Cancer Genetic Services Research Articles

P502: CLINICAL IMPLEMENTATION OF GERMLINE GENETIC TESTING FOR HEMATOLOGIC DISORDERS

Background: Up to 18% of adult hematology patients (pts) suspected of having an inherited predisposition are found to have a germline mutation leading to a hereditary hematologic disorder (HHD). Timely identification of these disorders leads to heightened surveillance for malignancies, specific treatment regimens, donor selection, transplant conditioning regimens, cascade testing in family members and supportive care. Unlike solid tumour hereditary cancer syndromes, the investigations in HHD are more complex and there is no formal consensus of referral criteria or genetic testing criteria. We describe our initial experience in this patient population at our centre, the Princess Margaret Cancer Centre (PM). We have established a workflow to initiate germline genetic testing in pts under suspicion for a HHD. This involves a collaboration with a genetics clinic to 1) capture pts based on their personal/family history of cancer and suggestive genetic findings identified on bone marrow/blood, 2) procure a skin biopsy for fibroblast culture and germline DNA extraction and 3) provide follow-up counselling and management for positive results. Aims: Our goal is to evaluate the positivity rate of germline mutations in adult hematology pts who were referred for genetics assessment. Methods: The PM is the largest leukemia Centre in Canada, and has seen over 3000 adult pts with a malignant disorder from 2015-2021 (AML:1597, MDS:472, ALL:286, MPN:664 and marrow failure:22). We performed a retrospective chart review of all adult hematology pts referred to cancer genetics service for HHD workup during this time period. Results: 116 pts (66 male, 50 female) were suspected for a HHD and referred for germline genetic testing on fibroblast DNA. 52 pts (45%) were ≤40y old and 64 pts (55%) >40y old (age range 18-86y, median 53y). 71 pts (61%) were referred with a positive family history of hematologic disorders (HD). In addition, 61 pts presented with a myeloid malignancy (46 with MDS, AML, or CML, and 15 with a MPN), 42 presented with a lymphoid malignancy (ALL, CLL, or lymphoma), 8 presented with bone marrow failure, and 5 presented with other HD. 40 pts were found to have a germline genetic mutation, 7 of which were associated with carrier status. In total, 33 (28.4%) referred pts were found to have at least one actionable germline mutation. This corresponds to a positive genetic result found in 30% of pts referred with MDS/AML, 33% of pts referred with a lymphoid malignancy, and 18% of pts referred with bone marrow failure, MPN, or other HD. Additionally, 18 (55%) of these pts had a positive family history of HD, while 15 (45%) presented with no family history of HD. Of these 33 positive cases, 13 (11.2% of all referrals) occurred in a gene associated with a hematologic malignancy and resulted in a HHD diagnosis. 20 pts were found to have a mutation in a gene associated with a non-hematologic hereditary cancer syndrome. After the implementation of a HHD genetics workflow in 2018, we saw an increase in the total number of referrals to a genetics clinic over the past seven years, with 25 pts (6 positive cases) referred between 2015-2018, and 91 pts (27 positive cases) referred between 2019-2021. Image:Summary/Conclusion: Our overall positivity rate was 28.4% which includes mutations in any hereditary cancer gene, and 11.2% for HHDs. Our high pickup rate across all age groups and the increase in the number of referrals to genetics service suggests that more pts with HD, including older pts, would benefit from consultation with specialized centres that are experienced in the evaluation and treatment of these disorders.

Outcomes of the BRCA quality improvement dissemination program in three health systems.

10603 Background: The BRCA Quality Improvement Dissemination Program (BQIDP) was disseminated to 3 community-based health systems’ oncology clinics in 2017. The BQIDP occurred over 3 years and aimed to increase rates of guideline-recommended referral (ref), genetic counseling (GC), and germline genetic testing (GT) for patients diagnosed with invasive epithelial ovarian, fallopian tube, and primary peritoneal cancer (OC) and triple-negative breast cancer diagnosed at age 60 or younger (TNBC). The BQIDP applied virtual implementation facilitation to support sites’ development, implementation, and tracking of quality improvement (QI) interventions. Interventions were adapted from prior QI initiatives and published interventions. Methods: Baseline metrics (patients diagnosed 1/1/2015 to site’s BQIDP launch date Autumn 2017) were compared to metrics of patients diagnosed during BQIDP implementation (site launch dates Autumn 2017 to Autumn 2020). Two-sample test of proportions was used to assess for statistically significant change in rates pre and post BQIDP implementation at each site. QI interventions targeted provider and patient education, retrospective and prospective case finding with alerts to providers and patients, case finding by review of somatic test results and genetic counselor tumor board attendance, streamlined ref and scheduling processes, and infusion-suite based GC. Results: All clinics increased rates compared to baseline (Table). Statistically significant improvement was noted for patients with OC in receipt of GC at Site A, ref and receipt of GC at site B, and receipt of GC at site C. Statistically significant improvement was noted for patients with TNBC in ref and GT at sites A and B. Conclusions: Improved rates of ref, GC and GT for patients with OC and TNBC were observed at all 3 sites compared to baseline. Baseline ref, GC, and GT metrics for patients with TNBC were higher than for patients with OC at all sites. Tailored and facilitated QI efforts can promote patients’ receipt of guideline-recommended cancer genetics services in health system oncology clinics. [Table: see text]

Awareness of breast cancer genetic risk and role of genetic testing among women in Egypt: An online survey

Introduction: Emerging evidence suggests that cancer genetic services are less likely to be delivered in Low-to-Middle Income Countries (LMIC). Anecdotal evidence from clinical practice suggests that women decline genetic testing mainly due to high self-funded cost and low uptake of risk-reduction measures. Here, we aim to assess awareness of breast cancer inherited risk and willingness to accept genetic testing in low-resource settings.

Disparities in Cancer Genetic Testing and Variants of Uncertain Significance in the Hispanic Population of South Texas.

Racial and ethnic disparities have included a lack of access to both genetic testing and research, resulting in poor understanding of the genomic architecture in under-represented populations. The South Texas population is primarily of Hispanic background and has been largely devoid of genetic services. We extended access to this underserved population and uncovered genetic variants previously not observed, emphasizing the need to continually improve both genomic databases and clarification of variant significance to provide meaningful patient counseling. This study consisted of a retrospective cohort review of patients seen through a cancer genetics education and service program across 24 counties in South Texas. In total, 1,595 individuals were identified as appropriate for cancer genetic counseling and 1,377 completed genetic testing. Eighty percent of those receiving genetic counseling self-identified as Hispanic, 16% as non-Hispanic White (NHW), 3% as African American, and 1% as other race/ethnicity. Of reported variants, 18.8% were pathogenic and 13.7% were reported as a variant of uncertain significance (VUS). VUS was reported in 17.2% of the Hispanic individuals compared with 9% NHW (P = .005). Individuals of Hispanic ethnicity were significantly more likely to harbor a VUS compared with NHW. The extended reach into our regional communities revealed a gap in the ability to accurately interpret genomic variation with implications for advising patients on screening, prevention, and management strategies. A higher percentage of VUS also emphasizes the challenge of continued follow-up amid existing barriers that led to disparities in access. As understanding of the variants develops, hopefully gaps in knowledge of the genomic landscape will be lessened with increased clarity to provide accurate cancer risk assessment and recommendations for implementing prevention initiatives.

Outcomes of an advanced practice nurse (APN)-led cancer genetics service.

71 Background: In oncology practice, there are increasing numbers of patients for whom genetic testing is recommended by the National Cancer Care Network (NCCN), including all metastatic and high-risk localized prostate cancer patients. However, there is a critical shortage of genetics services providers. Acuity for these consults can be high, particularly in the context of a treatment related decision. We hypothesized that nurses, particularly advanced practice nurses (APNs), can provide a workforce within VA that can address genetic testing and genetic care needs of prostate cancer patients. Methods: We initiated a cancer genetics service staffed with an advanced practice nurse (APN) geneticist and evaluated the success of the program at a large urban, academic-affiliated Veteran’s Affairs Medical Center (VAMC). Results: In the one year prior to the initiation of the APN geneticist-run program (10/1/2019-9/30/2020), 61 unaffected patients with a family history of cancer and 85 patients with cancer (36 with prostate cancer) were referred to a VA centralized telegenetics service. An average of seven cancer patients (average three with prostate cancer) were referred to VA telegenetics per month. Genetic testing was completed in eleven (18%) of unaffected patients and 21 (25%) of cancer patients. Five (13%) of tested patients were found to have a pathogenic or likely pathogenic mutation or variant of uncertain significance (VUS). In the eight months after initiation of the APN geneticist-run consult service (10/1/2020 - 5/30/2021), 39 unaffected patients with a family history of cancer and 90 patients with cancer (38 with prostate cancer) were referred. An average of 11 cancer patients (average five with prostate cancer) per month were referred. This represents a 57% increase in all cancer patient and a 67% increase in prostate cancer patient referrals. For those patients referred to the APN geneticist-run consult service, genetic testing was completed in three (7%) of unaffected patients and 30 (33%) of cancer patients (including 15 prostate cancer patients). The genetic testing rate therefore improved from 1.7 oncology patients per month to 3.9 oncology patients per month, an 130% increase in genetic testing. For prostate cancer patients, the genetic testing rate improved from 0.8 to 1.9 patients tested per month, representing a 137% increase. Comparison of genetic testing outcomes at one year will be included in the final presentation. Conclusions: Inclusion of an APN geneticist-run consult service embedded in oncology clinics will likely improve access to genetics services and genetic testing rates in cancer patients.

Applying citizen science to engage families affected by ovarian cancer in developing genetic service outreach strategies.

Citizen science (CS) approaches involving non-professional researchers (citizens) as research collaborators has been used infrequently in health promotion generally and specifically, in cancer prevention. Standardized CS approaches may be especially useful for developing communication interventions to encourage families to consider cancer genetic services. We engaged survivors of ovarian cancer and their close relatives as CS collaborators to collect and help interpret data to inform content for a website, printed invitation materials, and short-message reminders. We applied an implementation quality framework, and posed four research questions regarding the feasibility of CS: recruitment, data collection, data quality and evaluation of the experience. CS members were recruited through three networks: clinical sites, local and national cancer support organizations, and online ovarian cancer patient support groups. The professional research team operationalized theory-aligned CS tasks, five data collection options, question banks/scripts for creating surveys, structured interviews, online training and ongoing support from research coaches. 14 CS members agreed to the 12-week and 20-hour commitment for an honorarium. CS members opted to do both qualitative and quantitative assessments. CS members collected 261 surveys and 39 structured interviews. The largest number of surveys were collected for Task 1 (n = 102) to assess survivors' reactions to different possible options for motivating survivors to visit a study website; 77% of this data were complete (i.e., no missing values). Data collected for tasks 2, 3, 4, and 5 (e.g., assessment of survivors' and relatives' respective communication preferences) ranged from 10 to 58 surveys (80% to 84% completeness). All data were collected within the specified time frame. CSs reported 17 hours of work on average and regarded the experience positively. Our experience suggests that CS engagement is feasible, can yield comprehensive quantitative and qualitative data, and is achievable in a relatively a short timeline.

Predicting the Likelihood of Carrying a BRCA1 or BRCA2 Mutation in Asian Patients With Breast Cancer.

With the development of poly (ADP-ribose) polymerase inhibitors for treatment of patients with cancer with an altered BRCA1 or BRCA2 gene, there is an urgent need to ensure that there are appropriate strategies for identifying mutation carriers while balancing the increased demand for and cost of cancer genetics services. To date, the majority of mutation prediction tools have been developed in women of European descent where the age and cancer-subtype distributions are different from that in Asian women. In this study, we built a new model (Asian Risk Calculator) for estimating the likelihood of carrying a pathogenic variant in BRCA1 or BRCA2 gene, using germline BRCA genetic testing results in a cross-sectional population-based study of 8,162 Asian patients with breast cancer. We compared the model performance to existing mutation prediction models. The models were evaluated for discrimination and calibration. Asian Risk Calculator included age of diagnosis, ethnicity, bilateral breast cancer, tumor biomarkers, and family history of breast cancer or ovarian cancer as predictors. The inclusion of tumor grade improved significantly the model performance. The full model was calibrated (Hosmer-Lemeshow P value = .614) and discriminated well between BRCA and non-BRCA pathogenic variant carriers (area under receiver operating curve, 0.80; 95% CI, 0.75 to 0.84). Addition of grade to the existing clinical genetic testing criteria targeting patients with breast cancer age younger than 45 years reduced the proportion of patients referred for genetic counseling and testing from 37% to 33% (P value = .003), thereby improving the overall efficacy. Population-specific customization of mutation prediction models and clinical genetic testing criteria improved the accuracy of BRCA mutation prediction in Asian patients.

Evaluation of a mainstream genetic testing program for women with ovarian or breast cancer.

Mainstream genetic testing refers to genetic testing arranged by a patient's treating specialist. The aim of this study was to retrospectively review a Sydney-based ovarian cancer mainstream genetic testing program. A Cancer Genetics Service (CGS)-supported mainstream genetic testing program was commenced in 2015. The CGS provided training, paperwork and ongoing and adaptable advice regarding appropriate genes for testing and interpretation of results. Written and electronic medical records were reviewed until August 2019 to assess patient and family history characteristics, genetic testing eligibility, results and posttest management for women who had testing coordinated via mainstreaming or by the CGS. Genetic testing was arranged for 289 women with ovarian cancer. Prior to 2017, 44% of genetic tests were mainstreamed, compared with 76% of tests from 2017 onwards. CGS was more likely to arrange testing for women with a strong family history of cancer and nonserous pathology. Germline pathogenic variants were detected in 13.7% (19/138) of women who had mainstream testing and 20.3% (14/69) of women tested by the CGS. Referral for posttest counseling occurred for pathogenic variant carriers identified through mainstreaming. This study demonstrated successful uptake of a mainstream ovarian cancer genetic testing program by medical oncologists, as evidenced by higher proportion and absolute numbers of eligible ovarian cancer patients accessing genetic testing through this pathway over time. The genetic testing criteria were appropriately assessed by oncologists and posttest referral occurred where required.

An overview of genetic services delivery for hereditary breast cancer.

Breast cancer is the most common cancer diagnosed in women worldwide, with approximately 5–10% of cases attributed to high penetrance hereditary breast cancer (HBC) genes. The tremendous advances in precision oncology have broadened indications for germline genetic testing to guide both systemic and surgical treatment, with increasing demand for cancer genetic services. The HBC continuum of care includes (1) identification, access, and uptake of genetic counseling and testing; (2) the delivery of genetic counseling and testing services; and (3) initiation of guideline-adherent follow-up care and family communication of results. Challenges to delivering care on the HBC care continuum include factors such as access to services, cost, discrimination and bias, and lack of education and awareness, which can be mitigated through implementing a multi-level approach. This includes strategies such as increasing awareness and utilization of genetic counseling and testing, developing new methods to meet the growing demand for genetic services, and improving the uptake of follow-up care by increasing patient and provider awareness of the management recommendations.

Psychosocial factors associated with genetic testing status among African American women with ovarian cancer: Results from the African American Cancer Epidemiology Study.

BackgroundRacial disparities in the uptake of cancer genetic services are well documented among African American (AA) women. Understanding the multiple social and psychological factors that can influence the uptake of genetic testing among AA women is needed.MethodsData came from 270 AA women diagnosed with ovarian cancer and participating in a population‐based, case‐control study of ovarian cancer who were asked about genetic testing. Logistic regression analyses tested the associations of predisposing, enabling, and need factors with reported genetic testing uptake.ResultsOne‐third of the sample (35%) reported having had genetic testing. In the multivariable model, AA women with higher incomes had more than double the odds of being tested than those with the lowest income (odds ratio [OR] for $25,000‐$74,999, 2.04; 95% confidence interval [CI], 1.06‐3.99; OR for ≥$75,000, 2.32; 95% CI, 0.92‐5.94). AA women who reported employment discrimination were significantly less likely to report genetic testing than those who did not report job discrimination (OR, 0.39; 95% CI, 0.14‐0.95). Marital status, Medicaid versus other insurance, prayer frequency, and perceived social support were significantly associated with genetic testing uptake in bivariate analyses but were not significant contributors in multivariable analyses.ConclusionsConsistent with other studies of AA women, a minority of African American Cancer Epidemiology Study participants had undergone genetic testing. Having a lower income and experiencing job discrimination decreased the likelihood of testing. These results provide foundational evidence supporting the need for interventions to improve the uptake of genetic testing among AA women by reducing cost barriers and providing credible assurances that genetic results will be kept private and not affect social factors such as employability.

Patient Interactions With an Automated Conversational Agent Delivering Pretest Genetics Education: Descriptive Study.

BackgroundCancer genetic testing to assess an individual’s cancer risk and to enable genomics-informed cancer treatment has grown exponentially in the past decade. Because of this continued growth and a shortage of health care workers, there is a need for automated strategies that provide high-quality genetics services to patients to reduce the clinical demand for genetics providers. Conversational agents have shown promise in managing mental health, pain, and other chronic conditions and are increasingly being used in cancer genetic services. However, research on how patients interact with these agents to satisfy their information needs is limited.ObjectiveOur primary aim is to assess user interactions with a conversational agent for pretest genetics education.MethodsWe conducted a feasibility study of user interactions with a conversational agent who delivers pretest genetics education to primary care patients without cancer who are eligible for cancer genetic evaluation. The conversational agent provided scripted content similar to that delivered in a pretest genetic counseling visit for cancer genetic testing. Outside of a core set of information delivered to all patients, users were able to navigate within the chat to request additional content in their areas of interest. An artificial intelligence–based preprogrammed library was also established to allow users to ask open-ended questions to the conversational agent. Transcripts of the interactions were recorded. Here, we describe the information selected, time spent to complete the chat, and use of the open-ended question feature. Descriptive statistics were used for quantitative measures, and thematic analyses were used for qualitative responses.ResultsWe invited 103 patients to participate, of which 88.3% (91/103) were offered access to the conversational agent, 39% (36/91) started the chat, and 32% (30/91) completed the chat. Most users who completed the chat indicated that they wanted to continue with genetic testing (21/30, 70%), few were unsure (9/30, 30%), and no patient declined to move forward with testing. Those who decided to test spent an average of 10 (SD 2.57) minutes on the chat, selected an average of 1.87 (SD 1.2) additional pieces of information, and generally did not ask open-ended questions. Those who were unsure spent 4 more minutes on average (mean 14.1, SD 7.41; P=.03) on the chat, selected an average of 3.67 (SD 2.9) additional pieces of information, and asked at least one open-ended question.ConclusionsThe pretest chat provided enough information for most patients to decide on cancer genetic testing, as indicated by the small number of open-ended questions. A subset of participants were still unsure about receiving genetic testing and may require additional education or interpersonal support before making a testing decision. Conversational agents have the potential to become a scalable alternative for pretest genetics education, reducing the clinical demand on genetics providers.

Impact of Variant Reclassification in Cancer Predisposition Genes on Clinical Care

Genetic testing has clinical utility in the management of patients with hereditary cancer syndromes. However, the increased likelihood of encountering a variant of uncertain significance in individuals of non-European descent such as Asians may be challenging to both clinicians and patients. This study aims to evaluate the impact of variant reclassification in an Asian country with variants of uncertain significance reported in cancer predisposition genes. A retrospective analysis of patients seen at the Cancer Genetics Service at the National Cancer Centre Singapore between February 2014 and March 2020 was conducted. The frequency, direction, and time to variant reclassification were evaluated by comparing the reclassified report against the original report. A total of 1,412 variants of uncertain significance were reported in 49.9% (845 of 1,695) of patients. Over 6 years, 6.7% (94 of 1,412) of variants were reclassified. Most variants of uncertain significance (94.1%, 80 of 85) were downgraded to benign or likely benign variant, with a smaller proportion of variants of uncertain significance (5.9%, 5 of 85) upgraded to pathogenic or likely pathogenic variant. Actionable variants of uncertain significance upgrades and pathogenic or likely pathogenic variant downgrades, which resulted in management changes, happened in 31.0% (39 of 126) of patients. The median and mean time taken for reclassification were 1 and 1.62 year(s), respectively. We propose a clinical guideline to standardize management of patients reported to have variants of uncertain significance. Management should be based on the patient's personal history, family history, and variant interpretation. For clinically relevant or suspicious variants of uncertain significance, follow-up is recommended every 2 years, as actionable reclassifications may happen during this period.

\u201cLeft in limbo\u201d: Exploring how patients with colorectal cancer interpret and respond to a suspected Lynch syndrome diagnosis

BackgroundA diagnosis of suspected Lynch syndrome (SLS) is given when a tumour displays characteristics consistent with Lynch syndrome (LS), but no germline pathogenic variant is identified. This inconclusive diagnosis results in uncertainty around appropriate cancer risk management. This qualitative study explored how patients with CRC interpret and respond to an SLS diagnosis.MethodsSemi-structured telephone interviews were conducted with 15 patients with CRC who received an SLS diagnosis, recruited from cancer genetics services across Australia. Interviews were transcribed verbatim and analysed using thematic analysis. Participant responses were compared with appointment summary letters from cancer genetics services.ResultsParticipants’ interpretations of genetic test results were found to vary widely. While this variation often aligned with variation in interpretations by cancer genetics services, participants also had difficulties with the complexity and recall of genetic test results. Participants had a range of psychological responses to the uncertainty that their results presented, from relief to disappointment and doubt. Cancer risk perceptions also varied widely, with participants’ interpretations of their genetic test results just one of several influencing factors. Despite this variability, almost all participants adhered to cancer risk management advice, although different participants received different advice. All participants also communicated any cancer risk management advice to first-degree relatives, motivated by protecting them, but information communicated was not always consistent with advice received.ConclusionsOur study findings highlight the variability in patients’ interpretations of their diagnosis, cancer risk management and family communication when a diagnosis of SLS is received, and provide novel insights into how healthcare professionals can better support patients with SLS.

Large-scale group genetic counseling: Evaluation of a novel service delivery model in a Canadian hereditary cancer clinic.

Increasing demand for genetic services has led to the development of streamlined genetic counseling (GC) models. We piloted large-scale group pre-test GC with up to 50 patients per group and compared this to a traditional one-on-one approach. Patients referred to the British Columbia (BC) Cancer Hereditary Cancer Program were eligible if they had: (a) family history meeting our program's referral criteria; (b) no relevant personal history of cancer; (c) no prior genetic testing in the family; and (d) no living testable relative in BC. Patient-reported outcome measures included: (a) Genetic Counselling Outcome Scale (GCOS) prior to pre-test GC (T1) and at 4weeks post-test GC (T2); (b) Satisfaction Survey after pre-test GC; and (c) the Multidimensional Impact of Cancer Risk Assessment (MICRA) for patients undergoing testing (4weeks after post-test GC). In total, 391 patients underwent GC, 184 by group and 207 by one-on-one appointments. Between May 2018 and May 2019, 6 pre-test group sessions were conducted (median number of patients per group=28; range 15-48). 8% of patients (n=32) declined large group GC due to personal preference for one-on-one GC. There were no statistically significant differences in MICRA and GCOS survey results when comparing the pre-test large group versus traditional pre-test one-on-one models (based on 3 MICRA subscales: p=0.063, p=0.612, p=0.842; and GCOS p=0.169). Overall, the large group pre-test counseling approach was more time-efficient with 15-48 patient group sessions conducted over a mean duration of 80min as compared to 42min per patient with the traditional one-on-one GC model. Large-scale group GC was feasible and acceptable to patients and represents a novel streamlined model for GC to enable timely access to cancer genetic services.

Developing genetic counselling services in an underdeveloped healthcare setting

Genetic counselling services are well established in North America, Western Europe and Australia. In other regions, genetic counselling services are still emerging. Where this is the case, an in-depth understanding of the main stakeholders’ needs, challenges and opportunities will inform the changes and innovations required to bring genetic counselling closer to the community. The present study explored the needs and challenges of patients, family members and professionals with a view to setting up a cancer genetic counselling service in Romania. In order to get a comprehensive outlook, key stakeholders were interviewed using data source triangulation method. Thirty-four semi-structured interviews were conducted (13 patients, 11 family members and 10 professionals). Thematic analysis was used to explore and identify needs, barriers and opportunities in emerging cancer genetic counselling services. Three major themes were identified: (1) the “Needs” theme mainly focuses on various types of support that participants mentioned wanting: psychosocial, peer and additional support; (2) the “Challenges” theme includes aspects related to limited access to healthcare, lack of integrated services and pressure on the families; (3) the “Hopes” theme highlights the wish for integrated healthcare and an empathic rapport with healthcare providers. Our findings highlighted the main needs, challenges and hopes the patients, family members and professionals have and provides the groundwork for setting up cancer genetic counselling services.

Strategies for Lynch syndrome identification in selected and unselected gynecological cancers.

Endometrial carcinoma represents a sentinel cancer for Lynch syndrome (LS) identification. It is crucial to highlight how other types of tumors can arise in the gynecological tract acting as sentinel tumors in LS patients.Up to now, no established LS patient management strategy has incorporated the presence of these additional candidate sentinel tumors to improve the prevention and management of LS tumors. In order to investigate the involvement of the most frequent gynecological cancers in gynecological cancers, we studied different subsets of gynecological cancers using both somatic approaches, including mismatch repair (MMR) gene immunohistochemical expression, microsatellite instability, and germline analyses ofMSH2, MSH6, MLH1, PMS2 and EPCAM genes.A total of 261 patients referring to the Cancer Genetic Counselling Service of our institution were included in the study. In detail, our series was composed of 131 patients affected by uterus cancers including endometrial, isthmus and non-HPV endocervical carcinomas, 113 patients affected by ovarian cancers and 17 patients affected by synchronous endometrial/ovarian carcinomas (SEOC).In addition, we studied 115 cases of endometrial cancers identified by 2 years of universal testing (endometrial cancers/UTs) using IHC analysis of four MMR proteins. The incidence of MMR defective gynecological cancers ranged from 7.1 to 47.1% depending on cancer site and selection. LS patients carriers of pathogenetic MMR variants were identified in 19.8% of uterus cancers, 35.3% of SEOC, 4.4% of ovarian cancers. In addition, pathogenetic MMR variants were identified in 4.3% of endometrial cancers/universal testing investigated with universal screening.In conclusion, gynecological cancers are heavily involved in LS and our study shows that MMR screening using immunohistochemical pattern and MSI analysis of endometrial and ovarian cancers as well as of rare entities such as non-HPV related endocervical cancers and synchronous endometrial and ovarian cancers are sentinels for LS.Tumor testing approach improves early identification of MMR defective gynecological cancers and this is an effective strategy to detect high-risk patients and to offer them and their relatives personalized cancer prevention.

Feasibility of genetic testing for cancer risk assessment programme in Nigeria.

BackgroundA high frequency of BRCA mutations has been established in Nigerian breast cancer (BC) patients. Recently, patients’ and first-degree relatives’ interest have been raised on cancer genetic risk assessment through our awareness activities in Nigeria. This led to the emergence of nurse-led cancer genetic counselling (CGC) and testing aimed at providing standard-of-care for individuals at increased risk of hereditary breast and ovarian cancers.MethodsIn June 2018, CGC and testing of patients with BC and ovarian cancer (OC) commenced in collaboration with Color Genomics Inc. for a 30-panel gene testing. Previously trained nurses in CGC at the University College Hospital, Ibadan offered genetic counselling (GC) to willing patients with BC and gynaecological cancer in four out-patient oncology clinics and departments for the pilot study. Consultation consisted of CGC, patient’s history, pedigree and sample collection for genetic testing (GT).ResultsForty-seven patients – 40 with BC, five with OC and two with endometrial cancer received GC, and all chose to undergo GT. The average age at testing was 48.2 ± 12.1 years. Eight women reported a known family cancer history and there were more perceived benefits than barriers to GT with the patients experiencing the desire for none of their relative to have cancer. Results revealed no mutations in 27 (57.4%), 16 (4.0%) variants of unknown significance and 4 (8.5%) pathogenic mutations.ConclusionPersonalised cancer care utilises GC and testing for cancer risk assessment towards prevention and early detection in high risk women. The study indicates the necessity of expanded cancer genetic services for integration into patient care and cancer prevention.

Comparing models of delivery for cancer genetics services among patients receiving primary care who meet criteria for genetic evaluation in two healthcare systems: BRIDGE randomized controlled trial

BackgroundAdvances in genetics and sequencing technologies are enabling the identification of more individuals with inherited cancer susceptibility who could benefit from tailored screening and prevention recommendations. While cancer family history information is used in primary care settings to identify unaffected patients who could benefit from a cancer genetics evaluation, this information is underutilized. System-level population health management strategies are needed to assist health care systems in identifying patients who may benefit from genetic services. In addition, because of the limited number of trained genetics specialists and increasing patient volume, the development of innovative and sustainable approaches to delivering cancer genetic services is essential.MethodsWe are conducting a randomized controlled trial, entitled Broadening the Reach, Impact, and Delivery of Genetic Services (BRIDGE), to address these needs. The trial is comparing uptake of genetic counseling, uptake of genetic testing, and patient adherence to management recommendations for automated, patient-directed versus enhanced standard of care cancer genetics services delivery models. An algorithm-based system that utilizes structured cancer family history data available in the electronic health record (EHR) is used to identify unaffected patients who receive primary care at the study sites and meet current guidelines for cancer genetic testing. We are enrolling eligible patients at two healthcare systems (University of Utah Health and New York University Langone Health) through outreach to a randomly selected sample of 2780 eligible patients in the two sites, with 1:1 randomization to the genetic services delivery arms within sites. Study outcomes are assessed through genetics clinic records, EHR, and two follow-up questionnaires at 4 weeks and 12 months after last genetic counseling contactpre-test genetic counseling.DiscussionBRIDGE is being conducted in two healthcare systems with different clinical structures and patient populations. Innovative aspects of the trial include a randomized comparison of a chatbot-based genetic services delivery model to standard of care, as well as identification of at-risk individuals through a sustainable EHR-based system. The findings from the BRIDGE trial will advance the state of the science in identification of unaffected patients with inherited cancer susceptibility and delivery of genetic services to those patients.Trial registrationBRIDGE is registered as NCT03985852. The trial was registered on June 6, 2019 at clinicaltrials.gov.

Variant reclassification and its impact on clinical care in an Asian cancer center.

10583 Background: Genetic testing has demonstrated clinical utility in the identification and subsequent surveillance of patients with cancer predisposition syndromes. However, the increased likelihood of encountering a variant of uncertain significance (VUS) in individuals of non-European descent such as Asians may be challenging to both clinicians and patients in interpretation and management. VUS can be reclassified as more data becomes available. VUS reclassification is important, as it may have implications for surveillance and treatment. This study aims to evaluate the prevalence and patterns of variant reclassification in an Asian country and its impact on patient management. Methods: A prospective cohort of patients seen at the Cancer Genetics Service at the National Cancer Center Singapore between February 2014 to March 2020 was evaluated. The frequency, direction and time to variant reclassification was assessed by comparing the reclassified report against the original report. Results: A total of 1412 VUS were reported in 49.9% (845/1695) of patients. Over six-years, 6.7% (94/1412) of variants were reclassified. Most VUS (94.1%; 80/85) were downgraded to benign/likely benign variant, with a smaller proportion of VUS (5.9%; 5/85) upgraded to pathogenic/likely pathogenic variant. Actionable VUS upgrades and pathogenic/likely pathogenic variant downgrades, that resulted in management changes, happened in 31.0% (39/126) of patients. The median and mean time taken for reclassification were 1 and 1.62 year(s) respectively. Conclusions: Clinicians need to put in place a system for review of variants, as variant reclassification can lead to changes in management in nearly 1/3 of patients. Management should be based on the patient’s personal history, family history and variant interpretation. We propose a clinical guideline to standardize management of patients with VUS. For clinically relevant or suspicious VUS, follow-up is recommended every two years, as actionable reclassifications may happen during this period.

The impact of converting to telehealth for cancer genetic counseling and testing during the COVID-19 pandemic.

e13612 Background: The COVID-19 outbreak in March 2020 resulted in the shift to telemedicine for many specialties including cancer genetic counseling (GC). We sought to understand the impact that converting GC services to telehealth (TH) would have on patient acceptance of recommended genetic testing, time to completion of testing, and time to follow-up GC consultation. Methods: Data analyzing GC in-patient vs. TH consultations were collected using both electronic medical record as well as a laboratory’s testing portal. Statistical analysis was performed using R statistical software. The rates of patient agreement to genetic testing and sample success, along with the time to report availability and to GC follow-up visit was compared between traditional in-person visits and TH visits during the COVID-19 pandemic. In-person visits from March -July 2019 were compared with date matched visits from March -July 2020, when all visits had been converted to TH. Patients who received an in-person consultation received a blood draw on the day of their appointment while TH patients were asked to mail a saliva sample back to the testing laboratory. Results: An analysis of a case-matched cohort between 2019 in-person new visits (n = 30) and 2020 TH new visits (n = 48) was performed. There was not a significant difference in rate of consent to suggested testing between in-person (93.3%) and TH (91.2%) (p = 0.29), though a few TH patients who consented failed to submit a sample (% tested = 93.3% vs. 85.4%, p = 0.01). TH patients had a longer time between their initial consult and when the test report was generated with average turn-around time increasing from 14.33 to 33.82 days (p < 0.1). There was no increase in time from initial consultation to follow up GC appointments (70.46 vs. 75.96 days, p = 0.74) for TH and in-person, respectively. Conclusions: Our data shows that during COVID-19, TH allowed patients to access GC with no significant differences in the length of time between initial consultation and follow up appointments. The type of GC received did not greatly influence a patient’s willingness to consent to testing, despite challenges related to the COVID-19 pandemic, indicating that TH services may be an acceptable substitute. However, TH services are not without their limitations as time between the initial appointment and receipt of test results was significantly longer and sample failure rates were higher. We postulate that the delay was due to the time it took to ship the saliva kit, have the patient collect the sample at home, and return the specimen back to the lab rather than the immediate blood draw that occurs during the in-person visit. The higher sample failure rate seen in TH is likely due to the differences between blood and saliva collections. Additional research is needed to fully understand the outcomes observed in this study in order to assist in developing the most effective strategies for cancer genetic TH services.