Genetic counselors' and community clinicians' implementation and perceived barriers to informed consent during pre-test counseling for hereditary cancer risk.

As demand for genetic cancer risk assessment (GCRA) continues to increase, so does the sense of urgency to scale up efforts to triage patients, facilitate informed consent, and order genetic testing for cancer risk. The National Society of Genetic Counselors outlines the elements of informed consent that should be addressed in a GCRA session. While this practice resource aims to improve health equity, research on how well the elements of informed consent are implemented in practice is lacking. This retrospective and prospective mixed-methods study assessed how adequately the elements of informed consent are addressed during pre-test GCRA among 307 community clinicians (CC) and 129 cancer genetic counselors (GC), and barriers they face to addressing these elements. Results revealed that more than 90% of both cohorts consistently addressed components of at least 5 of the 10 elements of informed consent during a pre-test consultation. Technical aspects and accuracy of the test and utilization of test results were the most similarly addressed elements. Notably, GCs more often review the purpose of the test and who to test, general information about the gene(s), and economic considerations whereas CCs more often review alternatives to testing. Both cohorts reported psychosocial aspects of the informed consent process as the least adequately addressed element. Time constraints and patient-related concerns were most often cited by both cohorts as barriers to optimal facilitation of informed consent. Additional barriers reported by CCs included provider lack of awareness, experience, or education, and availability of resources and institutional support. Findings from this study may contribute to the development of alternative delivery models that incorporate supplementary educational tools to enhance patient understanding about the utility of genetic testing, while helping to mitigate the barrier of time constraints. Equally important is the use of this information to develop continuing education tools for providers.

First estimates of diffuse gastric cancer risks for carriers of CTNNA1 germline pathogenic variants.

BACKGROUND: Pathogenic variants (PV) of CTNNA1 are found in families fulfilling criteria for hereditary diffuse gastric cancer (HDGC) but no risk estimates were available until now. The aim of this study is to evaluate diffuse gastric cancer (DGC) risks for carriers of germline CTNNA1 PV. METHODS: Data from published CTNNA1 families were updated and new families were identified through international collaborations. The cumulative risk of DGC by age for PV carriers was estimated with the genotype restricted likelihood (GRL) method, taking into account non-genotyped individuals and conditioning on all observed phenotypes and genotypes of the index case to obtain unbiased estimates. A non-parametric (NP) and the Weibull functions were used to model the shape of penetrance function with the GRL. Kaplan-Meier incidence curve and standardised incidence ratios were also computed. A 'leave-one-out' strategy was used to evaluate estimate uncertainty. RESULTS: Thirteen families with 46 carriers of PV were included. The cumulative risks of DGC at 80 years for carriers of CTNNA1 PV are 49% and 57%, respectively with the Weibull GRL and NP GRL methods. Risk ratios to population incidence reach particularly high values at early ages and decrease with age. At 40 years, they are equal to 65 and 833, respectively with the Weibull GRL and NP GRL. CONCLUSION: This is the largest series of CTNNA1 families that provides the first risk estimates of GC. These data will help to improve management and surveillance for these patients and support inclusion of CTNNA1 in germline testing panels.

Cross-sectional clinical cancer genomics community of practice survey analysis of provider attitudes and beliefs regarding the use of deceased family member tissue to guide living family member genetic cancer risk assessment.

Next-generation tumor tissue sequencing techniques may result in the detection of putative germline pathogenic variants (PVs), raising the possibility that germline cancer predisposition could be identified from archival medical tissue samples of deceased relatives. The approach, termed traceback, is designed to inform risk management recommendations for living family members. Provider perspectives regarding traceback testing have not yet been explored, so we conducted a cross-sectional survey of Clinical Cancer Genomics Community of Practice providers regarding their attitudes and beliefs toward traceback testing. Self-reported demographics, provider characteristics, attitudes and perceived barriers were collected. We evaluated responses in the context of whether providers had previous experience with traceback testing. Data were analyzed using chi-square and Fisher's exact testing. Among 207 respondents (of 816 eligible), most were women (89.4%), white (85.5%), and not Hispanic or Latino (89.7%). US-based providers represented the majority of respondents (87.4%). Relatively, few providers 32 of 207 (15.5%) had previous experience with traceback. Among the individuals without experience in traceback, 84.0% thought there would be barriers to implementation; however, only 68.8% of individuals with previous traceback experience agreed (p = .04). Respondents in both groups thought that traceback would be valuable in their practice (82.6%, p = .22) and that they would feel comfortable discussing the concept (83.6%, p = .83), interpreting the results (72.2%, p = .24), and discussing the results with their patients (80.7%, p = .38). Patient interest and cost were seen as less of a barrier by those with experience with traceback testing. Recurrent themes obtained in open-ended responses are also presented. Overall, providers believe that traceback would be a valuable tool in their practice. Individuals with previous experience identified less barriers with implementation of this testing, highlighting an area for future research and education.

Multigene assessment of genetic risk for women for two or more breast cancers.

PURPOSE: The prevalence, penetrance, and spectrum of pathogenic variants that predispose women to two or more breast cancers is largely unknown. METHODS: We queried clinical and genetic data from women with one or more breast cancer diagnosis who received multigene panel testing between 2013 and 2018. Clinical data were obtained from provider-completed test request forms. For each gene on the panel, a multivariable logistic regression model was constructed to test for association with risk of multiple breast cancer diagnoses. Models accounted for age of diagnosis, personal and family cancer history, and ancestry. Results are reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: This study included 98,979 patients: 88,759 (89.7%) with a single breast cancer and 10,220 (10.3%) with ≥ 2 breast cancers. Of women with two or more breast cancers, 13.2% had a pathogenic variant in a cancer predisposition gene compared to 9.4% with a single breast cancer. BRCA1, BRCA2, CDH1, CHEK2, MSH6, PALB2, PTEN, and TP53 were significantly associated with two or more breast cancers, with ORs ranging from 1.35 for CHEK2 to 3.80 for PTEN. Overall, pathogenic variants in all breast cancer risk genes combined were associated with both metachronous (OR 1.65, 95% CI 1.53-1.79, p = 7.2 × 10-33) and synchronous (OR 1.33, 95% CI 1.19-1.50, p = 2.4 × 10-6) breast cancers. CONCLUSIONS: This study demonstrated that several high and moderate penetrance breast cancer susceptibility genes are associated with ≥ 2 breast cancers, affirming the association of two or more breast cancers with diverse genetic etiologies.

Loss-of-function variants in CTNNA1 detected on multigene panel testing in individuals with gastric or breast cancer.

PURPOSE: CTNNA1 is a potential diffuse gastric cancer risk gene, however CTNNA1 testing on multigene panel testing (MGPT) remains unstudied. METHODS: De-identified data from 151,425 individuals who underwent CTNNA1 testing at a commercial laboratory between October 2015 and July 2019 were reviewed. Tissue α-E-catenin immunohistochemistry was performed on CTNNA1 c.1351C>T (p.Arg451*) carriers. RESULTS: Fifty-two individuals (0.03% tested) had CTNNA1 loss-of-function (LOF) variants and 1057 individuals (0.7% tested) had a total of 302 distinct missense variants of uncertain significance. Detailed history was available on 33 CTNNA1 LOF carriers, with 21 unique CTNNA1 LOF variants. Four (12%) individuals had diffuse gastric cancer and 22 (67%) had breast cancer. Six (21%) and 24 (83%) of the 29 families reported a history of gastric or breast cancer, respectively. The CTNNA1 c.1351C>T nonsense variant was identified in three separate families with early-onset diffuse gastric cancer or breast cancer. Immunohistochemistry showed decreased α-E-catenin expression in gastric cancers. CONCLUSION: CTNNA1 LOF variants are detected on MGPT with a majority of these individuals having gastric or breast cancer. The overall risk of gastric cancer for CTNNA1 LOF carriers may be lower than expected. Given the uncertain phenotype and penetrance, management of individuals with CTNNA1 LOF variants remains challenging.

Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer.

BACKGROUND: Breast cancer (BC) is the most common cancer and related cause of mortality among Hispanics, yet susceptibility has been understudied. BRCA1 and BRCA2 (BRCA) mutations explain less than one-half of hereditary BC, and the proportion associated with other BC susceptibility genes is unknown. METHODS: Germline DNA from 1054 BRCA-mutation-negative Hispanic women with hereditary BC (BC diagnosed at age <51 years, bilateral BC, breast and ovarian cancer, or BC diagnosed at ages 51-70 years with ≥2 first-degree or second-degree relatives who had BC diagnosed at age <70 years), 312 local controls, and 887 multiethnic cohort controls was sequenced and analyzed for 12 known and suspected, high-penetrance and moderate-penetrance cancer susceptibility genes (ataxia telangiectasia mutated [ATM], breast cancer 1 interacting protein C-terminal helicase 1 [BRIP1], cadherin 1 [CDH1], checkpoint kinase 2 [CHEK2], nibrin [NBN], neurofibromatosis type 1 [NF1], partner and localizer of BRCA2 [PALB2], phosphatase and tensin homolog [PTEN], RAD51 paralog 3 [RAD51C], RAD51D, serine/threonine kinase 11 [STK11], and TP53). RESULTS: Forty-nine (4.6%) pathogenic or likely pathogenic variants (PVs) in 47 of 1054 participants (4.5%), including 21 truncating frameshift, 20 missense, 5 nonsense, and 4 splice variants, were identified in CHEK2 (n = 20), PALB2 (n = 18), ATM (n = 5), TP53 (n = 3), BRIP1 (n = 2), and CDH1 and NF1 (both n = 1) and none were identified in NBN, PTEN, STK11, RAD51C, or RAD51D. Nine participants carried the PALB2 c.2167_2168del PV (0.85%), and 14 carried the CHEK2 c.707T>C PV (1.32%). CONCLUSIONS: Of 1054 BRCA-negative, high-risk Hispanic women, 4.5% carried a PV in a cancer susceptibility gene, increasing understanding of hereditary BC in this population. Recurrent PVs in PALB2 and CHEK2 represented 47% (23 of 49) of the total, suggesting a founder effect. Accurate classification of variants was enabled by carefully controlling for ancestry and the increased identification of at-risk Hispanics for screening and prevention.

Experience Gained from the Development and Execution of a Multidisciplinary Multi-syndrome Hereditary Colon Cancer Family Conference.

Genetic healthcare professionals provide genetic cancer risk assessment and follow-up care for patients facing hereditary cancers. To meet the needs of those affected by hereditary colorectal cancer, City of Hope and the Hereditary Colon Cancer Foundation collaborated to develop a "Family Day" conference. We describe the development of our conference based upon the Hereditary Colon Cancer Foundation's "Family Day" program model, with refinements completed using the Participatory Action Research theoretical framework, which incorporated input from conference participants and researchers. Thirty-one participants attended the conference, representing patients with, or families, friends, and caregivers of those with, multiple colorectal cancer predisposition syndromes, including Lynch, familial adenomatous polyposis, and juvenile polyposis. Participants who completed the feedback surveys (n = 22) were highly satisfied with the presentation content, ranking the keynote lecture on family communication the highest of the conference events. Participants also provided feedback regarding how to improve future conferences. In conclusion, we share our experience and provide guidance for developing a successful hereditary colon cancer predisposition patient and family conference.

Somatic TP53 variants frequently confound germ-line testing results.

PURPOSE: Blood/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. METHODS: Pathogenic 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. RESULTS: Among 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). CONCLUSION: ACE 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.

Clonal Hematopoiesis and Mosaicism Revealed by a Multi-Tissue Analysis of Constitutional TP53 Status.

BACKGROUND: Though germline TP53 pathogenic/likely pathogenic variants (PV) are associated with Li-Fraumeni syndrome, many detected by multigene panels represent aberrant clonal expansion (ACE), most due to clonal hematopoiesis (CH). Discerning ACE/CH from germline variants and postzygotic mosaicism (PZM) is critically needed for risk assessment and management. METHODS: Participants in the Li-Fraumeni & TP53 Understanding & Progress (LiFT UP) study with a TP53 PV were eligible. Demographics, personal/family cancer history, and clinical laboratory test reports were obtained. DNA from multiple tissues was analyzed using a custom QIAseq assay (ACE panel) that included TP53 and other CH-associated genes; the ACE panel and eyebrow follicles were assessed in a workflow to discern TP53 PV clinical categories. RESULTS: Among 134 participants there was a significant difference for the age at diagnosis (P < 0.001), component cancers (P = 0.007), and clinical testing criteria (P < 0.001), comparing germline with PZM or ACE. ACE panel analysis of DNA from 55 sets of eyebrow follicles (mean 1.4 ug) and 36 formalin-fixed, paraffin imbedded tissues demonstrated low variance (SE, 3%; P = 0.993) for TP53 variant allele fraction, with no significant difference (P = 0.965) between tissue types, and detected CH gene PVs. Of 55 multi-tissue cases, germline status was confirmed for 20, PZM in seven, ACE for 25, and three were indeterminate. Additional CH variants were detected in six ACE and two germline cases. CONCLUSIONS: We demonstrated an effective approach and tools for discerning germline TP53 status. IMPACT: Discernment of PZM and TP53-driven CH increases diagnostic accuracy and enables risk-appropriate care.

Development and Pilot Implementation of the Genomic Risk Assessment for Cancer Implementation and Sustainment (GRACIAS) Intervention in Mexico.

PURPOSE: Genomic cancer risk assessment (GCRA) is standard-of-care practice that uses genomic tools to identify individuals with increased cancer risk, enabling screening for early detection and cancer prevention interventions. GCRA is not available in most of Mexico, where breast cancer (BC) is the leading cause of cancer death and ovarian cancer has a high mortality rate. METHODS: Guided by an implementation science framework, we piloted the Genomic Risk Assessment for Cancer Implementation and Sustainment (GRACIAS) intervention, combining GCRA training, practice support, and low-cost BRCA1/2 (BRCA) gene testing at four centers in Mexico. The RE-AIM model was adapted to evaluate GRACIAS intervention outcomes, including reach, the proportion of new patients meeting adapted National Comprehensive Cancer Network criteria who participated in GCRA. Barriers to GCRA were identified through roundtable sessions and semistructured interviews. RESULTS: Eleven clinicians were trained across four sites. Mean pre-post knowledge score increased from 60% to 67.2% (range 53%-86%). GCRA self-efficacy scores increased by 31% (95% CI, 6.47 to 55.54; P = .02). Participant feedback recommended Spanish content to improve learning. GRACIAS promoted reach at all sites: 77% in Universidad de Guadalajara, 86% in Instituto Nacional de Cancerología, 90% in Tecnológico de Monterrey, and 77% in Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán. Overall, a pathogenic BRCA variant was identified in 15.6% (195 of 1,253) of patients. All trainees continue to provide GCRA and address barriers to care. CONCLUSION: We describe the first project to use implementation science methods to develop and deliver an innovative multicomponent implementation intervention, combining low-cost BRCA testing, comprehensive GCRA training, and practice support in Mexico. Scale-up of the GRACIAS intervention will promote risk-appropriate care, cancer prevention, and reduction in related mortality.

Genetic epidemiology of BRCA1- and BRCA2-associated cancer across Latin America.

The prevalence and contribution of BRCA1/2 (BRCA) pathogenic variants (PVs) to the cancer burden in Latin America are not well understood. This study aims to address this disparity. BRCA analyses were performed on prospectively enrolled Latin American Clinical Cancer Genomics Community Research Network participants via a combination of methods: a Hispanic Mutation Panel (HISPANEL) on MassARRAY; semiconductor sequencing; and copy number variant (CNV) detection. BRCA PV probability was calculated using BRCAPRO. Among 1,627 participants (95.2% with cancer), we detected 236 (14.5%) BRCA PVs; 160 BRCA1 (31% CNVs); 76 BRCA2 PV frequency varied by country: 26% Brazil, 9% Colombia, 13% Peru, and 17% Mexico. Recurrent PVs (seen ≥3 times), some region-specific, represented 42.8% (101/236) of PVs. There was no ClinVar entry for 14% (17/125) of unique PVs, and 57% (111/196) of unique VUS. The area under the ROC curve for BRCAPRO was 0.76. In summary, we implemented a low-cost BRCA testing strategy and documented a significant burden of non-ClinVar reported BRCA PVs among Latin Americans. There are recurrent, population-specific PVs and CNVs, and we note that the BRCAPRO mutation probability model performs adequately. This study helps address the gap in our understanding of BRCA-associated cancer in Latin America.

Hereditary Pancreatic Cancer Syndromes: Providing Care to At-Risk Families.

Hereditary pancreatic cancer continues to pose challenges to providers, as well as to patients and their families. Pancreatic cancer has a poor prognosis, and individuals with family histories of pancreatic cancer are often motivated to pursue genetic testing. This article reviews various hereditary pancreatic cancer syndromes, as well as pancreatic cancer screening recommendations, options, and limitations.

The Burden of Breast Cancer Predisposition Variants Across The Age Spectrum Among 10 000 Patients.

BACKGROUND/OBJECTIVES: Women diagnosed with breast cancer (BC) at an older age are less likely to undergo genetic cancer risk assessment and genetic testing since the guidelines and referrals are biased toward earlier age at diagnosis. Thus, we determined the prevalence and type of pathogenic cancer predisposition variants among women with a history of BC diagnosed at the age of 65 years or older vs younger than 65 years. DESIGN: Prospective registration cohort. SETTING: The Clinical Cancer Genomics Community Research Network, including 40 community-based clinics in the United States and 5 in Latin America. PARTICIPANTS: Women with BC and genetic testing results. MEASUREMENTS: Sociodemographic characteristics, clinical variables, and genetic profiles were compared between women aged 65 years and older and those younger than 65 years at BC diagnosis. RESULTS: Among 588 women diagnosed with BC and aged 65 years and older and 9412 diagnosed at younger than 65 years, BC-associated pathogenic variants (PVs) were detected in 5.6% of those aged 65 years and older (n = 33) and 14.2% of those younger than 65 years (n = 1340) (P < .01). PVs in high-risk genes (eg, BRCA1 and BRCA2) represented 81.1% of carriers among women aged 65 years and older (n = 27) and 93.1% of those younger than 65 years (n = 1248) (P = .01). BRCA2 PVs represented 42.4% of high-risk gene findings for those aged 65 years and older, whereas BRCA1 PVs were most common among carriers younger than 65 years (49.7%). PVs (n = 7) in moderate-risk genes represented 21.2% for carriers aged 65 years and older and 7.3% of those younger than 65 years (n = 98; P < .01). CHEK2 PVs were the most common moderate-risk gene finding in both groups. CONCLUSION: Clinically actionable BC susceptibility PVs, particularly in BRCA2 and CHEK2, were relatively prevalent among older women undergoing genetic testing. The significant burden of PVs for older women with BC provides a critical reminder to recognize the full spectrum of eligibility and provide genetic testing for older women, rather than exclusion based on chronological age alone. J Am Geriatr Soc 67:884-888, 2019.

The spectrum of genetic variants in hereditary pancreatic cancer includes Fanconi anemia genes.

Approximately 5-10% of all pancreatic cancer patients carry a predisposing mutation in a known susceptibility gene. Since >90% of patients present with late stage disease, it is crucial to identify high risk individuals who may be amenable to early detection or other prevention. To explore the spectrum of hereditary pancreatic cancer susceptibility, we evaluated germline DNA from pancreatic cancer participants (n = 53) from a large hereditary cancer registry. For those without a known predisposition mutation gene (n = 49), germline next generation sequencing was completed using targeted capture for 706 candidate genes. We identified 16 of 53 participants (30%) with a pathogenic (P) or likely pathogenic (LP) variant that may be related to their hereditary pancreatic cancer predisposition; seven had mutations in genes associated with well-known cancer syndromes (13%) [ATM (2), BRCA2 (3), MSH2 (1), MSH6 (1)]. Many had mutations in Fanconi anemia complex genes [BRCA2 (3 participants), FANCF, FANCM]. Eight participants had rare protein truncating variants of uncertain significance with no other P or LP variants. Earlier age of pancreatic cancer diagnosis (57.5 vs 64.8 years) was indicative of possessing a P or LP variant, as was cancer family history (p values <0.0001). Our multigene panel approach for identifying known cancer predisposing genetic susceptibility in those at risk for hereditary pancreatic cancer may have direct applicability to clinical practice in cases with mutations in actionable genes. Future pancreatic cancer predisposition studies should include evaluation of the Fanconi anemia genes.

Prospective Study of Cancer Genetic Variants: Variation in Rate of Reclassification by Ancestry.

Background: In germline genetic testing, variants from understudied ancestries have been disproportionately classified as being of uncertain significance. We hypothesized that the rate of variant reclassification likewise differs by ancestry. Methods: Nonbenign variants in actionable genes were collected from consenting subjects undergoing genetic testing at two Southern California sites from September 1996 through December 2016. Variant reclassifications were recorded as they were received, until February 2017 or reclassification to benign. Excluding duplicate variants (same ancestry, laboratory, classification), generalized linear models for the hereditary breast cancer genes (BRCA1/2) and other variants investigated whether rate of reclassification differed for seven categories of ancestry compared with non-Hispanic European. Models took into account laboratory, year, gene, sex, and current classification (handled as a time-dependent covariate) and were adjusted for multiple hypothesis testing. Results: Among 1483 nonbenign variants, 693 (46.7%) involved BRCA1/2. Overall, 268 (18.1%) variants were reclassified at least once. Few (9.7%) reclassified variants underwent a net upgrade in pathogenicity. For BRCA1/2 variants, reclassification rates varied by ancestry and increased over time, more steeply for ancestries with lower initial rates (African, Ashkenazi, Chinese) than for ancestries whose initial rates were high (Middle Eastern) or similar to non-Hispanic European (non-Chinese Asian, Native American, Hispanic). In contrast, reclassification rates of non-BRCA1/2 variants did not vary over time but were elevated for most minority ancestries except non-Chinese Asian and Native American. Conclusions: For nonbenign variants in cancer-related genes, the rates at which reclassifications are issued vary by ancestry in ways that differ between BRCA1/2 and other genes.

Genetic Gastric Cancer Susceptibility in the International Clinical Cancer Genomics Community Research Network.

Few susceptibility genes for gastric cancer have been identified. We sought to identify germline susceptibility genes from participants with gastric cancer from an international hereditary cancer research network. Adults with gastric cancer of any histology, and with a germline DNA sample (n = 51), were retrospectively selected. For those without previously identified germline mutations (n = 43), sequencing was performed for 706 candidate genes. Twenty pathogenic or likely pathogenic variants were identified among 18 participants. Eight of the 18 participants had previous positive clinical testing, including six with CDH1 pathogenic or likely pathogenic variants, and two with pathogenic MSH2 and TP53 variants. Of the remaining 10, six were in BRCA1 DNA damage response pathway genes (ATM, ATR, BRCA2, BRIP1, FANCC, TP53), other variants were identified in CTNNA1, FLCN, SBDS, and GNAS. Participants identified with pathogenic or likely pathogenic variants were younger at gastric cancer diagnosis than those without, 39.1 versus 48.0 years, and over 50% had a close family member with gastric cancer (p-values < 0.0001). In conclusion, many participants were identified with mutations in clinically-actionable genes. Age of onset and family history of gastric cancer were mutation status predictors. Our findings support multigene panels in identifying gastric cancer predisposition.

Baseline Surveillance in Li-Fraumeni Syndrome Using Whole-Body Magnetic Resonance Imaging: A Meta-analysis.

Importance: Guidelines for clinical management in Li-Fraumeni syndrome, a multiple-organ cancer predisposition condition, are limited. Whole-body magnetic resonance imaging (WBMRI) may play a role in surveillance of this high-risk population. Objective: To assess the clinical utility of WBMRI in germline TP53 mutation carriers at baseline. Data Sources: Clinical and research surveillance cohorts were identified through the Li-Fraumeni Exploration Research Consortium. Study Selection: Cohorts that incorporated WBMRI for individuals with germline TP53 mutations from January 1, 2004, through October 1, 2016, were included. Data Extraction and Synthesis: Data were extracted by investigators from each cohort independently and synthesized by 2 investigators. Random-effects meta-analysis methods were used to estimate proportions. Main Outcomes and Measures: The proportions of participants at baseline in whom a lesion was detected that required follow-up and in whom a new primary malignant neoplasm was detected. Results: A total of 578 participants (376 female [65.1%] and 202 male [34.9%]; mean [SD] age, 33.2 [17.1] years) from 13 cohorts in 6 countries were included in the analysis. Two hundred twenty-five lesions requiring clinical follow-up were detected by WBMRI in 173 participants. Sixty-one lesions were diagnosed in 54 individuals as benign or malignant neoplasms. Overall, 42 cancers were identified in 39 individuals, with 35 new localized cancers treated with curative intent. The overall estimated detection rate for new, localized primary cancers was 7% (95% CI, 5%-9%). Conclusions and Relevance: These data suggest clinical utility of baseline WBMRI in TP53 germline mutation carriers and may form an integral part of baseline clinical risk management in this high-risk population.

Corrigendum: Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management.

[This corrects the article on p. 208 in vol. 5, PMID: 26484312.].

Next-Generation Testing for Cancer Risk: Perceptions, Experiences, and Needs Among Early Adopters in Community Healthcare Settings.

BACKGROUND: Advances in next-generation sequencing (NGS) technologies are driving a shift from single-gene to multigene panel testing for clinical genetic cancer risk assessment (GCRA). This study explored perceptions, experiences, and challenges with NGS testing for GCRA among U.S. community-based clinicians. METHODS: Surveys delivered at initial and 8-month time points, and 12-month tracking of cases presented in a multidisciplinary web-based case conference series, were conducted with GCRA providers who participated in a 235-member nationwide community of practice. RESULTS: The proportion of respondents ordering panel tests rose from 29% at initial survey (27/94) to 44% (46/107) within 8 months. Respondents reported significantly less confidence about interpreting and counseling about NGS compared with single-gene test results (p < 0.0001 for all comparisons). The most cited reasons for not ordering NGS tests included concerns about clinical utility, interpreting and communicating results, and lack of knowledge/skills. Multigene panels were used in 204/668 cases presented during 2013, yielding 37 (18%) deleterious (7% in low/moderate-penetrance genes), 88 (43%) with ≥1 variant of uncertain significance, 77 (38%) uninformative negative, and 2 (1%) inconclusive results. CONCLUSIONS: Despite concerns about utility and ability to interpret/counsel about NGS results, a rapidly increasing uptake of NGS testing among community clinicians was documented. Challenges identified in case discussions point to the need for ongoing education, practice-based support, and opportunities to partner in research that contributes to characterization of lesser known genes.

Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management.

BACKGROUND: Multigene panels can be a cost- and time-effective alternative to sequentially testing multiple genes, especially with a mixed family cancer phenotype. However, moving beyond our single-gene testing paradigm has unveiled many new challenges to the clinician. The purpose of this article is to familiarize the reader with some of the challenges, as well as potential opportunities, of expanded hereditary cancer panel testing. METHODS: We include results from 348 commercial multigene panel tests ordered from January 1, 2014, through October 1, 2014, by clinicians associated with the City of Hope's Clinical Cancer Genetics Community of Practice. We also discuss specific challenging cases that arose during this period involving abnormalities in the genes: CDH1, TP53, PMS2, PALB2, CHEK2, NBN, and RAD51C. RESULTS: If historically high risk genes only were included in the panels (BRCA1, BRCA2, MSH6, PMS2, TP53, APC, CDH1), the results would have been positive only 6.2% of the time, instead of 17%. Results returned with variants of uncertain significance (VUS) 42% of the time. CONCLUSION: These figures and cases stress the importance of adequate pre-test counseling in anticipation of higher percentages of positive, VUS, unexpected, and ambiguous test results. Test result ambiguity can be limited by the use of phenotype-specific panels; if found, multiple resources (the literature, reference laboratory, colleagues, national experts, and research efforts) can be accessed to better clarify counseling and management for the patient and family. For pathogenic variants in low and moderate risk genes, empiric risk modeling based on the patient's personal and family history of cancer may supersede gene-specific risk. Commercial laboratory and patient contributions to public databases and research efforts will be needed to better classify variants and reduce clinical ambiguity of multigene panels.