Combining clinical and molecular characterization of CDH1: a multidisciplinary approach to reclassification of a splicing variant.

Pathogenic germline variants (PGVs) in the CDH1 gene are associated with diffuse gastric and lobular breast cancer syndrome (DGLBC) and can increase the lifetime risk for both diffuse gastric cancer and lobular breast cancer. Given the risk for diffuse gastric cancer among individuals with CDH1 PGVs is up to 30-40%, prophylactic total gastrectomy is often recommended to affected individuals. Therefore, accurate interpretation of CDH1 variants is of the utmost importance for proper clinical decision-making. Herein we present a 45-year-old female, with lobular breast cancer and a father with gastric cancer of unknown pathology at age 48, who was identified to have an intronic variant of uncertain significance in the CDH1 gene, specifically c.833-9 C > G. Although the proband did not meet the International Gastric Cancer Linkage Consortium (IGCLC) criteria for gastric surveillance, she elected to pursue an upper endoscopy where non-targeted gastric biopsies identified a focus of signet ring cell carcinoma (SRCC). The proband then underwent a total gastrectomy, revealing numerous SRCC foci, but no invasive diffuse gastric cancer. Simultaneously, a genetic testing laboratory performed RNA sequencing to further analyze the CDH1 intronic variant, identifying an abnormal transcript from a novel acceptor splice site. The RNA analysis in conjunction with the patient's gastric foci of SRCC and family history was sufficient evidence for reclassification of the variant from uncertain significance to likely pathogenic. In conclusion, we report the first case of the CDH1 c.833-9 C > G intronic variant being associated with DGLBC and illustrate how collaboration among clinicians, laboratory personnel, and patients is crucial for variant resolution.

Development of a communication protocol for telephone disclosure of genetic test results for cancer predisposition.

BACKGROUND: Dissemination of genetic testing for disease susceptibility, one application of "personalized medicine", holds the potential to empower patients and providers through informed risk reduction and prevention recommendations. Genetic testing has become a standard practice in cancer prevention for high-risk populations. Heightened consumer awareness of "cancer genes" and genes for other diseases (eg, cardiovascular and Alzheimer's disease), as well as the burgeoning availability of increasingly complex genomic tests (ie, multi-gene, whole-exome and -genome sequencing), has escalated interest in and demand for genetic risk assessment and the specialists who provide it. Increasing demand is expected to surpass access to genetic specialists. Thus, there is urgent need to develop effective and efficient models of delivery of genetic information that comparably balance the risks and benefits to the current standard of in-person communication. OBJECTIVE: The aim of this pilot study was to develop and evaluate a theoretically grounded and rigorously developed protocol for telephone communication of BRCA1/2 (breast cancer) test results that might be generalizable to genetic testing for other hereditary cancer and noncancer syndromes. METHODS: Stakeholder data, health communication literature, and our theoretical model grounded in Self-Regulation Theory of Health Behavior were used to develop a telephone communication protocol for the communication of BRCA1/2 genetic test results. Framework analysis of selected audiotapes of disclosure sessions and stakeholders' feedback were utilized to evaluate the efficacy and inform refinements to this protocol. RESULTS: Stakeholder feedback (n=86) and audiotapes (38%, 33/86) of telephone disclosures revealed perceived disadvantages and challenges including environmental factors (eg, non-private environment), patient-related factors (eg, low health literacy), testing-related factors (eg, additional testing needed), and communication factors (eg, no visual cues). Resulting modifications to the communication protocol for BRCA1/2 test results included clarified patient instructions, scheduled appointments, refined visual aids, expanded disclosure checklist items, and enhanced provider training. CONCLUSIONS: Analyses of stakeholders' experiences and audiotapes of telephone disclosure of BRCA1/2 test results informed revisions to communication strategies and a protocol to enhance patient outcomes when utilizing telephone to disclose genetic test results.

A team approach to systematic behavioral screening and intervention.

OBJECTIVES: Unhealthy behaviors are responsible for most chronic disease, ample healthcare costs, and around 40% of deaths. This study assessed patient satisfaction and behavioral outcomes for a program that enables healthcare settings to deliver evidence-based, cost-saving behavioral screening and intervention (BSI) services, as recommended by the US Preventive Services Task Force and others. STUDY DESIGN: Pre-post program evaluation. METHODS: Thirty-one diverse primary care clinics and 2 other sites participated. Over 110,000 patients completed multibehavioral screening questionnaires. Those with positive alcohol or drug screens met with dedicated, on-site health educators for further assessment, and then received either reinforcement, brief intervention, or referral. Over 300 patients completed satisfaction questionnaires during year 3 of the program. A pseudo-randomly selected group of 675 patients participated in a 6-month follow-up telephone interview. In addition, for a short time in a pilot project at 3 clinics, 29 patients received depression screening, collaborative care, and behavioral activation, and 22 completed a 3-month follow-up telephone interview. RESULTS: Mean patient satisfaction scores for all services exceeded 4.2 on a 5-point scale. Over 6 months, binge drinking episodes declined by over 20% for most subgroups. Recent marijuana use decreased by 15%. Depression symptom scores decreased by 55%. CONCLUSIONS: With intensive training and ongoing support, cost-efficient paraprofessionals can deliver effective alcohol, drug, and depression screening and intervention services in busy healthcare settings. The approach holds promise for systematically addressing on a population-wide basis a variety of important behavioral health determinants and reducing related healthcare costs.

Implementation and outcomes of telephone disclosure of clinical BRCA1/2 test results.

OBJECTIVES: With an increasing demand for genetic services, effective and efficient delivery models for genetic testing are needed. METHODS: In this prospective single-arm communication study, participants received clinical BRCA1/2 results by telephone with a genetic counselor and completed surveys at baseline, after telephone disclosure (TD) and after in-person clinical follow-up. RESULTS: Sixty percent of women agreed to participate; 73% of decliners preferred in-person communication. Anxiety decreased from baseline to post-TD (p=0.03) and satisfaction increased (p<0.01). Knowledge did not change significantly from baseline to post-TD, but was higher post-clinical follow-up (p=0.04). Cancer patients had greater declines in state anxiety and African-American participants reported less increase in satisfaction. 28% of participants did not return for in-person clinical follow-up, particularly those with less formal education, and higher post-disclosure anxiety and depression (p<0.01). CONCLUSIONS: Telephone disclosure of BRCA1/2 test results may not be associated with negative cognitive and affective responses among willing patients, although some subgroups may experience less favorable responses. Some patients do not return for in-person clinical follow-up and longitudinal outcomes are unknown. PRACTICE IMPLICATIONS: Further evaluation of longitudinal outcomes of telephone disclosure and differences among subgroups can inform how to best incorporate telephone communication into delivery of genetic services.

Mentoring nurses in familial cancer risk assessment and counseling: lessons learned from a formative evaluation.

BACKGROUND: As familial cancer genetic services moves into community practice increased numbers of trained health professionals are needed to counsel individuals seeking cancer risk information. Nurses have been targeted to provide cancer risk assessment and counseling. To help prepare nurses for this role, a 5-day training in familial cancer risk assessment and counseling followed by a long-distance mentorship to support continued skill development in the work environment was conducted by Fox Chase Cancer Center, Philadelphia, PA. METHODS: Four cohorts (N = 41) have completed the training and were randomized to either an immediate or delayed mentorship. A formative evaluation assessed the nurse's ability to consult with other genetic health professionals and build self-efficacy in counseling skills via responses to questionnaire. A post-mentorship interview evaluated the usefulness, timing and length of the mentorship. RESULTS: For both groups, there was a statistically significant improvement in self-efficacy for all skills from baseline to 6 months and an increased number of nurses consulting with genetic health professionals. All the nurses reported the value of the mentorship and those with less cancer risk counseling experience prior to the training needed support and resources for further skill and program development. Lessons learned from this formative evaluation are provided.