Guidelines For Genetic Testing Research Articles

The impact of virtual live education on the competence and knowledge of gynecologists caring for ovarian cancer patients.

e23003 Background: About 35% of ovarian cancer patients in the US have geographic-related disparities in their access to gynecologic oncologists. This disparity becomes more apparent as advances in the treatment of ovarian cancer continues to improve, particularly in regard to maintenance therapy (e.g., PARP inhibitors). Thus, it is critical for gynecologists who are most likely to see these patients over the span of their lives, have an intimate understanding of the management of these patients. Methods: CEC Oncology developed an educational initiative presented at four American College of Obstetricians and Gynecologists District Meetings, targeting obstetricians, gynecologists, and other health professionals. Education focused on PARP inhibitors in ovarian cancer, identification of those eligible for genetic testing and counseling, and strategies to improve patient outcomes. Evaluations were collected from attendees attending the District Meetings to assess impact on practice, increased competency, and intent to make a change in practice. This was objectively assessed by analyzing pre-test, post-test, and follow-up survey data (sent 4-6 weeks post-activity). Chi-square analysis was conducted with a priori significance set at 0.05. Results: A total of 183 clinicians were educated, practicing in academic settings (44%), community hospital settings (24%), private practice (25%), and government (7%). Attendees were asked case questions at baseline, immediately after the activity, and 4-6 weeks after the activity to assess knowledge about the DNA damage response pathway, genetic testing guidelines, and management of therapy toxicities. Knowledge increased from pre- to post-test and from pre-test to follow-up for all topics, with the greatest increase in the management of adverse events (41% increase from pre- to post-test; 50% increase from pre-test to follow-up; P< 0.01). Additionally, there was a 22% and 24% increase in confidence in identifying patients eligible for germline genetic testing and in recognizing toxicities with PARP inhibitors from pre-test to six-week follow-up, respectively. 60% of participants stated that there was a lack of patient education regarding the importance of genetic testing and counseling. At follow-up, 100% stated that they had educated patients on genetic testing and counseling, highlighting the value of educating gynecologists on this topic. Conclusions: Attendees of this educational initiative were eager to take back the knowledge learned to their clinical practices. While there was a measurable increase in knowledge with regard to different ovarian cancer related topics, educational gaps remain. Collectively, this particular audience stated that they care for > 1,000 ovarian cancer patients, elucidating the need for OB/GYNs to feel more comfortable regarding PARP inhibitor toxicities, as they become more prevalent in practice.

Adherence to genetic testing guidelines in pancreatic cancer and impact on treatment.

e16238 Background: NCCN June 2019 Guidelines recommend that clinicians consider germline (GL) testing for patients(pts) diagnosed with pancreatic cancer (PDAC) and consider molecular analysis of tumors in pts with metastatic disease. Up to 25% of advanced PDAC pts have GL or somatic mutations in the DNA damage repair (DDR) pathway which are predictive of response to platinum chemotherapy (plat) and maintenance therapy with olaparib. Referral for genetic testing (GT) at our institution is currently made at provider discretion. We aimed to determine rates of GT, factors associated with GT, and outcomes of those tested. Methods: Frequency of GT testing was examined in pts with non-endocrine PDAC and >2 visits between 6/2019 and 6/2021 at Mount Sinai Health System. Clinicopathological variables and treatment outcomes were also recorded. Results: 149 pts were included. 71 pts (48%) were male. 25 pts (17%) had a personal history of cancer and 8 (5.3%) with history of DDR related cancer (prostate, breast, ovarian). 66 pts (44%) had GL testing: 42 (28%) at diagnosis with the remainder later in treatment. The rate of GL testing increased every year: 33% (2019), 44% (2020), 61% (2021). There was no statistically significant association between decision to do GL testing and age, ECOG, race, personal or family history (FH) of cancer. A FH of DDR related cancer was positively associated with GL testing (47% vs 27% p=0.039). 8 pts (12% of pts tested) had pathological gMut: BRCA1 (1), BRCA2 (1), ATM (2), PALB2 (2) , NTHL1 (1), both CHEK2 and APC (1). 6 pts (75%) had GL testing at diagnosis. One g BRCA2 pt had a plat response. Neither g BRCA pt received a PARP inhibitor. 24 pts in total had a response to plat, 16 (67%) of whom had GL testing. 94 pts (63%) had molecular tumor testing (including 65% of pts with metastases). Pathogenic mut in DDR genes were identified in 9 pts: ARID1A (2), BRCA2 (3), ATM (2), PALB2 (2), CHEK2 (1). Four of these pts had corresponding gMuts. One pt with somatic ATM mut had g BRCA1 mut. Two pts with BRCA2 somatic mut did not have GL testing. Conclusions: GT based on provider discretion resulted in suboptimal rates of GL testing. However, since inception of national guidelines, testing rates nearly doubled. Rates of GL DDR mutations were lower than previously reported, with varying response to plat in this cohort. Future studies are needed to understand barriers to GT and improve implementation.[Table: see text]

Improving access to cancer genetic testing for underserved women in southeast Texas.

6548 Background: Hereditary breast cancer accounts for 5-10% of all cases, but only 20% of eligible women undergo NCCN guideline-concordant screening. We demonstrated previously that our simple genetic risk screening tool (GRST) and telegenetics improved adherence to genetic testing guidelines and increased high-risk cancer surveillance. Our objective was to identify women eligible for genetic testing using breast cancer screening clinics in underserved communities as entry points, reach them with our tailored program, and measure impact. Methods: This is a prospective study in women presenting for breast cancer screening at The Rose, which provides breast imaging to underserved patients in Houston, TX. Women who consented to participate filled out the GRST and provided socio-demographic information. Those at high risk for hereditary cancer after GRST scoring were provided with educational materials and sent a saliva-based genetic testing kit. When results included a pathogenic variant (PV) or variant of uncertain significance (VUS), individuals received telegenetic counseling and risk reduction resources. Others were notified of negative results by phone. The program included education for providers about importance of genetic testing. Socio-demographic characteristics were analyzed using descriptive statistics. All statistical tests were two-sided. Results: 501 women filled out the GRST. Median age was 52. Median annual salary was $45,000 (IQR 21-75K). 151 (36.3%) were uninsured. 252 (50.3%) identified as White, 230 (45.9%) as Hispanic/Latino, and 106 (21.2%) as Black/African American. 150 (33%) were eligible for genetic testing; 100 could be contacted. Of the 100, 41 declined testing, 40 were lost to follow-up, 19 agreed, and 15 (10% of those eligible) returned the kits. Results included 11 negative, 2 VUS, 1 PV (NF1). Among 41 who declined testing, reported reasons included not wanting to know the results or preference to follow-up with their primary care doctor in 11 (26.8%) each, not enough time or prior genetic testing in 6 (14.6%) each, no reason given by five, and perception that testing was unnecessary in two. Completion of genetic testing was not associated with insurance, salary, family history, or race/ethnicity (p > 0. 05). Conclusions: Our study was successful in identifying underserved women at high risk of hereditary cancer who have not previously undergone genetic testing using a simple screening tool. We reduced barriers to genetic testing by working with a trusted community organization and using remote testing and telegenetics. We did not find any factors associated with genetic testing completion, though results are limited by small sample size. Given the low proportion of patients who completed testing, the next project phase will focus on improving convenience for patients and exploring patient and program-related reasons for non-completion of testing and strategies to overcome these.

Usage of Genetic Panels in an Adult Epilepsy Clinic.

There is limited data on the utility, yield, and cost efficiency of genetic testing in adults with epilepsy. We aimed to describe the yield and utility of genetic panels in our adult epilepsy clinic. We performed a retrospective, cross-sectional study of all patients followed by an epileptologist at a Canadian tertiary care centre's epilepsy clinic between January 2016 and August 2021 for whom a genetic panel was ordered. A panel was generally ordered when the etiology was unknown or in the presence of a malformation of cortical development. We determined the yield of panel positivity and of confirmed genetic diagnoses. We also estimated the proportion of these diagnoses that were clinically actionable. In total, 164 panels were ordered in 164 patients. Most had refractory epilepsy (80%), and few had comorbid intellectual disability (10%) or a positive family history of epilepsy (11%). The yield of panel positivity was 11%. Panel results were uncertain 49% of the time and negative 40% of the time. Genetic diagnoses were confirmed in 7 (4.3%) patients. These genetic conditions involved the following genes: SCARB2, DEPDC5, PCDH19, LGI1, SCN1A, MT-TL1, and CHRNA7. Of the seven genetic diagnoses, 5 (71%) were evaluated to be clinically actionable. We report a lower diagnostic yield for genetic panels in adults with epilepsy than what has so far been reported. Although the field of the genetics of epilepsy is a fast-moving one and more data is required, our findings suggest that guidelines for genetic testing in adults are warranted.

Demographic Barriers for Genetic Testing in High-Risk Breast Cancer Patients in the Northern Michigan Area.

Introduction: The National Comprehensive Cancer Network (NCCN) has outlined guidelines for criteria regarding genetic testing for high-penetrance breast and/or ovarian cancer susceptibility genes. Due to the lack of availability of genetic counseling services in Northern Michigan prior to COVID-19, the utilization of genetic testing falls well below recommended guidelines.Methods: Patients diagnosed with breast cancer in 2019 were randomly selected from Ascension Michigan's Northern Ministries Tumor Registry. A retrospective chart review was conducted. For patients who met NCCN criteria, their medical records were used to determine if genetic testing was recommended and if genetic testing was completed. Univariate (Crosstabs and t-tests) and multivariate tests with logistic regression were used to identify significant associations between the variables of interest.Results: One hundred and two (102) patient charts were reviewed in this group; 55 (52.4%) were eligible by the NCCN guidelines for genetic testing. From this eligible subset of patients, only 29 were offered genetic testing, and only 21 were tested. The mean age of the patients offered genetic counseling was 56.2 years compared and 67.6 years in the group not offered counseling (p < 0.001). The patient's insurance type was an independent factor for obtaining genetic testing, specifically, the subgroup who had Medicare (OR = 0.73, CI = 0.01-0.54; p = 0.02). Patients insured through Medicare were less likely to obtain genetic testing after referral to a genetic counselor (p = 0.01).Conclusion: Genetic counseling for high-risk breast cancer patients is below average in Northern Michigan, likely related to lack of physician referral, poor availability of counseling services, low socioeconomic status as well as a lower level of concern in older ages.

Novel Interactive Tool for Breast and Ovarian Cancer Risk Assessment (Bright Pink Assess Your Risk): Development and Usability Study.

BackgroundThe lifetime risk of breast and ovarian cancer is significantly higher among women with genetic susceptibility or a strong family history. However, current risk assessment tools and clinical practices may identify only 10% of asymptomatic carriers of susceptibility genes. Bright Pink developed the Assess Your Risk (AYR) tool to estimate breast and ovarian cancer risk through a user-friendly, informative web-based quiz for risk assessment at the population level.ObjectiveThis study aims to present the AYR tool, describe AYR users, and present evidence that AYR works as expected by comparing classification using the AYR tool with gold standard genetic testing guidelines.MethodsThe AYR is a recently developed population-level risk assessment tool that includes 26 questions based on the National Comprehensive Cancer Network (NCCN) guidelines and factors from other commonly used risk assessment tools. We included all women who completed the AYR between November 2018 and January 2019, with the exception of self-reported cancer or no knowledge of family history. We compared AYR classifications with those that were independently created using NCCN criteria using measures of validity and the McNemar test.ResultsThere were 143,657 AYR completions, and most participants were either at increased or average risk for breast cancer or ovarian cancer (137,315/143,657, 95.59%). Using our estimates of increased and average risk as the gold standard, based on the NCCN guidelines, we estimated the sensitivity and specificity for the AYR algorithm–generated risk categories as 100% and 89.9%, respectively (P<.001). The specificity improved when we considered the additional questions asked by the AYR to define increased risk, which were not examined by the NCCN criteria. By race, ethnicity, and age group; we found that the lowest observed specificity was for the Asian race (85.9%) and the 30 to 39 years age group (87.6%) for the AYR-generated categories compared with the NCCN criteria.ConclusionsThese results demonstrate that Bright Pink’s AYR is an accurate tool for use by the general population to identify women at increased risk of breast and ovarian cancer. We plan to validate the tool longitudinally in future studies, including the impact of race, ethnicity, and age on breast and ovarian cancer risk assessment.

Hereditary cancer risk assessment in the community urology practice setting.

278 Background: Professional guidelines recommend hereditary cancer risk assessment (HCRA) for men with prostate cancer to inform both risk of cancer (primary or subsequent) and treatment decisions. The objectives of the study were to evaluate the feasibility of integrating a HCRA protocol in urology practice for patients with prostate cancer and determine the response of providers and patients to the HCRA protocol. Methods: This prospective study was divided into 4 segments: process integration (4 wks.), practice (4 wks.), post-integration (8 wks.), and follow up (10 wks.). Study site staff were trained to perform HCRA for men with prostate cancer (integration). The sites then incorporated recommendations from the integration process into their normal practice workflow (practice). During the post-integration period, the HCRA process was implemented with eligible patients consented to participate. Eligible patients were ≥18 years old, had a personal history of prostate cancer, and met National Comprehensive Cancer Network guidelines for genetic testing (2.2018). Patients and providers completed surveys regarding testing ≥ 8 weeks of test delivery or 1 week of end of data collection period, respectively (follow up). Results: In the 8 weeks prior to the study, 4.2% of patients completed testing at the study sites. During the study, 8.4% of patients completed testing, about 1/2 of eligible patients screened. Of all patients who completed testing and consented for their results to be summarized (N = 182), 10.4% (N = 19) tested positive for a single pathogenic variant (PV; monoallelic MUTYH N = 4; BRCA2 N = 3; ATM, BRCA1, BRIP1, CHEK2, HOXB13 N = 2 each; RAD51C, RAD51D N = 1 each). Not all men who tested positive or a PV reported a family history of cancer and not all PVs detected were in known prostate cancer risk genes. During follow up, most providers (61.0%) felt HCRA was as important as other assessments regularly performed and 68.3% planned to continue to use the HCRA process. In contrast, only 9.8% of providers did not believe HCRA was as important and 12.2% did not plan to continue to use the process. Of the patients that responded to the survey (N = 166), most had shared (62.0%) or planned to share (25.3%) their results with family members post-testing. Conclusions: Urologists and patients responded favorably to HCRA protocol integration. Based on this study, education around and incorporation of an HCRA process in a community urology practice setting for men with prostate cancer appears effective at increasing appropriate uptake of genetic testing. Clinical trial information: NCT04015102.

Abstract ES6-4: Parp inhibitors for brca1/2mutation associated breast cancer

Abstract More than 15 years ago we and others showed the use of potent PARP1 inhibitors (PARPi), that both inhibit the catalytic activity of the PARP1 enzyme and trap PARP1 onto DNA, generate a “synthetic lethal” interaction with the malignant cell specific loss of function of genes crucial for homologous recombination (HR) gene function. This phenomenon has now been exploited with therapeutic intent in several contexts leading to approved single agent PARPi treatments for advanced forms of ovarian, prostate, pancreatic and breast cancers. These approvals have in large part been associated a biomarker requirement for evidence of loss of function of HR. Recently a number of trials have investigated PARPi in a (neo)adjuvant breast cancer treatment (NACT) setting in patients with (or enriched for) HR deficiency. These have included phase II neoadjuvant PARPi studies such as the NeoTALA study using single agent talazoparib in germline BRCA1 and BRCA2 mutation carriers and the combination chemotherapy and olaparib therapy studies GeparOLA and PARTNER, enriched for HR deficient breast cancer, that have reported important signals with regard efficacy and tolerability. Two recent phase III trials have influenced recent early breast cancer treatment guidelines. These are the BrighTNess trial in the neoadjuvant setting and OlympiA in the post-(neo)adjuvant setting. BrighTNess recruited patients with biologically heterogeneous triple negative breast cancer (TNBC) and used the weak PARP1 trapping PARPi veliparib and OlympiA restricted eligibility to patients with the germline “pathogenic” or “likely pathogenic” mutation in BRCA1 or BRCA2 but included patients with hormone receptor positive breast cancer. BrighTNess did not show convincing evidence of benefit to the addition of veliparib to standard of care in TNBC NACT but has shown the benefit to the addition of carboplatin to sequential paclitaxel-AC NACT with significant improvements in event free survival (HR 0.57 ) compared to sequential paclitaxel-AC alone. OlympiA has reported following an interim analysis showing 12 months of olaparib in the post-(neo)adjuvant chemotherapy setting improves both invasive disease free and distant disease free survival by approximately 40% with highly statistically significant hazard ratios of 0.58 and 0.57 respectively that met pre-specified early stopping boundaries. The publication of results for OlympiA has led to rapid updates of both genetic testing and treatment international guidelines for BRCA1 and BRCA2 mutation associated breast cancer to include use of olaparib in patients meeting the eligibility criteria for the trial. The lecture will both explore the data and the implications for practice of the adoption of these guidelines and some of the ongoing questions to be addressed by ongoing clinical trial and translational research initiatives. Citation Format: ANJ Tutt. Parp inhibitors for brca1/2mutation associated breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr ES6-4.

Abstract P2-09-12: Optimizing genetic testing in Hispanic women with breast cancer

Abstract Hispanic women with newly diagnosed breast cancer who qualify for genetic testing based on national guidelines are often not referred to genetic counseling at the same rate as non-Hispanics patients. The reasons for the lower referral and testing rate are not currently well understood. Often patients in a minority population face diverse barriers to accessing care, particularly care that requires specialized training, is expensive, and may not be completely covered by insurance. In our study, we sought to explore the rate of referral and testing of newly diagnosed breast cancer patients in a predominantly Hispanic population at UT Health Mays Cancer Center in San Antonio where more than 60% of patients are Hispanic. Included in this study were 153 sequential new patient referrals to the breast medical oncology clinic with the diagnosis of invasive carcinoma or ductal carcinoma in situ. Current NCCN guidelines for genetic testing were utilized. Data collected included age of diagnosis, current age, gender, race, ethnicity, preferred language, stage, family history of breast, ovarian, pancreatic, or prostate cancer. It was then determined if patients met criteria, if they were referred to genetic counselors, if they attended their appointment, and if they received genetic testing. The prevalence of Hispanic women meeting criteria for genetic testing was 63.9% compared with 61.7% of non-Hispanic women. Of the Hispanic women meeting criteria for genetic testing only 71.8% received testing. Our cancer center has many processes in place that would be expected to increase the rate of genetic testing for Hispanic patients. These include having Spanish speaking staff, a robust genetic counseling team, telemedicine visits, county programs that allow unfunded patients to access care at our cancer center, and grant funding from the state of Texas to cover the additional cost of testing for unfunded patients. Despite this, about 30% of Hispanic patients that met criteria go without testing. Based on review of this data set, the two most common reasons for not completing testing was failure to recognizing that the patients meet criteria and failure to complete the extra clinic visit with the genetic counselor after referral.This study shows that Hispanic patients meet criteria for genetic testing at a slightly higher rate than Non-Hispanic patients and are at risk for not completing genetic testing even in a specialized clinic. Additional patients continue to be added to this dataset, but initial potential interventions include same time genetic counselling and testing when appropriate at the initial consultation with medical oncology or the offering of universal testing to this high-risk population. Citation Format: Allysa Lynn Garcia, Niklesh Akula, Daniel Kade Derrick, Christopher M Worrell, Simren Lakhotia, Shwetha Menon, Kate Lathrop. Optimizing genetic testing in Hispanic women with breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-09-12.

Retrospective assessment of barriers and access to genetic services for hereditary cancer syndromes in an integrated health care delivery system

BackgroundA critical step in access to genetic testing for hereditary cancer syndromes is referral for genetic counseling to assess personal and family risk. Individuals meeting testing guidelines have the greatest need to be evaluated. However, referrals to genetics are underutilized in US patients with hereditary cancer syndromes, especially within traditionally underserved populations, including racial and ethnic minorities, low-income, and non-English speaking patients.MethodsWe studied existing processes for referral to genetic evaluation and testing for hereditary cancer risk to identify areas of potential improvement in delivering these services, especially for traditionally underserved patients.We conducted a retrospective review of 820 referrals to the Kaiser Permanente Northwest (KPNW) genetics department containing diagnosis codes for hereditary cancer risk. We classified referrals as high- or low-quality based on whether sufficient information was provided to determine if patients met national practice guidelines for testing. Through chart abstraction, we also assessed consistency with practice guidelines, whether the referral resulted in a visit to the genetics department for evaluation, and clinical characteristics of patients receiving genetic testing.ResultsMost referrals (n = 514, 63%) contained sufficient information to assess the appropriateness of referral; of those, 92% met practice guidelines for genetic testing. Half of referred patients (50%) were not offered genetic evaluation; only 31% received genetic testing. We identified several barriers to receiving genetic evaluation and testing, the biggest barrier being completion of a family history form sent to patients following the referral. Those with a referral consistent with testing guidelines, were more likely to receive genetic testing than those without (39% vs. 29%, respectively; p = 0.0058). Traditionally underserved patients were underrepresented in those receiving genetic evaluation and testing relative to the overall adult KPNW population.ConclusionsProcess improvements are needed to increase access to genetic services to diagnose hereditary cancer syndromes prior to development of cancer.

Germline Cancer Testing in Unselected Patients with Gastric and Esophageal Cancers: A Multi-center Prospective Study

Background and AimsTo determine prevalence and clinical utility of pathogenic germline variants (PGV) in gastric and esophageal cancer patients using universal genetic testing approach.MethodsWe undertook a prospective study of germline sequencing using an > 80 gene next-generation sequencing platform among patients with gastric and esophageal cancers receiving care at Mayo Clinic Cancer Center between April 1, 2018, and March 31, 2020. Patients were not selected based on cancer stage, family history of cancer, ethnicity, or age. Family cascade testing was offered at no cost.ResultsA total of 96 patients were evaluated. Median age was 66 years, 80.2% were male, 89.6% were white. Nearly 39% of the cohort had esophageal cancer, 35.4% gastric cancer and 26% gastroesophageal junction cancers. Approximately half (52%) of the patients had metastatic disease. Pathogenic germline variants (PGV) were detected in 15.6% (n = 15) patients. The prevalence of PGV was 10.8% in esophageal cancer, 17.6% in gastric cancer and 20% in gastroesophageal cancer. Eighty percent of patients with a positive result would not have been detected by screening with standard guidelines for genetic testing. Most PGV detected included genes with high and moderate penetrance related to DNA damage response including BRCA1, BRCA2, PALB2 and ATM.ConclusionsUniversal multi-gene panel testing in gastric and esophageal cancers was associated with detection of heritable mutations in 15% of patients. The majority of PGV would not be detected with current screening guidelines and are related to DNA damage response.

Guidelines for genetic testing of healthy adults who deposit samples and related data in bioresource collections and biobanks

Currently, a significant part of research in the fields of human and medical genetics is carried out using tissue samples, genealogical, population, medical and personal data. Their use is of particular relevance in the “genome era”, since only joint analysis of genomic data and health status of the population is crucial for understanding how genes are associated with health and disease. Genetic studies of adults without symptoms of diseases are carried out to obtain data on a possible predisposition to multifactorial diseases, to establish the carrier status of autosomal recessive mutations as part of preconception care and to assess individual sensitivity to drugs. In addition, healthy individuals can be tested to detect an inherited disease at presymptomatic stage. This situation increasingly emphasizes the importance of storing data on genome sequencing or any other patient tests for subsequent data reanalysis, as well as their safety, including biosamples from an individual and one’s family. The review article, based on international experience, summarizes guidelines for genetic testing of healthy individuals. The options for storing biological samples and related data are considered.

Guidelines for Genetic Testing and Management of Alport Syndrome.

Genetic testing for pathogenic COL4A3-5 variants is usually undertaken to investigate the cause of persistent hematuria, especially with a family history of hematuria or kidney function impairment. Alport syndrome experts now advocate genetic testing for persistent hematuria, even when a heterozygous pathogenic COL4A3 or COL4A4 is suspected, and cascade testing of their first-degree family members because of their risk of impaired kidney function. The experts recommend too that COL4A3 or COL4A4 heterozygotes do not act as kidney donors. Testing for variants in the COL4A3-COL4A5 genes should also be performed for persistent proteinuria and steroid-resistant nephrotic syndrome due to suspected inherited FSGS and for familial IgA glomerulonephritis and kidney failure of unknown cause.

Management of metastatic castration-resistant prostate cancer in Middle East African countries: Challenges and strategic recommendations.

Despite the reliance on Western guidelines for managing prostate cancer (PC), there are wide variations and gaps in treatment among developing countries such as the Middle East African (MEA) region. A multidisciplinary team of experts from the MEA region engaged in a comprehensive discussion to identify the real-world challenges in diagnostics and treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC) and provided insights on the urgent unmet needs. We present a consensus document on the region-specific barriers, key priority areas and strategic recommendations by experts for optimizing management of mCRPC in the MEA. Limited access to genetic testing and economic constraints were highlighted as major concerns in the MEA. As the therapeutic landscape continues to expand, treatment selection for mCRPC needs to be increasingly personalized. Enhanced genetic testing and judicious utilization of newer therapies like olaparib, articulated by reimbursement support, should be made accessible for the underserved populations in the MEA. Increasing awareness on testing through educational activities catalyzed by digital technologies can play a central role in overcoming barriers to patient care in the MEA region. The involvement of multidisciplinary teams can bridge the treatment gaps, facilitating holistic and optimal management of mCRPC. Region-specific guidelines can help health-care workers navigate challenges and deliver personalized management through collaborative efforts - thus curb health-care variations and drive consistency. Development of region-specific scalable guidelines for genetic testing and treatment of mCRPC, factoring in the trade-off for access, availability, and affordability, is crucial.

Understanding the Uptake and Challenges of Genetic Testing Guidelines for Prostate Cancer Patients

BackgroundMultiple studies have confirmed a high prevalence of prognostic germline mutations in prostate cancer. In recognition, the NCCN guidelines and recommendations for genetic counselling (GC) in prostate cancer patients were expanded. MethodsData on prostate cancer patients at a single tertiary cancer center from January 2019 – June 2019 were queried. The cohort of patients from the queried list were evaluated for their eligibility for genetic testing. From the patients that were eligible for testing, the rate of referrals was ascertained. A 10-item questionnaire was concurrently sent to providers to understand germline genetic testing patterns and potential barriers. ResultsOnly 39% of the eligible prostate cancer patients were referred, with testing completed in 11% with indications. 30% of providers reported they would be comfortable completing genetic counseling themselves. The identified barriers to provide genetic testing themselves were lack of time and expertise (50%). Other barriers included: lack of genetic counselor workforce (70%), lack of knowledge of genetic testing and the inadequate co-ordination of referrals (60%). ConclusionIn this retrospective study, many patients met the criteria for GC, however, the referrals for this patient population are inconsistent, and only a handful of the eligible patients completed testing. Identified barriers were provider's knowledge and comfort with guidelines and testing, systemic bottlenecks such as limited capacity of genetic counsellors, and the creation of improved workflows.

Absence of Germline BRCA1 c.68_69delAG and c.5266dupC Mutations among Hormone Receptor-negative Breast Cancer Patients: A First Impression at a Tertiary Cancer-care Facility in Tanzania

The germline BRCA1 c.68_69delAG (185delAG) and c.5266dupC (5382insC) mutations are associated with hormone receptor-negative breast cancer (BC). Limited studies have examined their contribution to alarming BC incidence in Sub Saharan Africa (SSA). Our study aimed to examine the contribution of germline BRCA1 c.68_69delAG and c.5266dupC mutations to BC incidence among hormone receptor-negative BC patients admitted to Ocean Road Cancer Institute in Tanzania. Face-to-face interviews were conducted to capture socio-demographic characteristics, anthropometric measurements, family history of cancer and reproductive information from each patient. Their histopathological data were extracted from the hospital medical records. The germline BRCA1 founder mutations were analyzed on blood samples using Sanger sequencing technology. The patients mean age at diagnosis was 47.05 ± 12.82 years. A family history of cancer was observed in 13.6% of patients. The germline BRCA1 c.68_69delAG and c.5266dupC mutations were not detected in the study group. Our findings indicate that the germline BRCA1 c.68_69delAG and c.5266dupC mutations do not contribute to BC manifestation in hormone receptor-negative BC patients in Tanzania. Thus, screening BC patients for these mutations has no clinical relevance. Our data further suggest that the c.68_69delAG and the c.5266dupC mutations should not be considered when developing genetic testing guidelines in Tanzania.&#x0D; Keywords: Breast cancer, germline BRCA1 mutation, c.68_69delAG (185delAG), c.5266dupC (5382insC), Tanzania

Access, utilization, and awareness for clinical genetic testing in autism spectrum disorder in Sweden: A survey study.

Clinical genetic testing is recommended for individuals diagnosed with autism spectrum disorder. There are only a few reports of how these recommendations are followed and especially missing for European countries. We aimed to analyze the rate of access, utilization, and awareness of clinical genetic testing among autistic individuals in Sweden through online surveys targeting parents with at least one autistic child and autistic adolescents (from 15 years) and adults. In total, 868 parents of autistic children and 213 autistic adolescents or adults completed the survey. Only 9.1% (n = 79) of parents and 2.8% (n = 6) of autistic adolescents/adults reported having received a referral for clinical genetic testing after autism spectrum disorder diagnosis. The autistic children offered a referral were younger at diagnosis (p < 0.001) and more likely to have an additional neurodevelopmental diagnosis (p < 0.01), including intellectual disability (p < 0.001) or a language disorder (p < 0.001). Genetic counseling was provided to less than half of the families that were referred for clinical genetic testing. Finally, we report that both respondent groups preferred to be informed by written text and an expert in genetics about clinical genetic testing. This study highlights a lack of awareness and access to clinical genetic testing after autism spectrum disorder diagnosis in Sweden and demonstrates the need for additional studies on how clinical guidelines for genetic testing are followed in different countries.Lay abstractSeveral medical professional societies recommend clinical genetic testing for autistic individuals as many genetic conditions are linked to autism. However, it is unclear to what extent autistic individuals and parents of autistic children are offered clinical genetic testing. We conducted a community-based survey to estimate the access, utilization, and awareness for clinical genetic testing in Sweden. In total, 868 parents of autistic children and 213 autistic adolescents or adults participated as respondents. The referral rate for clinical genetic testing after autism spectrum disorder diagnosis was low, with only 9.1% for the autistic children as reported by their parents and 2.8% for autistic adolescents/adults. The autistic children who got referrals were more likely to have intellectual disability and language disorder. We also report that awareness of the clinical genetic testing possibility was low in both respondent groups. We also highlight preferred communication means and needs for information before clinical genetic testing. Our results show that utilization and access are low in Sweden, and more studies should be conducted to report these rates in different countries to analyze the effects of clinical genetic testing on healthcare for autistic individuals. Our results highlight the most important information for the families and how the information should be communicated prior to clinical genetic testing.

Association of Family Cancer History With Pathogenic Variants in Specific Breast Cancer Susceptibility Genes.

Family cancer history is an important component of genetic testing guidelines that estimate which patients with breast cancer are most likely to carry a germline pathogenic variant (PV). However, we do not know whether more extensive family history is differentially associated with PVs in specific genes. All women diagnosed with breast cancer in 2013-2017 and reported to statewide SEER registries of Georgia and California were linked to clinical genetic testing results and family history from two laboratories. Family history was defined as strong (suggestive of PVs in high-penetrance genes such as BRCA1/2 or TP53, including male breast, ovarian, pancreatic, sarcoma, or multiple female breast cancers), moderate (any other cancer history), or none. Among established breast cancer susceptibility genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, and TP53), we evaluated PV prevalence according to family history extent and breast cancer subtype. We used a multivariable model to test for interaction between affected gene and family history extent for ATM, BRCA1/2, CHEK2, and PALB2. A total of 34,865 women linked to genetic results. Higher PV prevalence with increasing family history extent (P < .001) was observed only with BRCA1 (3.04% with none, 3.22% with moderate, and 4.06% with strong history) and in triple-negative breast cancer with PALB2 (0.75% with none, 2.23% with moderate, and 2.63% with strong history). In a multivariable model adjusted for age and subtype, there was no interaction between family history extent and PV prevalence for any gene except PALB2 (P = .037). Extent of family cancer history is not differentially associated with PVs across established breast cancer susceptibility genes and cannot be used to personalize genes selected for testing.

P62.11 Germline Genetic Testing in Patients with Lung Cancer in a Mexican Center

Germline variants explain a minority of Lung Cancer (LC) cases. Accumulating evidence have shown a role of genes of the Fanconi pathway, such as BRCA2, CHEK2 and PALB2, in LC. Suggested features of LC patients (pts) carrying germline mutations are young pts, pts with double primary tumor, and cancer family history (CFH). Nowadays, guidelines for genetic testing (GT) in LC have not been published. GT could provide benefits such as target therapy and cascade testing for relatives. Herein, we describe the result of germline GT with a Multigene (MPG) panel in LC pts.

Overview of hereditary breast and ovarian cancer (HBOC) guidelines across Europe

Hereditary breast and ovarian cancer (HBOC) is a syndrome defined by an increased risk of developing breast and/or ovarian cancer most commonly due to germline disease-causing variants in the BRCA1 and BRCA2 genes, but also other causative genes such as PALB2, ATM and CHEK2. As genetic testing becomes more prevalent and new clinical data emerge, updates of national guidelines are required to incorporate these advances in our knowledge. The aim of this work is to review the guidelines for HBOC genetic testing and clinical surveillance across European countries, mostly affiliated to the European Reference Network (ERN) for Genetic Tumor Risk Syndroms (GENTURIS). Young onset breast cancer (BC), triple negative phenotype, or bilateral BC are considered as criteria for genetic testing in all, with differences in age limits. Testing of invasive epithelial non-mucinous ovarian cancer is also universally accepted. While breast magnetic resonance imaging (MRI) is consistently recommended in high-risk individuals, age of onset for mammograms differ between 30 and 40 years. Risk-reducing mastectomy is commonly offered as an option, while risk-reducing salpingo-oophorectomy is universally recommended. The largest differences are observed with respect to ovarian surveillance prior to risk-reducing salpingo-oophorectomy and in breast surveillance for carriers of non-BRCA1/2 genes. These differences in national guidelines reflect the variations in clinical consensus that may be reached in the absence of consistent evidence for some recommendations.