Risk For Hereditary Cancer Syndromes Research Articles

Implementation of a dedicated cascade testing clinic for patients at risk for hereditary cancer syndromes.

Cascade testing, the site-specific genetic testing of relatives within families with an inherited condition, is underutilized. Long wait times for appointments in specialty genetics clinics are a known barrier to genetic testing access. In our cancer genetics, New Patient Clinic (NPC), the long wait time for an appointment (on average 5 months for routine referrals), was identified by both providers and patients as a barrier to uptake of cascade testing. Timely testing of at-risk relatives is essential to maximize the benefits of cascade testing and reduce cancer morbidity and mortality. Our objective was to improve access via implementation of a different clinical model that designated appointments for patients seeking cascade testing. A secondary goal was to improve use of genetic counselor time. We implemented a dedicated Cascade Testing Clinic (CTC) with an expedited triaging and unique scheduling model to decrease patient wait time to appointment and optimize clinician time. We report on the process and outcomes here. Between October 2016 and February 2020, the average wait time between referral date and first scheduled appointment date was 46 days for the CTC compared to 144 days for the NPC (p < 0.0001). No-show/cancelation/rescheduling rate was 11.7% in the CTC compared to 29.7% in the NPC (p < 0.0001). Genetic counselors saw approximately twice as many patients per half-day clinic in the CTC compared to the NPC (p < 0.00001). Modifications to clinic staffing and appointment times were made based on provider feedback. Implementation of a dedicated clinic specifically for patients seeking cascade testing significantly shortened wait times for this population, reduced patient drop-off, and improved clinician efficiency. The relatively straightforward indications and generally uncomplicated medical histories made this an ideal population for expedited appointments.

Conducting inclusive research in genetics for transgender, gender-diverse, and sex-diverse individuals: Case analyses and recommendations from a clinical genomics study.

A person's phenotypic sex (i.e., endogenous expression of primary, secondary, and endocrinological sex characteristics) can impact crucial aspects of genetic assessment and resulting clinical care recommendations. In studies with genetics components, it is critical to collect phenotypic sex, information about current organ/tissue inventory and hormonal milieu, and gender identity. If researchers do not carefully construct data models, transgender, gender diverse, and sex diverse (TGSD) individuals may be given inappropriate care recommendations and/or be subjected to misgendering, inflicting medical and psychosocial harms. The recognized need for an inclusive care experience should not be limited to clinical practice but should extend to the research setting, where researchers must build an inclusive experience for TGSD participants. Here, we review three TGSD participants in the Family History and Cancer Risk Study (FOREST) to critically evaluate sex- and gender-related survey measures and associated data models in a study seeking to identify patients at risk for hereditary cancer syndromes. Furthermore, we leverage these participants' responses to sex- and gender identity-related questions in FOREST to inform needed changes to the FOREST data model and to make recommendations for TGSD-inclusive genetics research design, data models, and processes.

Evaluating cancer genetic services in a safety net system: overcoming barriers for a lasting impact beyond the CHARM research project

Underserved patients face substantial barriers to receiving cancer genetic services. The Cancer Health Assessments Reaching Many (CHARM) study evaluated ways to increase access to genetic testing for individuals in underserved populations at risk for hereditary cancer syndromes (HCS). Here, we report the successful implementation of CHARM in a low-resource environment and the development of sustainable processes to continue genetic risk assessment in this setting. The research team involved key clinical personnel and patient advisors at Denver Health to provide input on study methods and materials. Through iterative and collaborative stakeholder engagement, the team identified barriers and developed solutions that would both facilitate participation in CHARM and be feasible to implement and sustain long term in clinical care. With a focus on infrastructure building, educational modules were developed to increase awareness among referring providers, and standard methods of identifying and managing HCS patients were implemented in the electronic medical record. Three hundred sixty-four DH patients successfully completed the risk assessment tool within the study, and we observed a sustained increase in referrals to genetics for HCS (from 179 in 2017 to 427 in 2021 post-intervention). Implementation of the CHARM study at a low-resourced safety net health system resulted in sustainable improvements in access to cancer genetic risk assessment and services that continue even after the study ended.Trial registration NCT03426878

Genetic testing for patients at risk of hereditary breast and ovarian cancer.

The field of cancer genetic testing has made great advances in correctly identifying patients at risk for hereditary cancer syndromes. These tests, used during a genetic consultation, promote earlier detection of cancer and potentially increase survival. Despite these advancements, a large number of persons at risk for BRCA1/2 mutations remain untested due to a shortage of genetic counselors and lack of clinician knowledge on how to properly screen, identify, and refer patients to genetic counseling. We suggest team-based practices that physician associates/assistants (PAs) and NPs can use in collaboration with genetic counselors. We also explore how PAs and NPs can alleviate the burden on genetic counselors by taking a comprehensive family history, providing elements of counseling, and ordering appropriate genetic tests. This approach maximizes the amount of time the patient spends receiving actual genetic counseling. By creating this collaborative relationship, PAs and NPs can help increase the number of qualifying patients who receive genetic testing and counseling for hereditary breast and ovarian cancer syndromes.

Cascade testing for hereditary cancer syndromes: Should we move towards direct relative contact? A systematic review and meta-analysis (384)

<b>Objectives:</b> Evidence-based guidelines recommend cascade testing for hereditary cancer syndromes, as identifying relatives with a familial mutation provides the opportunity for early detection and prevention of cancer. The current standard is for patients to contact their relatives (patient-mediated contact) and encourage genetic testing. However, patient-mediated cascade testing accomplishes genetic testing for <30% of relatives, representing a significant missed public health opportunity. Direct relative contact by the medical team has shown promise for other, non-oncologic, genetic syndromes but is complicated by privacy laws and the lack of current infrastructure within the medical system. We sought to evaluate the literature on patient-mediated and direct relative contact for cancer cascade testing and determine if any specific interventions or patient characteristics drive the utilization of services. <b>Methods:</b> We searched key electronic databases to identify studies evaluating cascade testing for hereditary cancer syndromes. Eligible trials were subjected to meta-analysis, and the moderating influence of health interventions and patient characteristics on rates of genetic assessment were examined. The current study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was preregistered with PROSPERO (registration no.: CRD42020134276). <b>Results:</b> Forty-eight studies were included (15 reports on direct relative contact, 36 on patient-mediated contact, three on both scenarios). When relatives were contacted directly by the medical team, 58% (95% CI: 47%-68%) completed genetic testing versus 36% (95% CI: 28%-45%) when contact was mediated by the patient. Methods of direct contact by the medical team included letters, telephone calls, and emails. Among the entire cohort, the following patient characteristics were associated with greater uptake of cascade testing: female versus male gender, first-degree relation versus more distant relation, and Lynch syndrome versus <i>BRCA1/2</i> (Table 1). Among families relying on patient-mediated contact, the use of an information aid resulted in 41% [95% CI: 31%-52%] completion of cascade testing versus 34% [95% CI: 24%-45%] without an information aid. <b>Conclusions:</b> The majority of relatives at risk for hereditary cancer syndromes do not undergo cascade testing and, therefore, forgo potentially life-saving medical interventions. Direct relative contact by the medical team results in higher completion rates of cascade testing than patient-mediated cascade testing. These data argue for a paradigm shift, whereby the medical system works with patients, respecting privacy laws while also offering methods for direct relative contact. Furthermore, cascade programs must consider the populations who currently are less likely to complete cascade testing, including males and <i>BRCA1/2</i> families.

Family history assessment to identify patients at risk for hereditary cancer syndromes in community oncology practices.

e18735 Background: Identification of hereditary cancer syndromes can have implications for cancer treatment and prevention. However, only a fraction of cancer patients undergo germline genetic testing (GT). We employed a family health history tool (FHHT) to assist in identifying cancer patients eligible for GT in the outpatient oncology setting. Methods: Patients with cancer with a visit scheduled at one of two community-based oncology practices received email invitations to complete a web-based FHHT that elicits cancer type and age at diagnosis for 1st and 2nd degree relatives. NCCN guidelines were applied to identify individuals meeting clinical criteria for GT. We compared proportions of individuals eligible for GT by sex and cancer type using Fisher’s exact tests. Results: Of the 1292 cancer patients seen over a 4-month period, 276 (21.4%) completed the FHHT. Of those, 58% were female (N = 160) and breast cancer was the most common cancer diagnosis (N = 73, 26.4%), followed by prostate (N = 25, 9.1%) and colorectal cancer (CRC) (N = 15, 5.4%). 59 (21.3%) patients met criteria for GT, including 49.3% of those with breast cancer (N = 36), 66.7% of those with CRC (N = 10), 28% of those with prostate (N = 7), and 100% of those with pancreatic and ovarian cancers (N = 3 each). Breast cancer accounted for 61% of those meeting GT criteria, including personal history of breast cancer age &lt; 50 (N = 17), and personal history of breast cancer with family history of ovarian cancer (N = 7). The proportion of CRC patients meeting GT criteria was higher than for breast cancer (66.7% vs 49.3%). Seven of 10 (70%) CRC patients meeting GT criteria would not have been identified without their accompanying family history. Overall, women were more likely than men to meet GT criteria (OR 1.8, 95% CI: 1.01 to 3.47, p = 0.045). Conclusions: Approximately 1 in 5 cancer patients who were invited to complete the FHHT met NCCN guidelines for GT. While a personal history of young breast cancer was the most common GT eligibility criterion, the proportion of patients eligible for GT was highest among CRC. Across all cancer types, family history increased the number of patient meeting GT criteria by 42.4%. Implementing a patient-facing family history tool can assist community oncologists in clinically appropriate identification of cancer patients who are eligible for GT. While 48% of patients who completed the FHHT met GT criteria, generalizability is limited due to small sample size.[Table: see text]

Can Automated Alerts in the Electronic Health Record Encourage Referrals for Genetic Counseling and Testing Among Patients at High Risk for Hereditary Cancer Syndromes?

Up to 10% of cancers may be associated with an inherited mutation that increases cancer risk. National guidelines emphasize referral for genetic counseling and testing for patients whose personal and/or family history increases their risk of having a hereditary cancer syndrome. To increase appropriate referrals for cancer genetic counseling and testing, we piloted an automated alert known as a Best Practice Advisory (BPA) in the electronic health record, Epic, to notify oncology providers when a patient had a personal and/or family history that merited referral to cancer genetics. Epic could not gather the complex clinical data needed for the referral decision automatically, necessitating staff completion of a questionnaire. After educating providers, the BPA was implemented with resources to support its use. Initial interaction with the alert was high but rapidly dwindled, resulting in questionnaire completion in 7.2% of more than 32,000 encounters and 14.9% of patients over 9 months. However, cancer genetics referrals increased 95.9% during the pilot (P < .0001), with 18.5% placed through the BPA and the rest from a non-BPA mechanism. Semistructured interviews with key stakeholders revealed not only general acceptance of the BPA concept but also barriers to completion, such as pressure to room patients quickly in the face of competing BPAs and lack of buy-in from some providers. These results suggest that provider engagement and BPA fatigue are significant obstacles to acceptance of a new automated alert. Despite interest in a tool for cancer genetics, the demand on clinical time for this complex BPA was poorly tolerated.

Hereditary Cancer Risk Using a Genetic Chatbot Before Routine Care Visits.

To examine user uptake and experience with a clinical chatbot that automates hereditary cancer risk triage by collecting personal and family cancer history in routine women's health care settings. We conducted a multicenter, retrospective observational study of patients who used a web-based chatbot before routine care appointments to assess their risk for hereditary breast and ovarian cancer, Lynch syndrome, and adenomatous polyposis syndromes. Outcome measures included uptake and completion of the risk-assessment and educational section of the chatbot interaction and identification of hereditary cancer risk as evaluated against National Comprehensive Cancer Network criteria. Of the 95,166 patients invited, 61,070 (64.2%) engaged with the clinical chatbot. The vast majority completed the cancer risk assessment (89.4%), and most completed the genetic testing education section (71.4%), indicating high acceptability among those who opted to engage. The mean duration of use was 15.4 minutes (SD 2 hours, 56.2 minutes) when gaps of inactivity longer than 5 minutes were excluded. A personal history of cancer was reported by 19.1% (10,849/56,656) and a family history of cancer was reported by 66.7% (36,469/54,652) of patients who provided the relevant information. One in four patients (14,850/54,547) screened with the chatbot before routine care appointments met National Comprehensive Cancer Network criteria for genetic testing. Among those who were tested, 5.6% (73/1,313) had a disease-causing pathogenic variant. A chatbot digital health tool can help identify patients at high risk for hereditary cancer syndromes before routine care appointments. This scalable intervention can effectively provide cancer risk assessment, engage patients with educational information, and facilitate a path toward preventive genetic testing. Implementation of the chatbot in clinics was funded by industry support from commercial genetic testing laboratories Ambry, Invitae, and Progenity.

Patient and Family Preferences on Health System-Led Direct Contact for Cascade Screening

Health benefits to relatives of people at known genetic risk for hereditary cancer syndromes is key to realizing the promise of precision medicine. We conducted a qualitative study to design a patient- and family-centered program for direct contact of relatives to recommend cascade genetic testing. We conducted two rounds of data collection using focus groups followed by individual interviews with patients with HBOC or Lynch syndrome and a separate sample of people with a family history of hereditary cancers. Results indicate that U.S.-based health system-led direct contact of relatives is acceptable to patients and families, should take a programmatic approach, include consent of relatives before proband testing, complement to existing patient-mediated disclosure, and allow for relative control of information. Our findings suggest a set of requirements for U.S.-based direct contact programs that could ultimately benefit more relatives than current approaches.

Identifying individuals with primary central nervous system tumors at risk for hereditary cancer syndromes using the Utah Population Database.

10532 Background: CNS tumors are the most common solid tumors and the deadliest cancers in children. Approximately 10% of children with a CNS tumor harbor a hereditary cancer syndrome (HCS), but many will not be tested for a HCS. The Utah Population Database (UPDB) contains comprehensive cancer registry data for Utah families and can determine multigenerational cancer pedigrees across an archive of 5.8 million individuals. Early identification of HCSs results in improved cancer surveillance and outcomes, reducing the impact of CNS tumors in children. We hypothesize that the UPDB can identify children and families with HCSs not previously identified. Methods: We queried the UPDB for individuals ages 0-39 diagnosed with a primary CNS tumor (malignant and benign) between 1966-2017 and generated cancer pedigrees of 3 generations or more for probands, extending to at least third-degree relatives. Specialized software calculated a familial standardized incidence ratio (FSIR) to determine families with excess clustering of CNS tumors. Clinical cancer genetics experts reviewed pedigrees to confirm patterns of HCS. Results: We identified 4,634 CNS tumors in 4,550 individuals, of whom 2,233 (49%) reside in high-quality pedigrees containing ≥2 grandparents, at least 1 from both maternal and paternal sides. To identify families with excess clustering of CNS tumors, we selected pedigrees with an FSIR P&lt; 0.05 and ≥2 affected patients, resulting in 161 high-risk families with a mean of 170 (median 96) relatives per pedigree of 3-6 generations. Among these 161 families, there were 2,017 unique relatives (first-third degree) of CNS probands with 2,355 tumors (any site), for a per pedigree average of 14.7 tumors in 12.5 relatives. Review of the 10 highest risk pedigrees indicated that 4 meet HCS criteria, including Li-Fraumeni (n = 2), von Hippel-Lindau (n = 1), and rhabdoid tumor predisposition (n = 1). Conclusions: The UPDB can produce multigenerational cancer pedigrees that identify individuals and families at risk of harboring a HCS who warrant germline testing. These findings should encourage clinicians to perform thorough family history screening and to always consider workup for associated HCSs.

Advanced adenomas may be a red flag for hereditary cancer syndromes

Background16–25% of colorectal cancers (CRCs) diagnosed under age 50 are associated with hereditary cancer syndromes. Advanced adenomas are considered precursors to CRC. Although polyp removal prevents cancer, polypectomy does not change underlying genetic risk. Patients with isolated advanced polyps do not currently qualify for genetic testing unless they have a personal or family history of cancer.AimDescribe the prevalence of hereditary cancer syndromes among patients with advanced colorectal polyps.MethodsWe performed a single center retrospective review from 2015 to 2019 of patients who underwent germline genetic testing with indication for testing listed as colorectal polyp. We excluded patients with a personal history of CRC and those with ≥10 cumulative polyps. We collected patient demographics, polyp characteristics, family history data and genetic testing results from the medical record. Discrete variables were reported as frequency and percentages and continuous variables reported as mean with range.ResultsA total of 42 patients underwent genetic testing due to a personal history of advanced adenoma. 17% of patients met current genetic testing criteria. All patients underwent multi-gene panel testing. Two patients (4.8%) had a germline pathogenic mutation (one in MLH1 and one in CHEK2). The patient with an MLH1 mutation met current criteria for genetic testing (PREMM5 score 5.8), however the patient with the CHEK2 mutation did not. Both mutation carriers had a personal history of synchronous or metachronous advanced adenomas. 38% had a variant of uncertain significance.Conclusions5% of patients with advanced adenomas in our retrospective series had a pathogenic germline mutation in a cancer predisposition gene. Though the patient with a pathogenic mutation in MLH1 met current clinical criteria for genetic testing, this was not recognized prior to referral; he was referred based on a personal history of advanced adenoma. Advanced polyps may be a red flag to identify patients who are at risk for hereditary cancer syndromes.

African-Americans Are Less Frequently Assessed For Hereditary Colon Cancer

IntroductionColorectal cancer (CRC) is the third most common malignancy in the United States and disproportionately affects African-Americans. Approximately 5-10% of CRC results from hereditary cancer syndromes. A detailed family history is recommended as an initial component of cancer risk assessment to help determine initiation, frequency, screening method and genetic counselling referral. This study evaluated the rate of hereditary CRC risk assessment in African-American and white patients. MethodsA chart review of all patients referred for CRC screening in a university gastroenterology clinic during a 3 month period was performed. Patient self-described race/ethnicity, gender, age, documentation of multi-generational family medical history (3+ generations) were obtained. Amsterdam II Criteria, Bethesda Criteria and Colorectal Cancer Risk Assessment Tool were used to determine which patients with family histories should receive referrals for genetic counselling. Statistical analysis was performed using Fisher's Exact Test with significance set at p < 0.05. The study was IRB approved. Results872 medical records were reviewed, including 452 African-American (276 females, 176 males; mean age 60.2), 263 White (123 females, 140 males; mean age 59.4), 45 Hispanic, and 42 Asian. Multi-generational family history was obtained from 143 (16.4%); 62 African-American (13.7%; 47 females, 15 males), 58 White (22.1%; 37 females, 21 whites), 3 Hispanic (6.7%), and 4 Asian (9.5%). There was a significant difference (p = 0.0050) in the rate of detailed family history in African-Americans and whites. However, African-Americans and Whites similarly qualified for genetic counselling when family history was obtained (p = 0.7915); 58.1% African-Americans (36; 30 females, 6 males) and 50% Whites (29: 19 females, 10 males) qualified for genetic counselling. Overall referral rate to genetic counselling was 16.5% with no significant difference (p = 0.7586) between African-Americans and whites. ConclusionsCRC risk assessment with detailed family medical history was inconsistently performed in all patients. There was significantly lower rate of obtaining multi-generational family medical histories in African-Americans. Referrals of all patients for genetic counselling and testing were also insufficient. Appropriate identification of individuals at increased risk for hereditary cancer syndromes, particularly African-Americans, is critical to prevention, early detection, and treatment of CRC and improving disparities in care.

BRCA sequencing of tumors: understanding its implications in the oncology community.

In the current era of personalized medicine, much more information can be gleaned through genetic testing and tumor sequencing. Unfortunately, this comes at a price of obtaining results that may beget more uncertainties. Sequencing for mutations on tumor samples is increasingly performed, more commonly to guide treatment for oncology patients, and occasionally as a proxy for germline testing when the ideal index patient to initiate genetic testing in a family at risk for hereditary cancer syndrome is no longer alive. Next-generation sequencing (NGS) involving tens to hundreds of genes as a testing platform is being used more routinely in the clinic now. However, one should keep in mind that the larger number of genes included in an NGS panel will yield a correspondingly higher probability of finding an incidental germline pathogenic mutation, which will have both clinical and ethical implications for patients and their families. The probability of identifying a tumor pathogenic BRCA1/2 variant is about 3-4%, with the majority (~80%) being germline in nature; thus, patients should be counselled accordingly prior to having their tumor samples sequenced. On the flip side, caution should be exercised when tumor sequencing is intended to be a surrogate for germline testing. This is because false negative rate is high at ~30%, making it an inadequate tool to sufficiently dismiss the presence of a germline BRCA1/2 mutation, especially in a setting where there is already a high clinical suspicion for a hereditary condition.

S3120 African Americans Are Less Frequently Assessed for Hereditary Colon Cancer

INTRODUCTION: Approximately 5% of colorectal cancer (CRC) results from hereditary cancer syndromes. Identification of individuals at increased risk for CRC is important to determine initiation, frequency, method of screening and referral for genetic counselling. A detailed family history is recommended as an initial component of cancer risk assessment. African-Americans (AA) are more often diagnosed with CRC, have more advanced disease and greater mortality rate. There is limited data on screening of AA for hereditary CRC. This study evaluated the rate of hereditary CRC risk assessment in AA and white patients in a university GI clinic. METHODS: A chart review of all self-described AA and white patients referred for CRC screening in a university GI clinic during a 3 month period was performed. Patient gender, age and documentation of multi-generational family medical history (3 + generations) were obtained. Amsterdam II Criteria, Bethesda Criteria and Colorectal Cancer Risk Assessment Tool were used to determine which patients had family histories that warrant genetic counseling and referrals. Statistical analysis was performed using Fisher’s Exact Test with significance set at P < 0.05. The study was IRB approved. RESULTS: 715 medical records were reviewed. There were 452 AA (276 females, 176 males; mean age 60.2) and 263 whites (123 females, 140 males; mean age 59.4). A multi-generational family history was obtained in 62 AA (13.7%; 47 females, 15 males) and 58 whites (22.1%; 37 females, 21 whites). There was a significant difference (P = 0.0050) in the rate at which a detailed family history is obtained AA and whites. There was no significant difference (P = 0.7915) in the rate at which AA (36, 58.1%; 30 females, 6 males) and whites (29, 50%; 19 females, 10 males) qualified for genetic counselling. There was no significant difference (P = 0.7586) in the referral rate of qualified AA (7, 19.4%; 6 females, 1 male) and whites (8; 27.6%; 6 females, 2 males) for genetic testing. CONCLUSION: This study revealed that CRC risk assessment with detailed family medical histories was inconsistently performed in all patients. There was a significantly lower rate of obtaining multi-generational family medical histories in AA. Additionally, there was insufficient referrals of all patients for genetic counselling and testing. It is important that there is appropriate identification of individuals at increased risk for hereditary cancer syndromes, with special attention to decreasing potential disparities in care.

Patient With Questions About Cancer Risk

Primary care nurse practitioners routinely care for patients with personal or family histories of cancer. Approximately 5% to 10% of all cancers are related to hereditary cancer syndromes (HCSs),1 which cause an increased risk for developing more cancers and cancers at earlier ages than the general population. Nurse practitioners in primary care must become comfortable with identifying patients at risk for HCSs. Ordering genetic tests can be a challenge because the number of genetic tests available is growing at a rapid pace. This case highlights a woman who survived breast cancer at age 25 and basal cell carcinoma at age 33.

Patients' willingness to reconsider cancer genetic testing after initially declining: Mention it again.

Patients at risk for hereditary cancer syndromes sometimes decline clinically appropriate genetic testing. The purpose of the current study was to understand what preferences, concerns, and desires informed their refusal as well as their current level of interest in being tested. We interviewed patients who had been seen in a hereditary cancer clinic at Vanderbilt University Medical Center and had declined genetic testing. In all, 21 in-depth, semi-structured qualitative interviews were conducted. Although patients provided many reasons for declining testing, they most often cited their psychosocial state at the time of the initial invitation to participate in genetic testing as their reason for refusal. The majority (67%) said that they either would or had changed their mind about testing if/when their clinicians 'mentioned it again'. Patients at risk for hereditary cancer who refuse testing at the time of genetic counseling may later change their mind. In particular, if a patient declines testing around the time of a major medical diagnosis or intervention, clinicians who are providing ongoing care may want to raise the topic afresh after the patient has had time to recover from initial distress related to diagnosis or treatment. Strategies to prompt clinicians to have these conversations are suggested.

Improving access to genetic counseling services in an adolescent and young adult (AYA) clinic.

e13009 Background: Numerous studies have explored genetic testing access and benefits in adult and pediatric cancer patients, however little is known about the use of these services in adolescents and young adult (AYA) cancer patients. Routine genetic counseling may be particularly important for AYAs who are survivors of childhood cancer, as 8.5% of children with cancer have an inherited pathogenic germline variant. Genetic testing also helps reduce cancer morbidity and mortality in adolescents, as well as helps to guide cancer prevention strategies in family members. This study describes an innovative approach to fostering AYA patients’ access to genetic counseling services. Methods: AYA patients (ages 15-29) with a new or prior cancer diagnosis were referred to MD Anderson Cancer Center’s AYA multi-disciplinary clinic. Prior to their clinic visits, a genetic counselor reviewed relevant medical and family history information for patients seen from 7/12/18 through 1/11/19. For those at risk for a hereditary cancer syndrome, a recommendation for a genetic counseling referral was given to the AYA medical provider based on established guidelines, professional consensus, and clinical judgement guided by thorough literature reviews. Results: In total, 254 AYA patients’ charts were reviewed and 70 (27.6%) patients had histories that warranted a genetic counseling referral. Of these 70 patients, 53 (75.7%) were not previously seen by genetics. Of the 53 patients newly recommended to be referred, 29 (54.7%) had referrals placed. Of the 24 patients not referred, 17 did not attend their AYA visit, 5 refused the referral, and 2 were not referred for undetermined reasons. Of those referred, 10 completed genetic counseling, 14 are scheduled for counseling, 3 did not attend their appointment, and 2 had counseling at another institution. This process led to a 41.3% absolute increase in referrals to genetic counseling for those at risk for hereditary cancer syndromes. Conclusions: The described clinic workflow identified gaps in genetic referrals and showed an innovative approach to fostering AYA access to genetic services. This approach may be useful for other institutions interested in increasing access to genetic services for AYAs.

The benefits of a model of interval comprehensive assessments (MICA) in hereditary cancer Syndromes: Hereditary diffuse gastric cancer (HDGC) as an example

A high percentage of individuals at risk for hereditary cancer syndromes are unaware of their risk. This is especially detrimental in syndromes such as hereditary diffuse gastric cancer due to a CDH1 germline mutation, for which lifesaving prevention is possible. Surveillance for diffuse gastric cancer in the syndrome is limited, hence the recommendation for prophylactic total gastrectomy for mutation carriers. Genetic counseling and testing is crucial in suspected families but initial contact could be limited, leading to the importance of an interval comprehensive review every 5–8 years to identify and screen additional high-risk individuals.Our contact with a hereditary diffuse gastric cancer family in Jordan in 2011 led to a number of family members receiving education and genetic counseling. Our model of interval comprehensive assessment (MICA) was constructed and implemented by conducting family information service, video call and emails to the high-risk individuals 7 years after initial contact. Using an updated family pedigree we reached out to an additional thirteen high-risk members in six different countries and provided them with genetic education, counseling, and testing. Six members agreed to CDH1 testing (46%). Four tested positive (66%) and one member (25%) underwent prophylactic total gastrectomy.

Abstract P4-03-06: Limitations of direct-to-consumer genetic screening for HBOC: False negatives, false positives and everything in between

Abstract Background Genetic screening of unaffected individuals for hereditary breast and ovarian cancer (HBOC) risk is a growing opportunity for personalized preventive medicine. The FDA recently authorized a direct-to-consumer (DTC) test to report on 3 BRCA1/2 variants, commonly found in individuals of Ashkenazi Jewish (AJ) heritage, out of more than 1000 known. Here we define the probability that DTC genetic screening for the 3 BRCA1/2 AJ founder variants would falsely reassure individuals of AJ and non-AJ ancestry of low risk for hereditary cancer syndromes (HCS). We also assess the frequency of false positive results reported by third parties from raw genotypes, which are routinely provided to clients who submit them for cancer risk analysis. Methods We analyzed de-identified data on three cohorts: 1) An indication-based cohort of 119,328 patients referred by healthcare providers for HBOC genetic testing due to personal or family history, 2) a screening cohort of 5,170 patients without personal or family history who had BRCA1/2 testing as a health screen, and 3) a confirmation cohort of 102 patients referred for clinical confirmatory testing instigated by positive DTC results from third party analysis of raw data. Results In the indication-based cohort 12,846 patients had a mutation in any HCS-associated gene: 4,733 (37%) were in BRCA1/2, of which 12% were one of the 3 AJ founder mutations. Ethnicity impacted AJ founder mutation frequency: 81% of AJ patients with any BRCA1/2 mutation had one of the 3 founder mutations, but only 6% of non-AJ patients. Overall clinical false-negative rate for the 3 AJ founder mutations in BRCA1/2 carriers was 88%; rates were 19% and 94% among AJ and non-AJ individuals, respectively. In the screening cohort, where 2.6% were AJ, 40 patients had a P/LP mutation in BRCA1/2; 12.5% were an AJ founder mutation. The clinical false-negative rate of 88.5% for any BRCA1/2 mutations in the screening cohort is similar to the indication-based cohort. Finally, in the confirmation cohort, among patients told of a positive DTC screening result, our analyses indicated 50% (52/102) were analytic false positives. Conclusions This study highlights the limitations of screening restricted to a few of the many genetic variants associated with HBOC risk. We found a greater rate of non-founder BRCA1/2 mutations in AJ patients than previously reported, and found a concerning rate of clinical false negatives with screening limited to the AJ founder variants. Although increasing access to genetic information is vital, the limitations of current DTC genetic screening, despite warnings from the FDA, may not be well understood by consumers and should be used with caution. Patients screened for HBOC on a platform limited to the AJ founder variants and supplemented by analysis of raw genotyping data, should receive confirmatory testing, regardless of having either a positive or negative result, a recommendation which the DTC companies and third party analysts of raw data ostensibly support. These results suggest that all HCS screening should include the support of a qualified clinician to assess the potential limitations and implement appropriate clinical management recommendations for patients and their family members. Citation Format: Esplin ED, Haverfield E, Yang S, Herrera B, Anderson M, Nussbaum RL. Limitations of direct-to-consumer genetic screening for HBOC: False negatives, false positives and everything in between [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-03-06.

Validation of a digital identification tool for individuals at risk for hereditary cancer syndromes

BackgroundThe number of individuals meeting criteria for genetic counseling and testing for hereditary cancer syndromes (HCS) is far less than the number that actually receive it. To facilitate identification of patients at risk for HCS, Counsyl developed a digital identification tool (digital ID tool) to match personal and family cancer history to National Comprehensive Cancer Network (NCCN) BRCA-related Hereditary Breast and Ovarian Cancer (HBOC), Lynch syndrome, and polyposis testing criteria in one-to-one, automated fashion. The purpose of this study was to validate the ability of the digital ID tool to accurately identify histories that do and do not meet NCCN testing criteria.MethodsThird-party recorded three-generation pedigrees were retrospectively reviewed by a certified genetic counselor (CGC) to determine if independent events included in pedigree histories met NCCN guidelines, and were then sorted into groups: high risk events (meets criteria) and low risk events (does not meet criteria). Events were entered into the digital ID tool to determine the extent of its concordance with events sorted by CGC review. Statistical tests of accuracy were calculated at a 95% confidence interval (CI).ResultsOne hundred ninety-seven pedigrees were reviewed consecutively representing 765 independent events for analysis across groups. 382/382 (100%) high risk events identified by the digital ID tool and 381/383 (99.47%) low risk events identified by the digital ID tool were concordant with CGC sorting. The digital ID tool had a sensitivity of 100% (99.04–100% CI) and specificity of 99.48% (98.13–99.94% CI). The overall accuracy of the digital ID tool was estimated to be 99.74% (99.06–99.97% CI), reflecting the rate at which the digital ID tool reached the same conclusion as that of CGC review of pedigree events for the recommendation of genetic testing for individuals at risk for HCS.ConclusionsThe digital ID tool accurately matches NCCN criteria in one-to-one fashion to identify at-risk individuals for HCS and may be useful in clinical practice, specifically for BRCA-related HBOC and Lynch Syndrome.