Cascade genetic testing: an underutilized pathway to equitable cancer care?

The Precision Medicine Initiative was launched upon the potential of genomic information to tailor medical care. Cascade genetic testing represents a powerful application of precision medicine and involves the process of familial diffusion or the "cascade" of genomic risk information. When an individual (proband) is found to carry a cancer-associated germline pathogenic mutation, the information should be cascaded or shared with at-risk relatives. First degree relatives have a 50% likelihood of carrying the same cancer-associated mutation. This process of cascade testing offers at-risk relatives the opportunity for genetic testing and, for those who also carry the cancer-associated mutation, genetically targeted primary disease prevention through intensive cancer surveillance, chemoprevention and risk-reducing surgery, reducing morbidity and preventing mortality. Cascade testing has been designated by the Centers for Disease Control and Prevention as a Tier 1 genomic application for hereditary breast and ovarian cancer. In this manuscript we describe a cascade genetic testing and in particular focus on its potential to provide necessary care to medically underserved and vulnerable populations.

Delivery of hereditary cancer genetics services to patients newly diagnosed with ovarian and endometrial cancers at three gynecologic oncology clinics in the USA, Brazil, and Mexico.

OBJECTIVE: Three gynecologic oncology clinics located in the USA, Brazil, and Mexico collaborated to evaluate their delivery of hereditary cancer genetics services. This descriptive retrospective review study aimed to establish baseline rates and timeliness of guideline-recommended genetics service delivery to patients with ovarian, fallopian tube, primary peritoneal (ovarian), and endometrial cancers at each clinic. METHODS: Patients who were newly diagnosed with ovarian and endometrial cancers between September 1, 2018 and December 31, 2020 were identified from the medical records of the clinics. Genetics service delivery metrics included the rates of mismatch repair deficiency tumor testing for patients with endometrial cancer (microsatellite instability/immunohistochemistry, MSI/IHC), referral to genetics services for patients with ovarian cancer, completed genetics consultations, and germline genetic testing for patients with ovarian and endometrial cancers. Timeliness was calculated as the average number of days between diagnosis and the relevant delivery metric. Descriptive statistics were used to analyze data. RESULTS: In total, 1195 patients (596 with ovarian cancer, 599 with endometrial cancer) were included in the analysis, and rates of genetics service delivery varied by clinic. For patients with ovarian cancer, referral rates ranged by clinic from 32.6% to 89.5%; 30.4-65.1% of patients completed genetics consultation and 32.6-68.7% completed genetic testing. The timeliness to genetic testing for patients with ovarian cancer ranged by clinic from 107 to 595 days. A smaller proportion of patients with endometrial cancer completed MSI/IHC testing (10.0-69.2%), with the average time to MSI/IHC ranging from 15 to 282 days. Rates of genetics consultation among patients with endometrial cancer ranged by clinic from 10.8% to 26.0% and 12.5-16.6% completed genetic testing. CONCLUSIONS: All clinics successfully established baseline rates and timeliness of delivering hereditary cancer genetics services to patients with ovarian and endometrial cancers. Lower rates of delivering genetics services to patients with endometrial cancer warrant additional research and quality improvement efforts.

Experiences of Family Communication and Cascade Genetic Testing for Hereditary Cancer in Medically Underserved Populations-A Qualitative Study.

We sought to explore the intrafamilial communication and cascade genetic testing (CGT) experiences of patients with hereditary cancer from diverse, medically underserved populations and their relatives. Participants included patients receiving oncology care at an urban, safety net hospital in Texas or comprehensive cancer center in Alabama and their first-degree relatives. In-depth semi-structured qualitative interviews were completed wherein patients shared their experiences with genetic counseling (GC), genetic testing (GT), and communicating their results to relatives. Relatives shared their experiences receiving information from the patient and considering CGT. Interviews were transcribed, coded, and themes were identified. Of 25 participating patients, most recalled key aspects of GC and their GT results. Most (80%) patients shared their results with relatives, but only some relatives underwent CGT; patients reported low perceived susceptibility to hereditary cancer as a common barrier to CGT for their relatives. Of 16 participating relatives, most reported feeling distress upon learning the patient's GT results. Relatives were fearful of learning their own CGT results but identified prevention and early detection as CGT benefits. Interviews identified opportunities during family communication to improve relatives' perceived susceptibility to hereditary cancer. Tailored resources may support patients and relatives experiencing distress and fear during GT. PREVENTION RELEVANCE: This study of intrafamilial communication and cascade genetic testing experiences of patients with hereditary cancer and their relatives from diverse, medically underserved populations identified relatives' perceived susceptibility to hereditary cancer risks, distress, and fear as frequent reactions and barriers to testing. These results may inform future hereditary cancer prevention efforts.

Creating and Activating an Implementation Community to Drive HPV Vaccine Uptake in Texas: The Role of an NCI-Designated Cancer Center.

The University of Texas MD Anderson Cancer Center, a comprehensive cancer center designated by the National Cancer Institute (NCI), defines its service population area as the State of Texas (29.1 M), the second most populous state in the country and the state with the greatest number of uninsured residents in the United States. Consistent with a novel and formal commitment to prevention as part of its core mission, alongside clear opportunities in Texas to drive vaccine uptake, MD Anderson assembled a transdisciplinary team to develop an institutional Framework to increase adolescent HPV vaccination and reduce HPV-related cancer burden. The Framework was developed and activated through a four-phase approach aligned with the NCI Cancer Center Support Grant Community Outreach and Engagement component. MD Anderson identified collaborators through data-driven outreach and constructed a portfolio of collaborative multi-sector initiatives through review processes designed to assess readiness, impact and sustainability. The result is an implementation community of 78 institutions collaboratively implementing 12 initiatives within a shared measurement framework impacting 18 counties. This paper describes a structured and rigorous process to set up the implementation of a multi-year investment in evidence-based strategies to increase HPV vaccination that solves challenges preventing implementation of recommended strategies and to encourage similar initiative replication.

Outcomes of the "BRCA Quality Improvement Dissemination Program": An initiative to improve patient receipt of cancer genetics services at five health systems.

OBJECTIVE: A quality improvement initiative (QII) was conducted with five community-based health systems' oncology care centers (sites A-E). The QII aimed to increase referrals, genetic counseling (GC), and germline genetic testing (GT) for patients with ovarian cancer (OC) and triple-negative breast cancer (TNBC). METHODS: QII activities occurred at sites over several years, all concluding by December 2020. Medical records of patients with OC and TNBC were reviewed, and rates of referral, GC, and GT of patients diagnosed during the 2 years before the QII were compared to those diagnosed during the QII. Outcomes were analyzed using descriptive statistics, two-sample t-test, chi-squared/Fisher's exact test, and logistic regression. RESULTS: For patients with OC, improvement was observed in the rate of referral (from 70% to 79%), GC (from 44% to 61%), GT (from 54% to 62%) and decreased time from diagnosis to GC and GT. For patients with TNBC, increased rates of referral (from 90% to 92%), GC (from 68% to 72%) and GT (81% to 86%) were observed. Effective interventions streamlined GC scheduling and standardized referral processes. CONCLUSION: A multi-year QII increased patient referral and uptake of recommended genetics services across five unique community-based oncology care settings.

Implementation and outcome evaluations of a multi-site improvement program in cancer genetics.

Program evaluation can identify the successes and challenges of implementing clinical programs, which can inform future dissemination efforts. A cancer genetics improvement program, disseminated from the Lead Team's institution to five health systems (Participating Sites), was genetic counselor led, using virtual implementation facilitation to support Participating Sites' performance of quality improvement (QI) activities over several years. Program implementation and outcome evaluations were performed and included evaluation of program delivery and initial effects of the program on Participating Sites. A logic model guided evaluation of program implementation (inputs, activities, outputs, delivery/fidelity, and coverage/reach) and initial outcomes (short-term and intermediate outcomes). Data were collected from program documents and an Evaluation Survey of Participating Site team members (21 respondents), compared against the Lead Team's expectations of participation, and analyzed using descriptive statistics. All program inputs, outputs, and activities were available and delivered as expected across the five Participating Sites. The most frequently used activities and inputs were facilitation-associated meetings and meeting resources, which were rated as useful/helpful by the majority of respondents. Nearly all respondents noted improvement in short-term outcomes following participation: 82.4% reported increased awareness of clinical processes, 94.1% increased knowledge of QI methods, 100% reported increased perceived importance of QI, 94.1% increased perceived feasibility of QI, and 76.5% reported increased problem-solving skills and self-efficacy to use QI at their site. Intermediate outcomes (identifying barriers, developing interventions, improved teamwork, and capacity) were achieved following program participation as indicated by the results of the program document review and Evaluation Survey responses. Implementation challenges at Participating Sites included staffing constraints, difficulties obtaining buy-in and participation, and developing interventions over time. The multi-site improvement program was delivered and implemented with high levels of fidelity and resulted in improved short and intermediate outcomes. Future research will evaluate long-term, patient-level outcomes associated with site-specific QI interventions.

Interventions to improve delivery of cancer genetics services in the United States: A scoping review.

PURPOSE: Interventions that decrease barriers and improve clinical processes can increase patient access to guideline-recommended cancer genetics services. We sought to identify and describe interventions to improve patient receipt of guideline-recommended cancer genetics services in the United States. METHODS: We performed a comprehensive search in Ovid MEDLINE and Embase, Scopus, and Web of Science from January 1, 2000 to February 12, 2020. Eligible articles reported interventions to improve the identification, referral, genetic counseling (GC), and genetic testing (GT) of patients in the United States. We independently screened titles and abstracts and reviewed full-text articles. Data were synthesized by grouping articles by clinical process. RESULTS: Of 44 included articles, 17 targeted identification of eligible patients, 14 targeted referral, 15 targeted GC, and 16 targeted GT. Patient identification interventions included universal tumor testing and screening of medical/family history. Referral interventions included medical record system adaptations, standardizing processes, and provider notifications. GC interventions included supplemental patient education, integrated GC within oncology clinics, appointment coordination, and alternative service delivery models. One article directly targeted the GT process by implementing provider-coordinated testing. CONCLUSION: This scoping review identified and described interventions to improve US patients' access to and receipt of guideline-recommended cancer genetics services.

Factors impacting adolescent and young adult cancer patients' decision to pursue genetic counseling and testing.

PURPOSE: Adolescent and young adult (AYA) cancer patients face challenges when navigating cancer treatment and survivorship. Many are at risk for cancer predisposition syndromes; however, factors influencing pursuit of genetic counseling and testing have not been reported. We describe AYA cancer patients' decision-making process, including motivational factors and barriers, as it relates to utilization of genetic services. METHODS: Thirty AYAs diagnosed with cancer previously referred for cancer predisposition genetic counseling completed semi-structured interviews via audio-only Zoom calls. Thematic analysis was used to perform qualitative analysis and identify major themes. RESULTS: The sample comprised 21 AYAs who had genetic counseling and nine who did not. Motivational factors identified included learning genetic counseling is an available service, concern about the impact of a hereditary syndrome on family members and family planning, learning about the need for cancer screening or prevention, affordability of genetic testing, and easing worry about additional cancer risks. For those who did not pursue genetic counseling, barriers included scheduling or other priorities, worry, and cost. However, the majority expressed they would reconsider genetic counseling in the future. CONCLUSION: AYA cancer patients have similar motivational factors to pursue genetic counseling compared to other patients; however, their younger age of diagnosis may alter how these factors affect decision-making. While there are barriers limiting access to genetic services, they did not decrease interest in future genetic counseling for most patients. Genetic counseling and testing should be discussed with patients who previously declined genetic services.

Clinical management among individuals with variant of uncertain significance in hereditary cancer: A systematic review and meta-analysis.

Improper medical use of variant of uncertain significance (VUS) remains a concern in hereditary cancer genetic testing. The goal of this study was to assess the association between pathogenic and likely pathogenic (P/LP), VUS, and benign and likely benign (B/LB) genetic test results and cancer-related surgical and screening management. Systematic searches of Medline, Embase, EBSCO CINAHL Plus, and PsycINFO were conducted from 1946 to August 26, 2020. Eligible studies included individuals with cancer genetic test result and surgical or screening management outcomes. We reviewed 885 abstracts and 22 studies that reported relevant surgical and screening outcomes were included. Meta-analysis revealed significantly higher surgical rates among individuals with P/LP than among those with VUS for therapeutic mastectomy with contralateral prophylactic mastectomy (OR = 7.35, 95% CI, 4.14-13.64), prophylactic mastectomy (OR = 3.05, 95% CI, 1.5-6.19), and oophorectomy (OR = 6.46, 95% CI, 3.64-11.44). There were no significant differences in therapeutic mastectomy, or breast conservation or lumpectomy rates between individuals with P/LP and VUS, or in any outcomes between patients with VUS and B/LB. Studies evaluating screening outcomes were limited, and results were conflicting. Comprehensive analysis do not indicate that a significant number of individuals with VUS results undergo inappropriate clinical management.

Disclosure of familial implications of pathogenic variants in breast-cancer genes to patients: Opportunity for prompting family communication.

Familial communication of pathogenic genetic variants is necessary to maximize the clinical utility of genetic testing and its public health benefits. Insights to family communication considerations may be obtained from existing clinical documentation available in medical records. The goal of this study was to describe and characterize information about family communication of pathogenic variants and cascade genetic testing from genetic counseling summary notes. We completed structured content analysis of 656 summary notes describing pathogenic variants in breast cancer genes, for patients seen at a tertiary cancer center. Patients were 89.5% female, median age of 49 years, 32.6% non-White, and were counseled by 23 unique genetic counselors (GCs) with mean post-certification experience of 3.7 years. Cascade genetic testing was documented in 92.2% of all notes. Specific relatives (i.e., relationship to patient) who would benefit from genetic counseling and cascade testing were referenced in 33.1% of notes. Specific risk messaging was 2.5 times more likely to be present in notes of high- compared to moderate-risk genes (OR=2.53, 95% CI: 1.71-3.80), and when summary notes indicated the presence of a friend or relative (OR=2.29, 95% CI: 1.50-3.48). Summary notes frequently attempted to contextualize the patients' familial relationships by referencing positive family communication patterns (41.6%) or negative communication issues (2.4%) and included various strategies to address barriers to communication and assist relatives with cascade testing. Overall, GCs consistently documented family communication recommendations when pathogenic variants are identified on patients' genetic testing, albeit with heterogeneous use of specific communication prompts.

Assessing relatives' readiness for hereditary cancer cascade genetic testing.

PURPOSE: To explore the readiness of living, untested first-degree relatives (FDRs) to have cascade genetic testing (CGT) for a hereditary predisposition to cancer. METHODS: Adults with a hereditary predisposition to cancer completed an anonymous, online survey about their genetic testing and their FDRs' vital status, awareness of the variant, uptake of CGT, and readiness for CGT among living, untested FDRs using transtheoretical model stages of change. RESULTS: One hundred fifty participants completed the survey and reported 825 FDRs. Overall, 70.3% of FDRs were reportedly aware of the variant and 30.5% had completed CGT. Siblings had higher rates of awareness and CGT than parents or children (p < 0.001). Relatives' sex was associated with awareness and CGT; mothers were aware and had CGT at higher rates than fathers (p = 0.049 and p < 0.001), sisters were aware and had CGT at higher rates than brothers (p = 0.041 and p = 0.002), and daughters had higher rates of awareness than sons (p = 0.038). Of 340 living, untested FDRs, 79.4% were in the precontemplation stage of change, with no difference by relatives' sex or relationship to the participant. CONCLUSIONS: Most living, untested FDRs were in precontemplation stage, indicating they are not ready or planning to have CGT within the next six months.

Clinical applicability of proposed algorithm for identifying individuals at risk for hereditary hematologic malignancies.

Multiple genes have been identified to cause hereditary predispositions to hematologic malignancies, and characterized by an increased risk to develop myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and/or aplastic anemia (AA). Referral algorithms for patients who may be at higher risk have been proposed, with limited data regarding applicability. Our study aimed to evaluate referral criteria on a population of MDS/AML/AA patients. Demographic information and medical history were obtained from 608 patients referred over a 9-month period. Median age at diagnosis was 67 years (56-73), 387 (64%) were male, and the majority of individuals (54.9%) had AML. Overall, 406 individuals (66.8%) had insufficient documentation to determine whether certain criteria were met. Two hundred and two (33.2%) individuals met at least one criteria for genetic counseling referral; however, only nine (4.5%) were referred. Increased documentation of personal and family history is necessary to better assess and validate the applicability of these criteria.

Disparities in gynecologic cancer genetics evaluation.

An estimated 2-5% of endometrial cancers and 15-20% of high-grade, non-mucinous epithelial ovarian cancers have an underlying hereditary cause. Appropriate risk assessment, genetic counseling, and germline genetic testing for cancer predisposition genes in both gynecologic cancer patients and their at-risk relatives is essential for effective delivery of tailored cancer treatment and cancer prevention. However, significant disparities exist within medically underserved and minority populations in the United States regarding awareness of, access to, and use of genetic services. The objectives of this review are to summarize the literature on genetic counseling and genetic testing of gynecologic cancer patients, the cascade genetic testing of their families following the identification of a germline mutation associated with susceptibility to cancer, to highlight disparities between populations, and to present some potential remedies.

Disseminating universal genetic testing to a diverse, indigent patient population at a county hospital gynecologic oncology clinic.

OBJECTIVE: The universal genetic testing initiative (UGTI) is a quality improvement effort to increase rates of guideline-based genetic counseling (GC) and genetic testing (GT) of patients with potentially hereditary cancers. The UGTI was disseminated to a county hospital gynecologic oncology clinic that serves a diverse, indigent patient population. METHODS: Using the Model for Improvement quality improvement framework, interventions including integrated GC, clinic tracking, assisted GC referrals, and provider education were tested over 26 months. A retrospective data review included patients with high-grade, non-mucinous epithelial ovarian, fallopian tube, and primary peritoneal cancers (HGOC) and endometrial cancers (EC) diagnosed between 9/1/12-8/31/16. Statistical analyses were performed to describe the population and to evaluate rates of recommendation and use of immunohistochemistry tumor testing (IHC), GC, and GT. RESULTS: A cohort of 241 patients (57 HGOC, 184 EC) were included. At the conclusion of the study 84.2% of HGOC patients were referred for GC, 89.6% (43/48) completed GC, and 90.7% (39/43) completed GT. Of EC patients, 81.0% were recommended to have IHC and 62.4% (93/149) completed IHC. Patients with HGOC diagnosed during dissemination of UGTI were significantly more likely to receive a recommendation for GC (p = 0.02) and to complete GT (p = 0.03) than those diagnosed before UGTI. Patients with EC were significantly more likely to complete IHC if diagnosed after UGTI than those diagnosed prior to dissemination (p < 0.001). CONCLUSIONS: The UGTI can be adapted to increase use of guideline-based cancer genetics services in a diverse, indigent, gynecologic cancer patient population.

Creation and Implementation of an Environmental Scan to Assess Cancer Genetics Services at Three Oncology Care Settings.

An environmental scan (ES) is an efficient mixed-methods approach to collect and interpret relevant data for strategic planning and project design. To date, the ES has not been used nor evaluated in the clinical cancer genetics setting. We created and implemented an ES to inform the design of a quality improvement (QI) project to increase the rates of adherence to national guidelines for cancer genetic counseling and genetic testing at three unique oncology care settings (OCS). The ES collected qualitative and quantitative data from reviews of internal processes, past QI efforts, the literature, and each OCS. The ES used a data collection form and semi-structured interviews to aid in data collection. The ES was completed within 6 months, and sufficient data were captured to identify opportunities and threats to the QI project's success, as well as potential barriers to, and facilitators of guideline-based cancer genetics services at each OCS. Previously unreported barriers were identified, including inefficient genetic counseling appointment scheduling processes and the inability to track referrals, genetics appointments, and genetic test results within electronic medical record systems. The ES was a valuable process for QI project planning at three OCS and may be used to evaluate genetics services in other settings.

Delivery Of Cascade Screening For Hereditary Conditions: A Scoping Review Of The Literature.

Cascade screening is the process of contacting relatives of people who have been diagnosed with certain hereditary conditions. Its purpose is to identify, inform, and manage those who are also at risk. We conducted a scoping review to obtain a broad overview of cascade screening interventions, facilitators and barriers to their use, relevant policy considerations, and future research needs. We searched for relevant peer-reviewed literature in the period 1990-2017 and reviewed 122 studies. Finally, we described 45 statutes and regulations related to the use and release of genetic information across the fifty states. We sought standardized best practices for optimizing cascade screening across various geographic and policy contexts, but we found none. Studies in which trained providers contacted relatives directly, rather than through probands (index patients), showed greater cascade screening uptake; however, policies in some states might limit this approach. Major barriers to cascade screening delivery include suboptimal communication between the proband and family and geographic barriers to obtaining genetic services. Few US studies examined interventions for cascade screening or used rigorous study designs such as randomized controlled trials. Moving forward, there remains an urgent need to conduct rigorous intervention studies on cascade screening in diverse US populations, while accounting for state policy considerations.

A universal genetic testing initiative for patients with high-grade, non-mucinous epithelial ovarian cancer and the implications for cancer treatment.

OBJECTIVE: Genetic counseling (GC) and germline genetic testing (GT) for BRCA1 and BRCA2 are considered standard of care for patients with high-grade, non-mucinous epithelial ovarian, fallopian tube, and primary peritoneal cancers (HGOC). We describe a universal genetic testing initiative to increase the rates of recommendation and acceptance of GC and GT to >80% for patients with HGOC at our institution. METHODS: Data from a consecutive cohort of patients seen in our gynecologic oncology clinics between 9/1/2012 and 8/31/2015 for evaluation of HGOC were retrospectively analyzed. Data were abstracted from the tumor registry, medical records, and research databases. Descriptive statistics were used to evaluate patient characteristics and GC, GT, and PARP inhibitor use. Various clinic interventions were developed, influenced by the Plan-Do-Study-Act cycle method, which included physician-coordinated GT, integrated GC, and assisted GC referrals. RESULTS: A cohort of 1636 patients presented to the gynecologic oncology clinics for evaluation of HGOC during our study period, and 1423 (87.0%) were recommended to have GC and GT. Of these, 1214 (85.3%) completed GT and 217 (17.9%) were found to have a BRCA1 or BRCA2 mutation. Among BRCA-positive patients, 167 had recurrent or progressive disease, and 56 of those received PARP inhibitor therapy. CONCLUSIONS: The rates of GC and GT recommendation and completion among patients with HGOC at our institution exceeded 80% following the implementation of a universal genetic testing initiative. Universal genetic testing of patients with HGOC is one strategy to identify those who may benefit from PARP inhibitor therapy.