Genetic counselors' perspectives on population-based screening for BRCA-related hereditary breast and ovarian cancer and Lynch syndrome.

Early identification of those with BRCA-related Hereditary Breast and Ovarian Cancer Syndrome (HBOC) and Lynch syndrome has the potential for early cancer detection and/or prevention; as such, these conditions are considered Tier 1 genetic conditions by the U.S. Center for Disease Control and Prevention. Given the decreasing cost of genetic testing, population-based screening (PBS) for such conditions may be the next step toward cancer prevention. This study aimed to understand genetic counselors' perspectives toward offering PBS for the Tier 1 conditions BRCA-related HBOC and Lynch syndrome. An online survey was distributed to 3,609 members of the National Society of Genetic Counselors. A total of 367 individuals participated in the study. Fifty percent of respondents felt that PBS for inherited cancer should not be offered; 93.3% felt that the current healthcare system is unprepared for implementation of PBS. However, most respondents agreed that PBS should be implemented within the next 10 years. Attitudes toward offering PBS were associated with respondents' work setting, cancer specialization, and perceived preparedness (p's < 0.05). The most commonly reported barriers to the implementation of PBS were shortage of genetic professionals and lack of infrastructure. Data in this study provide evidence that infrastructural barriers and educational gaps of non-genetic professionals would need to be addressed before successful integration of PBS into the healthcare system.

Utilization of breast cancer risk prediction models by cancer genetic counselors in clinical practice predominantly in the United States.

Risk assessment in cancer genetic counseling is essential in identifying individuals at high risk for developing breast cancer to recommend appropriate screening and management options. Historically, many breast cancer risk prediction models were developed to calculate an individual's risk to develop breast cancer or to carry a pathogenic variant in the BRCA1 or BRCA2 genes. However, how or when genetic counselors use these models in clinical settings is currently unknown. We explored genetic counselors' breast cancer risk model usage patterns including frequency of use, reasons for using or not using models, and change in usage since the adoption of multi-gene panel testing. An online survey was developed and sent to members of the National Society of Genetic Counselors; board-certified genetic counselors whose practice included cancer genetic counseling were eligible to participate in the study. The response rate was estimated at 23% (243/1,058), and respondents were predominantly working in the United States. The results showed that 93% of all respondents use at least one breast cancer risk prediction model in their clinical practice. Among the six risk models selected for the study, the Tyrer-Cuzick (IBIS) model was used most frequently (95%), and the BOADICEA model was used least (40%). Determining increased or decreased surveillance and breast MRI eligibility were the two most common reasons for most model usage, while time consumption and difficulty in navigation were the two most common reasons for not using models. This study provides insight into perceived benefits and limitations of risk models in clinical use in the United States, which may be useful information for software developers, genetic counseling program curriculum developers, and currently practicing cancer genetic counselors.

FDA Approval of PARP Inhibitors and the Impact on Genetic Counseling and Genetic Testing Practices.

In December 2014, the FDA approved olaparib, a poly(ADP-ribose) polymerase inhibitor (PARPi) for ovarian cancer patients who have failed three or more lines of chemotherapy and have a germline BRCA1/2 mutation identified through a companion diagnostic test (BRACAnalysis CDx™ (CDx™)) offered exclusively by Myriad Genetic Laboratories. This study explored the impact of PARPi/CDx™ on genetic counselors' (GCs) counseling and testing practices. One hundred twenty three GCs responded to an online survey regarding pre- and post-FDA approval referral patterns, testing strategies/influences, and anecdotal experiences with insurance coverage of PARPi for BRCA1/2 positive patients through a non-CDx™ platform. Following PARPi approval, 40% of respondents reported an increase in overall referrals of ovarian cancer patients and 20% had an increase in post-test counseling only referrals. The majority (61.9%) of respondents reported no change in genetic testing strategy, and there was no change in factors influencing choice of testing laboratory. Nearly all (98.1%) respondents who had experience with insurance covering PARPi indicated approval with mutations identified via non-CDx™ testing. Respondents indicated an increase in referral volume following FDA approval of PARPi/CDx™, but did not report changes in testing practices. Respondents were not aware of PARPi insurance coverage denial in the absence of CDx™.

Cancer Genetic Counseling and Testing in an Era of Rapid Change.

The impacts of the Association for Molecular Pathology vs. Myriad Supreme Court decision regarding patenting DNA segments and multi-gene testing on cancer genetic counseling practice have not been well described. We aimed to assess genetic counselors' perceptions of how their genetic testing-related practices for hereditary breast and/or ovarian cancer (HBOC) changed after these events. One-hundred fifty-two genetic counselors from the National Society of Genetic Counselors Cancer Special Interest Group completed an anonymous, online, mixed-methods survey in November 2013. The survey presented four hypothetical patients and asked about changes in testing practice. Across the vignettes, a majority of participants reported specific changes in testing decisions following Association for Molecular Pathology vs. Myriad and availability of multi-gene testing. Ninety-three percent of participants reported changing the types of first- and second-line tests they order for HBOC; the degree of change varied geographically. Qualitative analysis indicated that some counselors have altered the counseling session content, trading depth of information for breadth and spending more time counseling about uncertainty. This study shows that cancer genetic counselors are adapting quickly to genetic testing changes, but with wide variability. Findings suggest future research to elucidate clinicians' and patients' preferences for guidance on the clinical implementation of next-generation sequencing.

Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.

PURPOSE: Germ-line testing for panels of cancer genes using next-generation sequencing is becoming more common in clinical care. We report our experience as a clinical laboratory testing both well-established, high-risk cancer genes (e.g., BRCA1/2, MLH1, MSH2) as well as more recently identified cancer genes (e.g., PALB2, BRIP1), many of which have increased but less well-defined penetrance. METHODS: Clinical genetic testing was performed on over 10,000 consecutive cases referred for evaluation of germ-line cancer genes, and results were analyzed for frequency of pathogenic or likely pathogenic variants, and were stratified by testing panel, gene, and clinical history. RESULTS: Overall, a molecular diagnosis was made in 9.0% of patients tested, with the highest yield in the Lynch syndrome/colorectal cancer panel. In patients with breast, ovarian, or colon/stomach cancer, positive yields were 9.7, 13.4, and 14.8%, respectively. Approximately half of the pathogenic variants identified in patients with breast or ovarian cancer were in genes other than BRCA1/2. CONCLUSION: The high frequency of positive results in a wide range of cancer genes, including those of high penetrance and with clinical care guidelines, underscores both the genetic heterogeneity of hereditary cancer and the usefulness of multigene panels over genetic tests of one or two genes.Genet Med 18 8, 823-832.

Accuracy of Perceived Breast Cancer Risk in Black and White Women with an Elevated Risk.

Introduction: Perceived breast cancer risk predicts screening behaviors. However, perceived risk is often inaccurate, notably in Black women, who often underestimate their risk despite having higher disease-specific mortality rates. We examined predictors of perceived breast cancer risk, and its impact on surveillance. Methods: We used baseline data from a randomized trial targeting unaffected women recruited by relatives with early-onset breast cancer. Data collection occurred between 2012 and 2013. Accuracy of perceived risk was assessed by comparing perceived risk to objective lifetime breast cancer risks, calculated with the Gail and Claus models. A multivariate mixed model regression examined predictors of accuracy of perceived risk. The impact of perceived risk on breast cancer surveillance was assessed with one-way ANOVAS comparing Black to White women. Results: Among participants, 21.4% self-identified as Black and 78.6% as White. Overall, 72.9% (n=247/339), 16.2% (n=55/339), and 10.9% (n=37/339) of participants overestimated, accurately perceived, and underestimated, respectively, their lifetime breast cancer risk. Race did not predict the accuracy of risk perception. Younger participants were more likely to overestimate their risk (ß=-.455; CI [-.772, -.138]; P=.005). MRI utilization was predicted by a higher objective risk (F 1,263 [= 30.271]; P<.001) and more accurate risk perception (P=.010; Fisher's exact test). Conclusions: Most women with a family history of early-onset breast cancer inaccurately perceived their risk for developing the disease. Younger women were more likely to overestimate their risk. Findings can guide the development of tailored interventions to improve adherence to breast cancer surveillance recommendations.

Monoallelic MUTYH pathogenic variants ascertained via multi-gene hereditary cancer panels are not associated with colorectal, endometrial, or breast cancer.

We aimed to determine whether monoallelic MUTYH pathogenic and likely pathogenic variants (PVs) are associated with colorectal, breast, and endometrial cancer. Cases were individuals with colorectal, female breast, or endometrial cancer who reported European ancestry alone and underwent a multi-gene hereditary cancer panel at a large reference laboratory. Controls were individuals of European (non-Finnish) descent from GnomAD with cancer cohorts removed. We performed a Fisher's exact test to generate odds ratios (ORs) with 95% confidence intervals (CI). Prevalence of single MUTYH PVs in cancer cohorts versus controls, respectively, was: colorectal cancer, 2.1% vs. 1.8% (OR 1.2, 95% CI 0.99-1.5, p = 0.064); breast cancer 1.9% vs. 1.7% (OR 1.1, 95% CI 0.96-1.3, p = 0.15); and endometrial cancer, 1.7% vs. 1.7% (OR 0.98; 95% CI 0.70-1.3, p = 0.94). Using the largest colorectal and endometrial cancer cohorts and one of the largest breast cancer cohorts from a single case-control study, we did not observe a significant difference in the prevalence of monoallelic MUTYH PVs in these cohorts compared to controls. Additionally, frequencies among cancer cohorts were consistent with the published MUTYH carrier frequency of 1-2%. These findings suggest there is no association between colorectal, endometrial, or breast cancer and MUTYH heterozygosity in individuals of European ancestry.

Apparently Heterozygous TP53 Pathogenic Variants May Be Blood Limited in Patients Undergoing Hereditary Cancer Panel Testing.

Heterozygous (HET) TP53 pathogenic variants (PVs) are associated with Li-Fraumeni syndrome (LFS), a dominantly inherited condition causing high risk for sarcoma, breast, and other cancers. Recent reports describe patients without features of LFS and apparently HET TP53 PVs in blood cells but not fibroblasts (FBs), suggesting the variant occurred sporadically during hematopoiesis and rose to high allele fraction through clonal expansion. To explore possible clonal hematopoiesis in patients undergoing hereditary cancer testing, FB testing was performed for patients with apparently HET or mosaic TP53 PVs identified in blood, oral rinse, or buccal specimens via next-generation sequencing panels. Among 291 individuals with TP53 PVs, 146 (50.2%) appeared HET and 145 (49.8%) were mosaic. Twenty-eight HET cases were proven constitutional through familial testing. FB testing was completed for 17 apparently HET and 36 mosaic patients. FB testing was positive in 11 of 17 (64.7%) apparently HET patients, only one of whom met Chompret criteria. Of 36 mosaic patients, 5 (13.9%) were also mosaic in FBs, indicating constitutional mosaicism. Breast cancers in patients with constitutional TP53 PVs were diagnosed at younger ages (P < 0.0001) and more likely to demonstrate human epidermal growth factor receptor 2 overexpression (P = 0.0003). These results demonstrate the utility of cultured FB testing to clarify constitutional status for TP53 PVs identified on next-generation sequencing panels, particularly for patients not meeting LFS or Chompret criteria.

Initial clinical validation of Health Heritage, a patient-facing tool for personal and family history collection and cancer risk assessment.

Personal and family health histories remain important independent risk factors for cancer; however they are currently not being well collected or used effectively. Health Heritage was designed to address this need. The purpose of this study was to validate the ability of Health Heritage to identify patients appropriate for further genetic evaluation and to accurately stratify cancer risk. A retrospective chart review was conducted on 100 random patients seen at an adult genetics clinic presenting with concern for an inherited predisposition to cancer. Relevant personal and family history obtained from the patients' medical records was entered into Health Heritage. Recommendations by Health Heritage were compared to national guidelines of eligibility for genetic evaluation. Agreement between Health Heritage referral for genetic evaluation and guideline eligibility for genetic evaluation was 97% (sensitivity 98% and specificity 88%). Risk stratification for cancer was also compared between Health Heritage and those documented by a geneticist. For patients at increased risk for breast, ovarian, or colorectal cancer as determined by the geneticist, risk stratification by Health Heritage agreed 90, 93, and 75%, respectively. Discordances in risk stratification were attributed to both complex situations better handled by the geneticist and Health Heritage's adherence to incorporating all information into its algorithms. Health Heritage is a clinically valid tool to identify patients appropriate for further genetic evaluation and to encourage them to confirm the assessment and management recommendations with cancer genetic experts. Health Heritage also provides an estimate of cancer risk that is complementary to a genetics team.

Evaluation of laboratory perspectives on hereditary cancer panels.

Genetic counseling and testing for hereditary cancer susceptibility is a rapidly evolving field and partly a result of next-generation sequencing (NGS) allowing analysis of multiple cancer susceptibility genes simultaneously. This qualitative study explored laboratory perspectives on hereditary cancer panels. Semi-structured interviews were conducted with representatives of clinical laboratories offering hereditary cancer panels via NGS. Several themes emerged from the responses pertaining to hereditary cancer panel development, the importance of communication of panel properties with patients, variant reporting policies, and the future of hereditary cancer gene testing. Clinical utility was discussed as primary consideration during panel development. In addition, while participants indicated gene and syndrome overlap prompted panel development in general, laboratories differed in their opinions of whether phenotypic overlap warrants offering pan-cancer panels only versus cancer specific panels. Participants stressed the importance of patients understanding implications of panel testing, including what is tested for and limitations of testing. While all laboratories discussed the limitations of a variant of uncertain significance result, they differed significantly in their reporting methods. This study provides healthcare providers information on the laboratory approach to panel testing, highlighting both commonalities and differences in laboratory approaches, and may allow providers to make more informed decisions when ordering hereditary cancer panels.