Christina Rybak

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.

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.

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.

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.

Somatic TP53 variants frequently confound germ-line testing results

PurposeBlood/saliva DNA is thought to represent the germ line in genetic cancer-risk assessment. Cases with pathogenic TP53 variants detected by multigene panel testing are often discordant with Li-Fraumeni syndrome, raising concern about misinterpretation of acquired aberrant clonal expansions (ACEs) with TP53 variants as germ-line results.MethodsPathogenic TP53 variants with abnormal next-generation sequencing metrics (e.g., decreased ratio (<25%) of mutant to wild-type allele, more than two detected alleles) were selected from a CLIA laboratory testing cohort. Alternate tissues and/or close relatives were tested to distinguish between ACE and germ-line status. Clinical data and Li-Fraumeni syndrome testing criteria were examined.ResultsAmong 114,630 multigene panel tests and 1,454 TP53 gene-specific analyses, abnormal next-generation sequencing metrics were observed in 20% of 353 TP53-positive results, and ACE was confirmed for 91% of cases with ancillary materials, most of these due to clonal hematopoiesis. Only four met Chompret criteria. Individuals with ACE were older (50 years vs. 33.7; P = 0.02) and were identified more frequently in multigene panel tests (66/285; 23.2%) than in TP53 gene-specific tests (6/68; 8.8%, P = 0.005).ConclusionACE confounds germ-line diagnosis, may portend hematologic malignancy, and may provoke unwarranted clinical interventions. Ancillary testing to confirm germ-line status should precede Li-Fraumeni syndrome management.

Bilateral granulosa cell tumors: a novel malignant manifestation of multiple endocrine neoplasia 1 syndrome found in a patient with a rare menin in-frame deletion.

Introduction Multiple endocrine neoplasia 1 (MEN1) is a cancer syndrome resulting from mutations of the MEN1 gene. The syndrome is characterized by neoplasia of the parathyroid and pituitary glands, and malignant tumors of the endocrine pancreas. Other manifestations include benign lipomas, angiofibromas, and carcinoid tumors commonly originating in the colon, thymus, and lung. This is the first report of MEN1 syndrome manifesting as bilateral granulosa cell ovarian tumors, and which is associated with a rare intronic mutation of the MEN1 gene. Case report A 41-year-old woman presented with abdominal pain, increasing abdominal girth, and dysmenorrhea. Ultrasound demonstrated enlarged ovaries and uterine fibroids. After an exploratory laparotomy, she subsequently underwent bilateral salpingo–oophorectomy with hysterectomy where the pathology revealed bilateral cystic granulosa cell tumors of the ovaries. Additional workup including computed tomography imaging discovered a thymic mass, which the pathology showed was malignant, along with a pancreatic mass suspicious for a neuroendocrine tumor. Hyperparathyroidism was also discovered and was found to be secondary to a parathyroid adenoma. Genetic testing revealed an exceedingly rare mutation in the MEN1 gene (c.654 + 1 G>A). Discussion Mutations of the menin gene leading to MEN1 syndrome are classically nonsense or missense mutations producing a dysfunctional protein product. Recently, researchers described a novel mutation of MEN1 (c.654 + 1 G>A) in a male proband meeting the criteria for clinical MEN1 syndrome. Functional analysis performed on the stable mutant protein showed selective disruption of the transforming growth factor beta signaling pathway, yet it maintained its wild-type ability to inhibit nuclear factor kappa B and to suppress JunD transcriptional activity. Conclusion To our knowledge, this is the first report of MEN1 syndrome associated with bilateral granulosa cell malignancy. We postulate that this presentation may be due to the novel menin gene mutation recently described.

Evaluating the impact of a clinical universal mismatch repair screening initiative.

194 Background: Immunohistochemistry (IHC)-based universal mismatch repair (UMMR) screening of incident colorectal (CRC) and endometrial (EC) tumors for deficient MMR (dMMR) associated with Lynch syndrome (LS) is supported by expert recommendations and is cost-effective. Heterogeneity in the approach to implementation of UMMR screening nationwide has been observed, suggesting knowledge gaps that could adversely impact anticipated outcomes. Studies of clinical UMMR screening can inform efforts to optimize implementation in the real world setting. METHODS In September 2011, Fox Chase Cancer Center (FCCC) began UMMR screening of incident (surgical) CRC/EC tumors. Providers were emailed a tailored UMMR Results letter intended to facilitate discussion of hereditary cancer risks and for distribution to patients. Content supported genetics consultation for an abnormal UMMR screen or for high-risk history (Hx) regardless of MMR status (i.e., personal Hx of any cancer; or 1st/2nd degree relative with a LS cancer and/or cancer <50). For comparison, clinical data on all CRC/EC surgical cases 3 months prior to implementation of UMMR screening were extracted from the medical record. RESULTS 55 surgeries for CRC/EC occurred in the 3 months pre-implementation (PRE) and 130 in the 9 months post-implementation (POST). 1 yr PRE and POST data will be presented at the 2012 Quality Symposium. CONCLUSIONS The UMMR screening initiative greatly improved patient outcomes. Provider referral and documentation behavior was highly responsive to an abnormal screening result, but not high-risk cancer history alone. [Table: see text].

Abstract B7: Use of risk assessment services and predictive genetic testing (PGT) for hereditary gastrointestinal (GI) cancers: How do men and women differ?

Background: Uptake of risk assessment and PGT for hereditary GI cancer risk has lagged far behind that of the hereditary breast‐ovarian cancer syndrome and BRCA1/2, despite the parallel clinical availability of genetic services for hereditary GI cancers, the proportion of patients with incident colorectal cancers who demonstrate familial risk (∼ 1 in 3), and the prevalence of Lynch syndrome associated mismatch repair gene mutations among incident colorectal cancers (∼ 3–5%). The bulk of data on perceptions of PGT have focused on women considering BRCA1/2 testing for personal and/or familial risk estimation. Studies in men are less plentiful, and have often focused on men9s opinions about PGT for prostate cancer risk, although clinical PGT for hereditary prostate cancer is not currently available. Individuals enrolled in a high‐risk GI cancer registry represent a unique population in which important differences in perceptions of PGT between men and women may be directly examined to shed light on barriers to risk assessment and PGT, and cancer prevention services in general, that may differ by gender. Methods: The GI Tumor Risk Assessment Program (GI‐TRAP) registry at Fox Chase Cancer Center enrolls individuals at increased risk for GI cancers because of a suggestive personal or family history. At enrollment and prior to risk education and counseling, participants are asked to complete a detailed personal and family history and a questionnaire examining screening practices and psychosocial aspects of hereditary cancer risk. The GI‐TRAP registry currently contains information collected from members of 269 families. Results: Women (n=293) participants outnumbered men (n=105) almost 3 to 1, were younger (47.0 vs 50.8 yrs)(p=0.01), and were less likely to work full‐time (39.9% vs 59.0%)(p Conclusions: Compared to women, overall fewer men obtain available risk assessment services for hereditary GI cancers. Men seek risk assessment for similar reasons to women, but express lower concern for out‐of‐pocket costs or adverse personal and familial emotional reactions to testing results. Efforts to make cancer risk assessment services more visible and available to men and working individuals (e.g., expanded clinical hours, on‐site education/counseling at places of employment, health clubs, etc) may help to increase the identification of high‐risk individuals who would benefit from tailored GI prevention education, genetic counseling, and PGT. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B7.