An analysis of the impact of annual cancer genetic testing guideline updates on a past patient population.

Germline genetic testing for cancer predisposition genes has become an essential component of cancer treatment and risk reduction. The National Comprehensive Cancer Network (NCCN) releases annual genetic testing guidelines that identify characteristics of patients that could be affected by a hereditary cancer syndrome. These guidelines have broadened over time and the implications for past patients of cancer genetics clinics are not well understood. This study is a retrospective chart review aimed at determining the percentage and characteristics of past patients that meet updated NCCN guidelines (Breast, Ovarian, and Pancreas [BOP] v1.2022 and Colorectal [CRC] v1.2021), patients that attended a follow-up appointment, and patients who went on to receive genetic testing. Clinical data and characteristics were compared between the study population as a whole and the cohort of patients that met updated NCCN guidelines BOP v1.2022 and CRC v1.2021. The study population consisted of 280 patients with 76 (27.1%) patients meeting updated NCCN guidelines BOP v1.2022 and CRC v1.2021. The year of initial cancer genetic counseling appointment was statistically significant (p = 0.023) with patients more likely to meet NCCN guidelines BOP v1.2022 and CRC v1.2021 with earlier initial cancer genetic counseling appointments. In the cohort that met updated NCCN guidelines BOP v1.2022 and CRC v1.2021, the most common reason was a change in the NCCN guidelines (BOP or CRC) (54/76, 71.1%) with triple-negative breast cancer diagnosed at any age being the most impactful guideline change (19/54, 35.2%). Twenty-one patients attended a follow-up appointment (7.5%) and of those that received genetic testing (17/21, 81%) most received negative results (13/17, 61.9%), with one pathogenic, low penetrance result (1/17, 5.9%, CHEK2 p.I157T). Provider-initiated follow-up was attributed to most follow-up appointments (16/21, 76.2%) implying patients do not tend to follow-up on their own. Education to non-genetics providers as well as targeted implementation of follow-up protocols possibly managed by genetic counseling assistants and utilizing electronic medical record (EMR) patient messaging could lead to improved patient follow-up.

A Randomized Trial Comparing the Effectiveness of Pre-test Genetic Counseling Using an Artificial Intelligence Automated Chatbot and Traditional In-person Genetic Counseling in Women Newly Diagnosed with Breast Cancer.

BACKGROUND: Alternative service delivery models are critically needed to address the increasing demand for genetics services and limited supply of genetics experts available to provide pre-test counseling. METHODS: We conducted a prospective randomized controlled trial of women with stage 0-III breast cancer not meeting National Comprehensive Cancer Network (NCCN) criteria for genetic testing. Patients were randomized to pre-test counseling with a Chatbot or a certified genetic counselor (GC). Participants completed a questionnaire assessing their knowledge of breast cancer genetics and a survey assessing satisfaction with their decision regarding pre-test counseling. RESULTS: A total of 39 patients were enrolled and 37 were randomized to genetic counseling with an automated Chatbot or a GC; 19 were randomized to Chatbot and 18 to traditional genetic counseling, and 13 (38.2%) had a family member with breast cancer but did not meet NCCN criteria. All patients opted to undergo genetic testing. Testing revealed six pathogenic variants in five patients (13.5%): CHEK2 (n = 2), MSH3 (n = 1), MUTYH (n = 1), and BRCA1 and HOXB13 (n = 1). No patients had a delay in time-to-treatment due to genetic testing turnaround time, nor did any patients undergo additional risk reducing surgery. There was no significant difference in median knowledge score between Chatbot and traditional counseling (11 vs. 12, p = 0.09) or in median patient satisfaction score (30 vs. 30, p = 0.19). CONCLUSION: Satisfaction and comprehension in patients with breast cancer undergoing pre-test genetic counseling using an automated Chatbot is comparable to in-person genetic testing. Utilization of this technology can offer improved access to care and a much-needed alternative for pre-test counseling.

Primary care physician referral practices regarding BRCA1/2 genetic counseling in a major health system.

PURPOSE: The United States Preventive Services Task Force recommends primary care physicians refer patients at high risk for BRCA1/2 mutations to genetic testing when appropriate. The objective of our study was to describe referrals for BRCA1/2 testing in a large integrated health system and to assess factors associated with referral. METHODS: This retrospective cohort study includes female patients between 18 and 50 years who had a primary care visit in the Cleveland Clinic Health System between 2010 and 2019. We used multivariable logistic regression to estimate differences in the odds of a woman being referred for BRCA1/2 testing by patient factors and referring physician specialty. We also assessed variation in referrals by physicians. RESULTS: Among 279,568 women, 5% were high risk. Of those, 22% were referred for testing. Black patients were significantly less likely to be referred than white patients (aOR 0.87; 95% CI 0.77, 0.98) and Jewish patients were more likely to be referred than non-Jewish patients (aOR 2.13; 95% CI 1.68, 2.70). Patients primarily managed by OB/GYN were significantly more likely to be referred than those cared for via Internal/Family Medicine (aOR 1.45; 95% CI 1.30, 1.61). Less than a quarter of primary care physicians ever referred a patient for testing. CONCLUSION: The majority of primary care patients at high risk for a BRCA1/2 mutation were not referred for testing, and over a decade, most physicians never referred a single patient. Internal/Family Medicine physicians, in particular, need support in identifying and referring women who could benefit from testing.

Rapid implementation of telegenetic services during the COVID-19 pandemic allowed continuing patient access, but not equally for all.

Telegenetics is the use of telemedicine to deliver clinical genetic services to patients. During the COVID-19 public health emergency (PHE), telegenetics was essential for the Center of Personalized Genetic Healthcare (CPGH). This study reviews and analyzes in the context of the RE-AIM framework CPGH's rapid implementation of telegenetics and its impact. We conducted a chart review of all out-patient telegenetics encounters scheduled in CPGH during the first five weeks of the COVID-19 PHE. Data analyzed included demographics; number of encounters scheduled; subspecialties and providers; outcome of encounter (completed, cancelled, no- show); and telehealth platform used. Data were compared to data for out-patient encounters in 2019. In the first five weeks of the COVID-19 PHE, 465 virtual visits were scheduled and 428 were completed, involving all six subspecialties and 86% of CPGH providers. The no-show plus cancellation rate was significantly lower than in 2019. By week four, CPGH's virtual visit volume was 82% of its out-patient volume during the same time period in 2019. Patients over 60 and Black patients were significantly more likely to use phone-audio only appointments. CPGH rapidly implemented telegenetic services to continue providing care to patients. We identified success factors that enabled this. However, our analysis also identified a possible "digital divide" for Black and older patients.

Inherited Thrombocytopenia Caused by Germline ANKRD26 Mutation Should Be Considered in Young Patients With Suspected Myelodysplastic Syndrome.

Thrombocytopenia 2 (THC2) is an autosomal dominant disorder characterized by ankyrin repeat domain 26 mutation and moderate thrombocytopenia. THC2 exposes patients to a low risk of bleeding and an increased likelihood of myelodysplastic syndrome/acute myeloid leukemia. Germline evaluation for a genetic disorder should be considered when a patient presents with isolated thrombocytopenia and associated dysmegakaryopoiesis. In this case report, we present a male patient who presented with isolated thrombocytopenia but was ultimately confirmed to have an inherited THC2 thrombocytopenia/myelodysplastic syndrome. Given the rarity of the disease, no clear guidelines on how to follow THC2 patients over the long term have been established. We recommend a monthly complete blood count and clinical visits every 3 months at a minimum.

Updates in hereditary breast cancer genetic testing and practical high risk breast management in gene carriers.

Testing for hereditary predisposition to breast cancer is rapidly expanding in parallel with the emerging field of molecular genetics given the associated implications for screening, risk reduction and cancer therapeutics for identified gene mutation carriers. With the advent of next generation multigene panel testing for hereditary predisposition and decreasing cost for that testing, more breast cancer patients (and unaffected family members) are undergoing cancer genetic testing. With multiple genes being tested and the myriad of possible results and implications for patients and their families, the process of genetic counseling is of paramount importance in promoting understanding by both patients and providers of risks and options for risk management. Guidelines exist to facilitate a multidisciplinary approach to management of individuals identified as being at increased risk, and there must be an appreciation for flexibility as guidelines are applied to individual families. This update summarizes recommendations regarding who may benefit from breast cancer risk assessment and genetic counseling, controversies regarding inclusion for testing and provides a framework for the practical management of high risk gene carriers.

Genetic Counseling Service Delivery Models in the United States: Assessment of changes in use from 2010 to 2017.

In 2010, the National Society of Genetic Counselors (NSGC) membership was surveyed about their use of genetic counseling service delivery models (SDMs) including in-person, telephone, telegenetics, and group genetic counseling. Since that time, the demand for genetic counseling services has increased in the United States (US). We hypothesized that the use of various SDMs has increased to help address the growing demand. To assess for changes in SDM use and interest in implementing innovative SDMs, the NSGC SDM subcommittee sent an electronic survey to the NSGC membership (N = 3,616), which was open from August 2017 to December 2017. Descriptive statistics and chi-square analysis were used to compare and identify differences in SDM utilization between 2010 and 2017. There were 590 total responses (16.3% response rate) with 517 usable responses, representing multiple genetic counseling specialties. Compared to 2010, significantly fewer respondents indicated they 'always' provide services in-person in 2017 (p < .04, df = 4), with 92.6% of respondents reporting 'always' or 'often' utilizing in-person SDM in 2017. Telephone genetic counseling was reported by 12.5% as a model used always or often, compared to 8% in 2010; however, the shift toward or away from telephone genetic counseling since 2010 was not statistically significant (p = .27, df = 4). The number of respondents using telegenetics always or often increased from 2.3% in 2010 to 6.7% in 2017, and more respondents report using telegenetics at an increased frequency (p < .01, df = 4). In contrast, those reporting use of a group genetic counseling SDM always or often decreased from 3.0% to 1.4%, though there was not a significant shift toward or away the frequency of respondents using group genetic counseling (p = .21, df = 4). Almost all respondents (93%) were interested in implementing an additional and/or different SDM; however, many (74%) identified barriers to implementation. There was an increase in those reporting use of 3 or 4 SDMs in practice since 2010 (p < .02). Genetic counselors may be attempting to compensate for longer wait times by implementing additional SDMs to improve access for patients. There is strong interest in learning about and implementing innovative SDMs to improve access and efficiency. However, resources need to be developed to help genetic counselors identify and overcome implementation barriers to achieve these goals.

The current state of genetic counseling assistants in the United States.

Genetic counseling assistants (GCAs) have the potential to address the high demand for genetic counselors by promoting task-sharing, increasing genetic counselor efficiency, and allowing for higher level duties to be optimized by genetic counselors. However, little research has been published on the role of GCAs. This study explored current tasks of GCAs in the United States, the appropriateness of those tasks, the perceived impact on the profession, and how these findings compared between genetic counselors with and without GCAs. Full members of the National Society of Genetic Counselors (NSGC) with and without experience working with GCAs were recruited via the NSGC Student Research listserv to complete an online survey and 271 surveys were analyzed. Participants working in both clinical and laboratory settings and in all primary specialties reported working with GCAs (n = 131); GCAs were reported to frequently perform clerical tasks but were involved less often in clinical tasks such as calling patients with genetic test results. There was no difference between participants with GCAs and those without GCAs in tasks they reported GCAs are or may be performing, yet participants without GCAs believed GCAs performed more tasks on average than those with GCAs reported (p < 0.001). Participants did not differ on the appropriateness of tasks, reporting clerical tasks as more appropriate for GCAs than clinically involved tasks, with the exception of calling patients with variant of uncertain significance (VUS) results in which more participants working with GCAs reported it as an appropriate task (13%) than those without GCAs (4%; p < 0.05). Review of open-ended responses revealed themes pertaining to primary limitations, benefits, and concerns of the GCA role. The most commonly reported concern about GCAs was their poorly defined scope of practice (n = 182). Other reported limitations included a heavy workload, lack of training, and lack of experience for GCAs while the benefits of working with GCAs included increased time available for higher level duties, patient volumes, and efficiency. These data provide genetic counselors, their institutions, and the NSGC with a more generalizable understanding of current GCA roles on a national level, across specialties. Additionally, these data may help establish a scope of practice for GCAs by creating a baseline job description for genetic counselors and their institutions interested in implementing a GCA into their practice to increase patient access to genetic counseling services. It is recommended that further research objectively quantify the value added by GCAs using efficiency metrics and further clarify the role of laboratory GCAs.

Impact of Multigene Panel Testing on Surgical Decision Making in Breast Cancer Patients.

BACKGROUND: With the advent of multigene panel testing for breast cancer patients, germline mutations with unknown association with cancer risk, known as variants of uncertain significance (VUS), are being increasingly identified. Some studies have shown higher rates of contralateral prophylactic mastectomies (CPM) in these patients, despite lack of evidence to support this intervention. We analyzed surgical choices in patients who were identified to have VUS. STUDY DESIGN: A retrospective review was performed of patients with triple-negative breast cancer treated at a single institution after multigene panel tests became available (September 1, 2013 to February 28, 2017). Rates of genetic testing, results of testing, and surgical decision making were evaluated. Chi-square or Fisher's exact test was used to compare categorical variables. A p value <0.05 was considered statistically significant. RESULTS: There were 477 triple-negative breast cancer patients identified; 331 met established criteria for genetic testing and 226 (68.3%) underwent genetic testing (multigene panel, n = 130 and BRCA1/2 testing, n = 96). All of them received risk-appropriate genetic counseling and follow-up. Of these, 29 (12.8%) patients had pathogenic mutations in BRCA1/2 or PALB2 (Mut+), 42 (18.6%) had VUS (VUS+), and 155 (68.6%) had no mutations identified (Mut-). Variants of uncertain significance in 6 of 42 patients (14.3%) were later reclassified as normal variants. Eighty-eight percent of Mut+ patients underwent CPM compared with 20.1% of Mut- and 21.4% of VUS+ patients (p < 0.001 for both). Rates of CPM were not significantly different between VUS+ and Mut- (p = 0.37). Multigene panel testing detected pathogenic mutations in non-breast cancer-associated genes in 6 patients, with significant management implications. CONCLUSIONS: When combined with risk-appropriate genetic counseling, detection of VUS did not lead to excessive CPM in this cohort of triple-negative breast cancer patients. Furthermore, panel testing detected mutations in non-breast cancer-associated genes, which had significant implications on management and outcomes.

Impact of an embedded genetic counselor on breast cancer treatment.

BACKGROUND: We predicted that embedding a genetic counselor within our breast practice would improve identification of high-risk individuals, timeliness of care, and appropriateness of surgical decision making. The aim of this study is to compare cancer care between 2012 and 2014, prior to embedding a genetic counselor in the breast center and following the intervention, respectively. METHODS: A retrospective review of patients diagnosed with breast cancer in 2012 (n = 471) and 2014 (n = 440) was performed to assess patterns of medical genetics referral, compliance with referral, genetic testing findings, and impact on treatment. RESULTS: Between 2012 and 2014, patients were 49% more likely to be referred to genetics, 66% more likely to follow through with their genetic counseling appointment, experienced a 73% reduction in wait times to genetic counseling visits and 69% more likely to have genetic testing results prior to surgery. Notably, while the number of genetic mutations identified was in the expected range over both time periods (9% of those tested in 2012 vs. 6.6% of those tested in 2014), there was a 31% reduction in time to treatment in 2014 vs. 2012. CONCLUSION: Awareness of germline genetic mutations is critical in surgical decision making for newly diagnosed breast cancer patients. Having an experienced genetics specialist on site in a busy surgical breast clinic allows for timely access to genetic counseling and testing, and may have influenced time to treatment in our institution.

Patient Decisions to Receive Secondary Pharmacogenomic Findings and Development of a Multidisciplinary Practice Model to Integrate Results Into Patient Care.

Whole exome sequencing (WES) has the potential of identifying secondary findings that are predictive of poor pharmacotherapy outcomes. The purpose of this study was to investigate patients' wishes regarding the reporting of secondary pharmacogenomic findings. WES results (n = 106 patients) were retrospectively reviewed to determine the number of patients electing to receive secondary pharmacogenomic results. Phenotypes were assigned based on Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines. The percent of patients with a predicted phenotype associated with a gene-based CPIC dosing recommendation was determined. Ninety-nine patients (93.4%) elected to receive secondary pharmacogenomic findings. For each gene-drug pair analyzed, the number of patients with an actionable phenotype ranged from two (2%) to 43 patients (43.4%). Combining all gene-drug pairs, 84 unique patients (84.8%) had an actionable phenotype. A prospective multidisciplinary practice model was developed for integrating secondary pharmacogenomic findings into clinical practice. Our model highlights a unique collaboration between physician-geneticists, pharmacists, and genetic counselors.

Assessment of clinical workload for general and specialty genetic counsellors at an academic medical center: a tool for evaluating genetic counselling practices.

With genomics influencing clinical decisions, genetics professionals are exponentially called upon as part of multidisciplinary care. Increasing demand for genetic counselling, a limited workforce, necessitates practices improve efficiency. We hypothesised that distinct differences in clinical workload exist between various disciplines of genetic counselling, complicating practice standardisation and patient volume expectations. We thus sought to objectively define and assess workload among various specialties of genetic counselling. Twelve genetic counsellors (GCs), representing 9.3 clinical FTE, in general or specialty (cancer, cardiovascular or prenatal) services at an academic health system developed a data collection tool for assessing time and complexity. Over a 6-week period, the data were recorded for 583 patient visits (136 general and 447 specialty) and analysed comparing general versus specialty GCs. Variables were compared with hierarchical linear models for ordinal or continuous data and hierarchical logistic models for binary data. General GCs completed more pre- and post-visit activities (P=0.011) and spent more time (P=0.009) per case. General GCs reported greater case discussion with other providers (P<0.001), literature review (P=0.026), exploring testing options (P=0.041), electronic medical record review (P=0.040), insurance preauthorization (P=0.05) and fielding patient inquiries (P=0.003). Lesser redundancy in referral indication was observed by general GCs. GCs in general practice carry a higher pre- and post-visit workload compared with GCs in specialty practices. General GCs may require lower patient volumes than specialty GCs to allow time for additional pre- and post-visit activities. Non-clinical activities should be transferred to support staff.

The incorporation of predictive genomic testing into genetic counseling programs.

This study explored whether genetic counseling programs are incorporating instruction about the applications and techniques of predictive genomic testing (PGT) based on student recollection, and whether this is perceived as adequate by those students. For the purpose of this study, PGT was defined as the use of genome-based testing to assess a person's risk, or susceptibility, of developing a disorder with either a known or suspected genetic component. Surveys from 114 graduates were analyzed. The majority of respondents indicated that PGT was covered in their curriculum including methodology, information generated, benefits, risks, limitations, and impact on the field of genetic counseling. A statistically significant increase in incorporating information about PGT as a whole from 2008 to 2011 was also reported. The majority of respondents reported that coverage of PGT prepared them for the American Board of Genetic Counseling (ABGC) board exam (80.6 %), to interpret PGT test results (60.2 %) and to identify clinical situations warranting testing (53.1 %). Although the majority of respondents indicated learning about a wide variety of aspects surrounding PGT, many recent graduates indicated their training was less likely to cover aspects essential for the clinical application of PGT. Therefore, genetic counseling programs should place a greater emphasis on these skills, and the development of continuing education opportunities aimed at increasing genetic counselors abilities to interpret and discuss PGT tests and identify clinical situations warranting such testing may be helpful.

Predicting PTEN mutations: an evaluation of Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome clinical features.

BACKGROUND: Cowden syndrome (CS) is associated with benign hamartomatous lesions and risks for thyroid, breast and endometrial cancers. Bannayan-Riley-Ruvalcaba syndrome is an allelic disorder characterised by macrocephaly, intestinal polyps, lipomas, and pigmented penile macules. Diagnostic criteria for CS are based on the presence of a range of clinical features. However, prior data on the component clinical features have been based primarily on compilations of cases reported before development of consensus diagnostic criteria. OBJECTIVE: This study sought to determine the clinical features most predictive of a mutation in the largest single cohort of patients with clinical testing for PTEN mutations reported to date. METHODS: Molecular and clinical data were reviewed on 802 patients referred for PTEN analysis by a single laboratory. RESULTS: Deleterious mutations were found in 172 (21.4%) subjects. Among mutation carriers significant differences from previous reports were found for the frequencies of several clinical features, including macrocephaly, uterine fibroids, benign breast disease, and endometrial cancer. Logistic regression analyses indicated that female mutation carriers were best identified by the presence of macrocephaly, endometrial cancer, trichilemmomas, papillomatous papules, breast cancer, benign thyroid disease, and benign gastrointestinal (GI) lesions. For males, the most discriminating features were macrocephaly, lipomas, papillomatous papules, penile freckling, benign GI lesions, and benign thyroid disease. Age related differences were also identified. CONCLUSION: The mutation frequency in patients meeting CS diagnostic criteria (34%) was significantly lower than previously reported, suggesting a need for reevaluation of these criteria. A mutation prediction model has been developed which can help identify patients appropriate for PTEN testing in clinical practice.

Melanoma candidate genes CDKN2A/p16/INK4A, p14ARF, and CDK4 sequencing in patients with uveal melanoma with relative high-risk for hereditary cancer predisposition.

The reported frequencies of germline mutations in the melanoma candidate genes are low in patients with uveal melanoma (UM). However, the number of families studied is limited and the majority of the published reports used low-sensitivity techniques for mutational screening. Identifying the frequency of alterations in any of the melanoma genes in patients with UM with increased hereditary cancer risk is important for proper counseling of these patients. We studied a total of 47 patients with UM including three with a family history of UM, 18 with a family and/or personal history of cutaneous melanoma (CM), three with early age at diagnosis (<30), 11 with increased risk for a known familial cancer syndrome, and 12 with a second primary tumor. Germline screening for mutations in CDKN2A, p14ARF, and exon 2 of CDK4 was carried out by direct sequencing. We identified a variant (IVS1-69 C>T) of uncertain significance in exon 1b of p14ARF in one of the patients with UM and his mother who also had UM. The variant was neither detected in any of the other patients with UM nor in 146 controls. We did not identify pathogenic mutations in CDKN2A nor exon 2 of CDK4 gene. Our study supports the low frequency of germline mutation of the CM candidate genes in patients with UM with family histories suggestive of a high risk for hereditary cancer. Germline testing for CDKN2A might be reserved for patients with UM with a family history of two or more CM.