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.

BACKGROUND: Advances 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. METHODS: We 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. DISCUSSION: BRIDGE 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 REGISTRATION: BRIDGE is registered as NCT03985852 . The trial was registered on June 6, 2019 at clinicaltrials.gov .

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

BACKGROUND: Cancer 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. OBJECTIVE: Our primary aim is to assess user interactions with a conversational agent for pretest genetics education. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: The 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.

Longitudinal follow-up after telephone disclosure in the randomized COGENT study.

PURPOSE: To better understand the longitudinal risks and benefits of telephone disclosure of genetic test results in the era of multigene panel testing. METHODS: Adults who were proceeding with germline cancer genetic testing were randomized to telephone disclosure (TD) with a genetic counselor or in-person disclosure (IPD) (i.e., usual care) of test results. All participants who received TD were recommended to return to meet with a physician to discuss medical management recommendations. RESULTS: Four hundred seventy-three participants were randomized to TD and 497 to IPD. There were no differences between arms for any cognitive, affective, or behavioral outcomes at 6 and 12 months. Only 50% of participants in the TD arm returned for the medical follow-up appointment. Returning was associated with site (p < 0.0001), being female (p = 0.047), and not having a true negative result (p < 0.002). Mammography was lower at 12 months among those who had TD and did not return for medical follow-up (70%) compared with those who had TD and returned (86%) and those who had IPD (87%, adjusted p < 0.01). CONCLUSION: Telephone disclosure of genetic test results is a reasonable alternative to in-person disclosure, but attention to medical follow-up may remain important for optimizing appropriate use of genetic results.

Preferences for in-person disclosure: Patients declining telephone disclosure characteristics and outcomes in the multicenter Communication Of GENetic Test Results by Telephone study.

Telephone disclosure of cancer genetic test results is noninferior to in-person disclosure. However, how patients who prefer in-person communication of results differ from those who agree to telephone disclosure is unclear but important when considering delivery models for genetic medicine. Patients undergoing cancer genetic testing were recruited to a multicenter, randomized, noninferiority trial (NCT01736345) comparing telephone to in-person disclosure of genetic test results. We evaluated preferences for in-person disclosure, factors associated with this preference and outcomes compared to those who agreed to randomization. Among 1178 enrolled patients, 208 (18%) declined randomization, largely given a preference for in-person disclosure. These patients were more likely to be older (P = 0.007) and to have had multigene panel testing (P < 0.001). General anxiety (P = 0.007), state anxiety (P = 0.008), depression (P = 0.011), cancer-specific distress (P = 0.021) and uncertainty (P = 0.03) were higher after pretest counseling. After disclosure of results, they also had higher general anxiety (P = 0.003), depression (P = 0.002) and cancer-specific distress (P = 0.043). While telephone disclosure is a reasonable alternative to in-person disclosure in most patients, some patients have a strong preference for in-person communication. Patient age, distress and complexity of testing are important factors to consider and requests for in-person disclosure should be honored when possible.

Multigene panels in Ashkenazi Jewish patients yield high rates of actionable mutations in multiple non-BRCA cancer-associated genes.

OBJECTIVE: To evaluate the results of multigene panel testing among Ashkenazi Jewish compared with non-Ashkenazi Jewish patients. METHODS: We reviewed the medical records for all patients who underwent multigene panel testing and targeted BRCA1/2 testing at a single institution between 6/2013-1/2015. Clinical actionability for identified pathogenic mutations was characterized based on the National Comprehensive Cancer Network (NCCN) guidelines and consensus statements and expert opinion for genes not addressed by these guidelines. RESULTS: Four hundred and fifty-four patients underwent multigene panel screening, including 138 Ashkenazi Jewish patients. The median patient age was fifty-two years. Three hundred and fifty-four patients (78%) had a personal history of cancer. Two hundred and fifty-one patients had breast cancer, 49, ovarian cancer, 26, uterine cancer and 20, colorectal cancer. We identified 62 mutations in 56 patients and 291 variants of uncertain significance in 196 patients. Among the 56 patients with mutations, 51 (91%) had actionable mutations. Twenty mutations were identified by multigene panels among Ashkenazi Jewish patients, 18 of which were in genes other than BRCA1/2. A review of targeted BRCA1/2 testing performed over the same study period included 103 patients and identified six mutations in BRCA1/2, all of which occurred in Ashkenazi Jewish patients. Among all Ashkenazi Jewish patients undergoing genetic testing, 25/183 (14%) had a mutation, 24/25 of which were actionable (96%) and 17/25 patients (68%) had mutations in non BRCA1/2 genes. CONCLUSIONS: With the rapid acceptance of multigene panels there is a pressing need to understand how this testing will affect patient management. While traditionally many Ashkenazi Jewish patients have undergone targeted BRCA1/2 testing, our data suggest consideration of multigene panels in this population as the majority of the results are clinically actionable and often in genes other than BRCA1/2.

Development of a tiered and binned genetic counseling model for informed consent in the era of multiplex testing for cancer susceptibility.

PURPOSE: Multiplex genetic testing, including both moderate- and high-penetrance genes for cancer susceptibility, is associated with greater uncertainty than traditional testing, presenting challenges to informed consent and genetic counseling. We sought to develop a new model for informed consent and genetic counseling for four ongoing studies. METHODS: Drawing from professional guidelines, literature, conceptual frameworks, and clinical experience, a multidisciplinary group developed a tiered-binned genetic counseling approach proposed to facilitate informed consent and improve outcomes of cancer susceptibility multiplex testing. RESULTS: In this model, tier 1 "indispensable" information is presented to all patients. More specific tier 2 information is provided to support variable informational needs among diverse patient populations. Clinically relevant information is "binned" into groups to minimize information overload, support informed decision making, and facilitate adaptive responses to testing. Seven essential elements of informed consent are provided to address the unique limitations, risks, and uncertainties of multiplex testing. CONCLUSION: A tiered-binned model for informed consent and genetic counseling has the potential to address the challenges of multiplex testing for cancer susceptibility and to support informed decision making and adaptive responses to testing. Future prospective studies including patient-reported outcomes are needed to inform how to best incorporate multiplex testing for cancer susceptibility into clinical practice.Genet Med 17 6, 485-492.

Case Series of Men with the Germline APC I1307K variant and Treatment-Emergent Neuroendocrine Prostate Cancer.

INTRODUCTION: Somatic mutations in the Wnt signaling gene Adenomatous Polyposis Coli (APC) promote metastatic prostate cancer (PCa) progression. Less is known regarding the impact of germline APC mutations on PCa outcomes. We sought to investigate the prevalence of aggressive variant PCa (AVPC) and treatment-emergent neuroendocrine PCa (t-NEPC) in patients with the germline APC I1307K variant, an alteration found in 7% of Ashkenazi Jewish men. MATERIALS AND METHODS: We report a retrospective cohort study comparing patients with PCa and either APC I1307K germline mutation, APC somatic mutations, or unselected patients. Proportions of patients with AVPC among all the cases were estimated along with 95% Clopper-Pearson exact confidence intervals (CI). Odds ratios with 95% CI were provided for the prevalence of t-NEPC and AVPC in patients with germline APC I1307K compared to patients with frameshift alterations in APC. RESULTS: From 2016-2022, 18 patients with PCa at 3 institutions with the germline APC (I1307K) mutation were identified. Clinically-defined AVPC was found in 8 of the 15 cases with metastatic disease (53%; 95% CI: 26%-79%). Combined somatic alterations in two or more of RB1, TP53 or PTEN (molecularly-defined AVPC) were found in 5/18 cases (28%; 95% CI: 10%-54%). When compared to 20 patients with APC somatic frameshift mutations, patients with the germline APC I1307K variant had a significantly increased risk of AVPC (OR 7.2; 95% CI 1.27, 40.68). CONCLUSION: PCa that develops in the presence of the germline APC I1307K mutation appear to be enriched for clinically-defined and molecularly-defined AVPC and in particular, for t-NEPC.

Association of Disparities in Family History and Family Cancer History in the Electronic Health Record With Sex, Race, Hispanic or Latino Ethnicity, and Language Preference in 2 Large US Health Care Systems.

Importance: Clinical decision support (CDS) algorithms are increasingly being implemented in health care systems to identify patients for specialty care. However, systematic differences in missingness of electronic health record (EHR) data may lead to disparities in identification by CDS algorithms. Objective: To examine the availability and comprehensiveness of cancer family history information (FHI) in patients' EHRs by sex, race, Hispanic or Latino ethnicity, and language preference in 2 large health care systems in 2021. Design, Setting, and Participants: This retrospective EHR quality improvement study used EHR data from 2 health care systems: University of Utah Health (UHealth) and NYU Langone Health (NYULH). Participants included patients aged 25 to 60 years who had a primary care appointment in the previous 3 years. Data were collected or abstracted from the EHR from December 10, 2020, to October 31, 2021, and analyzed from June 15 to October 31, 2021. Exposures: Prior collection of cancer FHI in primary care settings. Main Outcomes and Measures: Availability was defined as having any FHI and any cancer FHI in the EHR and was examined at the patient level. Comprehensiveness was defined as whether a cancer family history observation in the EHR specified the type of cancer diagnosed in a family member, the relationship of the family member to the patient, and the age at onset for the family member and was examined at the observation level. Results: Among 144 484 patients in the UHealth system, 53.6% were women; 74.4% were non-Hispanic or non-Latino and 67.6% were White; and 83.0% had an English language preference. Among 377 621 patients in the NYULH system, 55.3% were women; 63.2% were non-Hispanic or non-Latino, and 55.3% were White; and 89.9% had an English language preference. Patients from historically medically undeserved groups-specifically, Black vs White patients (UHealth: 17.3% [95% CI, 16.1%-18.6%] vs 42.8% [95% CI, 42.5%-43.1%]; NYULH: 24.4% [95% CI, 24.0%-24.8%] vs 33.8% [95% CI, 33.6%-34.0%]), Hispanic or Latino vs non-Hispanic or non-Latino patients (UHealth: 27.2% [95% CI, 26.5%-27.8%] vs 40.2% [95% CI, 39.9%-40.5%]; NYULH: 24.4% [95% CI, 24.1%-24.7%] vs 31.6% [95% CI, 31.4%-31.8%]), Spanish-speaking vs English-speaking patients (UHealth: 18.4% [95% CI, 17.2%-19.1%] vs 40.0% [95% CI, 39.7%-40.3%]; NYULH: 15.1% [95% CI, 14.6%-15.6%] vs 31.1% [95% CI, 30.9%-31.2%), and men vs women (UHealth: 30.8% [95% CI, 30.4%-31.2%] vs 43.0% [95% CI, 42.6%-43.3%]; NYULH: 23.1% [95% CI, 22.9%-23.3%] vs 34.9% [95% CI, 34.7%-35.1%])-had significantly lower availability and comprehensiveness of cancer FHI (P < .001). Conclusions and Relevance: These findings suggest that systematic differences in the availability and comprehensiveness of FHI in the EHR may introduce informative presence bias as inputs to CDS algorithms. The observed differences may also exacerbate disparities for medically underserved groups. System-, clinician-, and patient-level efforts are needed to improve the collection of FHI.

GARDE: a standards-based clinical decision support platform for identifying population health management cohorts.

Population health management (PHM) is an important approach to promote wellness and deliver health care to targeted individuals who meet criteria for preventive measures or treatment. A critical component for any PHM program is a data analytics platform that can target those eligible individuals. OBJECTIVE: The aim of this study was to design and implement a scalable standards-based clinical decision support (CDS) approach to identify patient cohorts for PHM and maximize opportunities for multi-site dissemination. MATERIALS AND METHODS: An architecture was established to support bidirectional data exchanges between heterogeneous electronic health record (EHR) data sources, PHM systems, and CDS components. HL7 Fast Healthcare Interoperability Resources and CDS Hooks were used to facilitate interoperability and dissemination. The approach was validated by deploying the platform at multiple sites to identify patients who meet the criteria for genetic evaluation of familial cancer. RESULTS: The Genetic Cancer Risk Detector (GARDE) platform was created and is comprised of four components: (1) an open-source CDS Hooks server for computing patient eligibility for PHM cohorts, (2) an open-source Population Coordinator that processes GARDE requests and communicates results to a PHM system, (3) an EHR Patient Data Repository, and (4) EHR PHM Tools to manage patients and perform outreach functions. Site-specific deployments were performed on onsite virtual machines and cloud-based Amazon Web Services. DISCUSSION: GARDE's component architecture establishes generalizable standards-based methods for computing PHM cohorts. Replicating deployments using one of the established deployment methods requires minimal local customization. Most of the deployment effort was related to obtaining site-specific information technology governance approvals.

Use and Patient-Reported Outcomes of Clinical Multigene Panel Testing for Cancer Susceptibility in the Multicenter Communication of Genetic Test Results by Telephone Study.

PURPOSE: Multigene panels (MGPs) are increasingly being used despite questions regarding their clinical utility and no standard approach to genetic counseling. How frequently genetic providers use MGP testing and how patient-reported outcomes (PROs) differ from targeted testing (eg, BRCA1/2 only) are unknown. METHODS: We evaluated use of MGP testing and PROs in participants undergoing cancer genetic testing in the multicenter Communication of Genetic Test Results by Telephone study (ClinicalTrials.gov identifier: ), a randomized study of telephone versus in-person disclosure of genetic test results. PROs included genetic knowledge, general and state anxiety, depression, cancer-specific distress, uncertainty, and satisfaction. Genetic providers offered targeted or MGP testing based on clinical assessment. RESULTS: Since the inclusion of MGP testing in 2014, 395 patients (66%) were offered MGP testing. MGP testing increased over time from 57% in 2014 to 66% in 2015 (P = .02) and varied by site (46% to 78%; P < .01). Being offered MGP testing was significantly associated with not having Ashkenazi Jewish ancestry, having a history of cancer, not having a mutation in the family, not having made a treatment decision, and study site. After demographic adjustment, patients offered MGP testing had lower general anxiety (P = .04), state anxiety (P = .03), depression (P = .04), and uncertainty (P = .05) pre-disclosure compared with patients offered targeted testing. State anxiety (P = .05) and cancer-specific distress (P = .05) were lower at disclosure in the MGP group. There was a greater increase in change in uncertainty (P = .04) among patients who underwent MGP testing. CONCLUSION: MGP testing was more frequently offered to patients with lower anxiety, depression, and uncertainty and was associated with favorable outcomes, with the exception of a greater increase in uncertainty compared with patients who had targeted testing. Addressing uncertainty may be important as MGP testing is increasingly adopted.

Randomized Noninferiority Trial of Telephone vs In-Person Disclosure of Germline Cancer Genetic Test Results.

Background: Germline genetic testing is standard practice in oncology. Outcomes of telephone disclosure of a wide range of cancer genetic test results, including multigene panel testing (MGPT) are unknown. Methods: Patients undergoing cancer genetic testing were recruited to a multicenter, randomized, noninferiority trial (NCT01736345) comparing telephone disclosure (TD) of genetic test results with usual care, in-person disclosure (IPD) after tiered-binned in-person pretest counseling. Primary noninferiority outcomes included change in knowledge, state anxiety, and general anxiety. Secondary outcomes included cancer-specific distress, depression, uncertainty, satisfaction, and screening and risk-reducing surgery intentions. To declare noninferiority, we calculated the 98.3% one-sided confidence interval of the standardized effect; t tests were used for secondary subgroup analyses. Only noninferiority tests were one-sided, others were two-sided. Results: A total of 1178 patients enrolled in the study. Two hundred eight (17.7%) participants declined random assignment due to a preference for in-person disclosure; 473 participants were randomly assigned to TD and 497 to IPD; 291 (30.0%) had MGPT. TD was noninferior to IPD for general and state anxiety and all secondary outcomes immediately postdisclosure. TD did not meet the noninferiority threshold for knowledge in the primary analysis, but it did meet the threshold in the multiple imputation analysis. In secondary analyses, there were no statistically significant differences between arms in screening and risk-reducing surgery intentions, and no statistically significant differences in outcomes by arm among those who had MGPT. In subgroup analyses, patients with a positive result had statistically significantly greater decreases in general anxiety with telephone disclosure (TD -0.37 vs IPD +0.87, P = .02). Conclusions: Even in the era of multigene panel testing, these data suggest that telephone disclosure of cancer genetic test results is as an alternative to in-person disclosure for interested patients after in-person pretest counseling with a genetic counselor.

Integrated genomic analysis suggests MLL3 is a novel candidate susceptibility gene for familial nasopharyngeal carcinoma.

BACKGROUND: Little is known about genetic factors associated with nasopharyngeal carcinoma (NPC). To gain insight into NPC etiology, we performed whole exome sequencing on germline and tumor DNA from three closely related family members with NPC. METHODS: The family was ascertained through the Pediatric Familial Cancer Clinic at The University of Chicago (Chicago, IL). The diagnosis of NPC was confirmed pathologically for each individual. For each sample sequenced, 97.3% of the exome was covered at 5×, with an average depth of 44×. Candidate germline and somatic variants associated with NPC were identified and prioritized using a custom pipeline. RESULTS: We discovered 72 rare deleterious germline variants in 56 genes shared by all three individuals. Of these, only three are in previously identified NPC-associated genes, all of which are located within MLL3, a gene known to be somatically altered in NPC. One variant introduces an early stop codon in MLL3, which predicts complete loss-of-function. Tumor DNA analysis revealed somatic mutations and Epstein-Barr virus (EBV) integration events; none, however, were shared among all three individuals. CONCLUSIONS: These data suggest that inherited mutations in MLL3 may have predisposed these three individuals from a single family to develop NPC, and may cooperate with individually acquired somatic mutations or EBV integration events in NPC etiology. IMPACT: Our finding is the first instance of a plausible candidate high penetrance inherited mutation predisposing to NPC.