope National Medical Center. The goal is to provide clinicians the appropriate skills to provide GCRA services in areas where these are not available. Three generation pedigrees and sociodemographic information were collected including health literacy, education, self-reported income, employment status, and insurance status. We conducted a comparison of the patient characteristics along the continuum of GCRA, genetic testing, and mutation carriers, and for the latter group, we describe the BRCA mutation profile. RESULTS: 125 patients were offered GCRA and all accepted, of which 70% of this patient population was Hispanic and 66% did not have health insurance. Of the 125 patients, 84 (67%) were recommended to undergo genetic testing and 81 (96%) agreed. Of the 81 patients who underwent genetic testing, 68 were also asked to participate in the City of Hope Cancer Screening and Prevention registry and all but one (94%) agreed. Significant differences between patients who had genetic testing and those who did not were shown for race/ethnicity, insurance, and family history. A higher percentage of Hispanic patients and patients with no insurance underwent testing. Additional trends in differences between patients who were tested vs. those who were not were observed for education and health literacy but these were not statistically significant. Few differences were observed between women who had genetic testing and mutation carriers; however, the number of carriers was too small to merit statistical testing. Twelve of 81 (15%) patients were found to have deleterious mutations, seven BRCA 1 and five BRCA 2. Of the 12 mutation carriers, one patient had ovarian cancer and therefore had already undergone bilateral salpingo-oophorectomy and two others underwent RRSO. Six are either considering RRSO or getting financial assistance for the operation. The last three are still undergoing breast cancer treatment. CONCLUSION: Results of our experience at a safety net hospital with a largely minority and uninsured population show that limited GCRA and testing can be successfully implemented. The great majority of patients agree to undergo counseling, testing, and participate in biospecimen research registries. Current recommendations for genetic counseling are far from being met across the country and this model could be considered for similar safety net populations. Citation Format: Ian K Komenaka, Lisa M Winton, Jesse N Nodora, Lisa Madlensky, Meredith A Heberer, Richard Schwab, Marcia E Bouton, Jeffrey N Weitzel, Maria Elena Martinez. Implementation of cancer risk assessment and genetic testing in underserved patients [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P1-11-04.