The risk of skin cancer in women who carry BRCA1 or BRCA2 mutations.

BACKGROUND: It has not been clearly established if skin cancer or melanoma are manifestations of BRCA1 or BRCA2 mutation carrier status. Estimating the risk of skin cancer is an important step towards developing screening recommendations. METHODS: We report the findings of a prospective cohort study of 6,207 women from North America who carry BRCA1 or BRCA2 mutations. Women were followed from the date of baseline questionnaire to the diagnosis of skin cancer, to age 80 years, death from any cause, or the date of last follow-up. RESULTS: During the mean follow-up period of eight years, 3.7% of women with a BRCA1 mutation (133 of 3,623) and 3.8% of women with a BRCA2 mutation (99 of 2,584) reported a diagnosis of skin cancer (including both keratinocyte carcinomas and melanoma). The cumulative risk of all types of skin cancer from age 20 to 80 years was 14.1% for BRCA1 carriers and 10.7% for BRCA2 carriers. The cumulative risk of melanoma was 2.5% for BRCA1 carriers and 2.3% for BRCA2 carriers, compared to 1.5% for women in the general population in the United States. The strongest risk factor for skin cancer was a prior diagnosis of skin cancer. CONCLUSION: The risk of non-melanoma skin cancer in women who carry a mutation in BRCA1 or BRCA2 is similar to that of non-carrier women. The risk of melanoma appears to be slightly elevated. We suggest that a referral to a dermatologist or primary care provider for BRCA mutation carriers for annual skin examination and counselling regarding limiting UV exposure, the use of sunscreen and recognizing the early signs of melanoma might be warranted, but further studies are necessary.

A comprehensive genomic reporting structure for communicating all clinically significant primary and secondary findings.

Genomic sequencing (GS) can reveal secondary findings (SFs), findings unrelated to the reason for testing, that can be overwhelming to both patients and providers. An effective approach for communicating all clinically significant primary and secondary GS results is needed to effectively manage this large volume of results. The aim of this study was to develop a comprehensive approach to communicate all clinically significant primary and SF results. A genomic test report with accompanying patient and provider letters were developed in three phases: review of current clinical reporting practices, consulting with genetic and non-genetics experts, and iterative refinement through circulation to key stakeholders. The genomic test report and consultation letters present a myriad of clinically relevant GS results in distinct, tabulated sections, including primary (cancer) and secondary findings, with in-depth details of each finding generated from exome sequencing. They provide detailed variant and disease information, personal and familial risk assessments, clinical management details, and additional resources to help support providers and patients with implementing healthcare recommendations related to their GS results. The report and consultation letters represent a comprehensive approach to communicate all clinically significant SFs to patients and providers, facilitating clinical management of GS results.

Genetics Adviser: a protocol for a mixed-methods randomised controlled trial evaluating a digital platform for genetics service delivery.

INTRODUCTION: The high demand for genetic tests and limited supply of genetics professionals has created a need for alternative service delivery models. Digital tools are increasingly being used to support multiple points in the genetic testing journey; however, none are transferable across multiple clinical specialties and settings nor do they encompass the entire trajectory of the journey. We aim to evaluate the effectiveness of the Genetics Adviser, an interactive, patient-facing, online digital health tool that delivers pre-test counselling, provides support during the waiting period for results, and returns results with post-test counselling, encompassing the entire patient genetic testing journey. METHODS AND ANALYSIS: We will compare the Genetics Adviser paired with a brief genetic counselling session to genetic counselling alone in a randomised controlled trial. One hundred and forty patients who previously received uninformative genetic test results for their personal and family history of cancer will be recruited from familial cancer clinics in Toronto and offered all clinically significant results from genomic sequencing. Participants randomised into the intervention arm will use the Genetics Adviser to learn about genomic sequencing, receive pre-test counselling, support during the waiting period and results, supplemented with brief counselling from a genetic counsellor. Participants in the control arm will receive standard pre-test and post-test counselling for genomic sequencing from a genetic counsellor. Our primary outcome is decisional conflict following pre-test counselling from the Genetics Adviser+genetic counsellor or counsellor alone. Secondary outcomes include: knowledge, satisfaction with decision-making, anxiety, quality of life, psychological impact of results, empowerment, acceptability and economic impact for patients and the health system. A subset of patients will be interviewed to assess user experience. ETHICS AND DISSEMINATION: This study has been approved by Clinical Trials Ontario Streamlined Research Ethics Review System (REB#20-035). Results will be shared through stakeholder workshops, national and international conferences and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04725565.

Incidental findings from cancer next generation sequencing panels.

Next-generation sequencing (NGS) technologies have facilitated multi-gene panel (MGP) testing to detect germline DNA variants in hereditary cancer patients. This sensitive technique can uncover unexpected, non-germline incidental findings indicative of mosaicism, clonal hematopoiesis (CH), or hematologic malignancies. A retrospective chart review was conducted to identify cases of incidental findings from NGS-MGP testing. Inclusion criteria included: 1) multiple pathogenic variants in the same patient; 2) pathogenic variants at a low allele fraction; and/or 3) the presence of pathogenic variants not consistent with family history. Secondary tissue analysis, complete blood count (CBC) and medical record review were conducted to further delineate the etiology of the pathogenic variants. Of 6060 NGS-MGP tests, 24 cases fulfilling our inclusion criteria were identified. Pathogenic variants were detected in TP53, ATM, CHEK2, BRCA1 and APC. 18/24 (75.0%) patients were classified as CH, 3/24 (12.5%) as mosaic, 2/24 (8.3%) related to a hematologic malignancy, and 1/24 (4.2%) as true germline. We describe a case-specific workflow to identify and interpret the nature of incidental findings on NGS-MGP. This workflow will provide oncology and genetic clinics a practical guide for the management and counselling of patients with unexpected NGS-MGP findings.

A Comparison of Patient-Reported Outcomes Following Consent for Genetic Testing Using an Oncologist- or Genetic Counselor-Mediated Model of Care.

This study compares knowledge, experience and understanding of genetic testing, and psychological outcomes among breast and ovarian cancer patients undergoing multi-gene panel testing via genetic counselor-mediated (GMT) or oncologist-mediated (OMT) testing models. A pragmatic, prospective survey of breast and ovarian cancer patients pursuing genetic testing between January 2017 and August 2019 was conducted at the Princess Margaret Cancer Centre in Toronto, Canada. A total of 120 (80 GMT; 40 OMT) individuals completed a survey administered one week following consent to genetic testing. Compared to OMT, the GMT cohort had higher median knowledge (8 vs. 9; p = 0.025) and experience/understanding scores (8.5 vs. 10; p < 0.001) at the time of genetic testing. Significant differences were noted in the potential psychological concerns experienced, with individuals in the GMT cohort more likely to screen positive in the hereditary predisposition domain of the Psychosocial Aspects of Hereditary Cancer tool (55% vs. 27.5%; p = 0.005), and individuals in the OMT cohort more likely to screen positive in the general emotions domain (65.0% vs. 38.8%; p = 0.007). The results of this study suggest that OMT can be implemented to streamline genetic testing; however, post-test genetic counseling should remain available to all individuals undergoing genetic testing, to ensure any psychologic concerns are addressed and that individuals have a clear understanding of relevant implications and limitations of their test results.

Tumor surveillance for children and adolescents with cancer predisposition syndromes: The psychosocial impact reported by adolescents and caregivers.

PURPOSE: Individuals with cancer predisposition syndromes (CPS) are often followed in cancer screening programs, which aim to detect early stage tumors. While cancer surveillance has the potential to improve patient outcomes, its psychosocial impact is uncharacterized in the pediatric population. We examined the cancer surveillance experience from the perspectives of adolescents and parents of children at risk of developing cancer. PATIENTS AND METHODS: Using grounded theory and thematic analysis qualitative methodology, we conducted semi-structured interviews with parents and adolescents, separately. Interviews were transcribed verbatim and coded separately to derive overlapping and unique themes. RESULTS: We completed 20 semi-structured interviews (11 parents and nine adolescents). Positive experiences were related to feelings of reassurance and taking a proactive approach. Both adolescents and parents experienced worry, related to practical aspects of screening, and related to the reminder of cancer risk that manifests with surveillance appointments. This worry was cyclical, associated with appointments, and generally waned over time. Participants felt that the benefits of surveillance outweighed perceived challenges. Open communication with health care providers, and equipping parents/adolescents with vocabulary to discuss their diagnosis and care with others, were felt to be important for mitigating worries associated with cancer risk and surveillance. CONCLUSION: Parents and adolescents experience worry associated with surveillance for CPS, which may warrant regular psychosocial support, particularly during the first year following CPS diagnosis. Enhancing communication with the health care team and among and beyond immediate family members represents an additional important strategy to mitigate adverse experiences and perceptions.

Setting a baseline: A 7-year review of referral rates and outcomes for serous ovarian cancer prior to implementation of oncologist mediated genetic testing.

OBJECTIVE: Despite guidelines recommending that all women with invasive serous ovarian cancer (SOC) are offered genetic testing, published referral and testing rates have been poor. Many centers have implemented novel genetic counseling service delivery models to increase testing rates. In light of increased awareness and implementation of small process changes at our center, this study aims to establish baseline referral rates and testing outcomes prior to diverging from the traditional model of care. METHODS: A list of women diagnosed with SOC at Princess Margaret Cancer Center (PM) between 2010 and 2016 was obtained from the PM Cancer Registry and cross-referenced against the genetics database to determine referral rates and outcomes of genetic testing. RESULTS: Of 724 women with SOC, 68% were referred for genetic counseling, with an overall testing rate of 61%. Higher referral rates were seen among women with younger ages at diagnosis and high-grade tumors. Of women tested, 22% were found to have a pathogenic variant in BRCA1/2 and 9% in another cancer gene. Notably, 24% of women with a pathogenic variant reported no family history of breast or ovarian cancer. CONCLUSION: Genetic counseling referral and testing rates for women with SOC are higher than previously reported, yet barriers to referral remain. To maximize genetic testing rates and address increasing patient volumes, clinics may be faced with integrating novel genetic counseling delivery models. Findings from this study may serve as a more accurate baseline to which large scale service delivery changes can be compared.

Health outcomes, utility and costs of returning incidental results from genomic sequencing in a Canadian cancer population: protocol for a mixed-methods randomised controlled trial.

INTRODUCTION: Genomic sequencing has rapidly transitioned into clinical practice, improving diagnosis and treatment options for patients with hereditary disorders. However, large-scale implementation of genomic sequencing faces challenges, especially with regard to the return of incidental results, which refer to genetic variants uncovered during testing that are unrelated to the primary disease under investigation, but of potential clinical significance. High-quality evidence evaluating health outcomes and costs of receiving incidental results is critical for the adoption of genomic sequencing into clinical care and to understand the unintended consequences of adoption of genomic sequencing. We aim to evaluate the health outcomes and costs of receiving incidental results for patients undergoing genomic sequencing. METHODS AND ANALYSIS: We will compare health outcomes and costs of receiving, versus not receiving, incidental results for adult patients with cancer undergoing genomic sequencing in a mixed-methods randomised controlled trial. Two hundred and sixty patients who have previously undergone first or second-tier genetic testing for cancer and received uninformative results will be recruited from familial cancer clinics in Toronto, Ontario. Participants in both arms will receive cancer-related results. Participants in the intervention arm have the option to receive incidental results. Our primary outcome is psychological distress at 2 weeks following return of results. Secondary outcomes include behavioural consequences, clinical and personal utility assessed over the 12 months after results are returned and health service use and costs at 12 months and 5 years. A subset of participants and providers will complete qualitative interviews about utility of incidental results. ETHICS AND DISSEMINATION: This study has been approved by Clinical Trials Ontario Streamlined Research Ethics Review System that provides ethical review and oversight for multiple sites participating in the same clinical trial in Ontario.Results from the trial will be shared through stakeholder workshops, national and international conferences, and peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT03597165.

Next-Generation Service Delivery: A Scoping Review of Patient Outcomes Associated with Alternative Models of Genetic Counseling and Genetic Testing for Hereditary Cancer.

The combination of increased referral for genetic testing and the current shortage of genetic counselors has necessitated the development and implementation of alternative models of genetic counseling and testing for hereditary cancer assessment. The purpose of this scoping review is to provide an overview of the patient outcomes that are associated with alternative models of genetic testing and genetic counseling for hereditary cancer, including germline-only and tumor testing models. Seven databases were searched, selecting studies that were: (1) full-text articles published ≥2007 or conference abstracts published ≥2015, and (2) assessing patient outcomes of an alternative model of genetic counseling or testing. A total of 79 publications were included for review and synthesis. Data-charting was completed using a data-charting form that was developed by the study team for this review. Seven alternative models were identified, including four models that involved a genetic counselor: telephone, telegenic, group, and embedded genetic counseling models; and three models that did not: mainstreaming, direct, and tumor-first genetic testing models. Overall, these models may be an acceptable alternative to traditional models on knowledge, patient satisfaction, psychosocial measures, and the uptake of genetic testing; however, particular populations may be better served by traditional in-person genetic counseling. As precision medicine initiatives continue to advance, institutions should consider the implementation of new models of genetic service delivery, utilizing a model that will best serve the needs of their unique patient populations.

All in the Family: Barriers and Motivators to the Use of Cancer Family History Questionnaires and the Impact on Attendance Rates.

Data has demonstrated that family history questionnaires (FHQs) are an invaluable tool for assessing familial cancer risk and triaging patients for genetic counseling services. Despite their benefits, return rates of mailed FHQs from newly referred patients remain low, suggesting potential barriers to their use. To investigate this, a total of 461 participants, 239 who completed a FHQ (responders) and 222 who did not (non-responders), were surveyed at a subsequent appointment regarding potential barriers and motivators to using the FHQ. With respective rates of 51 and 56 %, there was no significant difference in the proportion of responders and non-responders who reported difficulty in completing the FHQ; however, for both groups factors related to family dynamics (large family size, lack of contact with relatives, and lack of knowledge of family history) were reported as major variables confounding completion of the FHQ. Responders were also significantly more likely to have a personal diagnosis of cancer (p = 0.02) and to report that their physician had discussed the reason for the appointment with them (p = 0.01). Overall, 19 % of non-responders returned their FHQ after being mailed an appointment letter and 67 % attended their scheduled genetic counseling appointment. These findings demonstrate that difficulty completing the FHQ is not inherent to its design but due to difficulty accessing one's family history, and that mailed appointment letters are a highly successful way to increase attendance rates in the non-responder population. Furthermore, these results demonstrate the important role that referring physicians play in the utilization of genetic counseling services.

Breast and ovarian cancer: the forgotten paternal contribution.

Five to 10% of all cases of breast and ovarian cancer are attributed to a heritable genetic predisposition. Transmission of BRCA1 and BRCA2 mutations is equally likely through maternal or paternal lineage; however, fewer referrals to cancer genetics clinics appear to be made for a paternal, than maternal, family history of breast and/or ovarian cancer. To examine this potential bias, a retrospective review of 315 patient and family charts was conducted by one familial cancer clinic in Toronto, Canada. Referral letters, risk estimates, and family histories were analyzed to identify significant differences between patients referred with maternal and paternal family histories. It was determined that patients are approximately five times more likely to be referred with a maternal family history of breast and/or ovarian cancer as compared to those with a paternal family history (p = <.0001). Individuals with a paternal family history were found to have a different, and higher, pattern of risk estimates (p = .00064). No significant difference was seen between the type of referrals sent by general practitioners, oncologists, and gynecologists. Recommendations to increase the awareness of paternal family history in assessing cancer risk are provided.

The use of family history questionnaires: an examination of genetic risk estimates and genetic testing eligibility in the non-responder population.

The use of mailed family history questionnaires (FHQs) has previously been established to be an effective method for obtaining family history information for the triage of patients for genetic counseling and genetic testing of hereditary breast and ovarian cancer syndrome; yet only 53% of patients complete their FHQ within 6 months from the date of mailing (Armel et al. Journal of Genetic Counseling, 18(4):366-378, 2009). Although literature exists evaluating why women may not attend genetic counseling, no data are currently available examining genetic risk or genetic testing eligibility in the population of patients not returning their FHQ (non-responders). Concern exists that if non-responders are not followed-up for the purpose of triage for genetic counseling, individuals at high-risk for a hereditary cancer syndrome may be missed. This article explores the demographics of the non-responder population to assess genetic risk estimates for mutations in the BRCA1 and BRCA2 genes and genetic testing eligibility as compared to a responder population of patients who completed a mailed FHQ. A total of 430 pedigrees were obtained, 215 from non-responders and 215 from responders. Results of this study indicate that 69% of non-responders were either unreachable by telephone (42%), declined an appointment (19%), or were previously seen in another center for a genetic counseling visit (8%). Additionally, results indicate that non-responders are less likely to be eligible for genetic testing (40%) as compared to responders (57%) (p = 0.0004). Together these data shed light on a population of patients for which limited information exists and suggest that we question how and to what extent clinics should pursue non-responders, particularly in light of global reductions in health care funding.

The effectiveness of family history questionnaires in cancer genetic counseling.

The number of individuals receiving genetic counseling for hereditary breast and ovarian cancer syndrome has steadily risen. To triage patients for genetic counseling and to help reduce the amount of time needed by a genetic counselor in direct patient contact, many clinics have implemented the use of family history questionnaires. Although such questionnaires are widely used, scant literature exists evaluating their effectiveness. This article explores the extent to which family history questionnaires are being used in Ontario and addresses the utility of such questionnaires in one familial cancer clinic. By comparing the pedigrees created from questionnaires to those updated during genetic counseling, the accuracy and effectiveness of the questionnaires was explored. Of 121 families recruited into the study, 12% acquired changes to their pedigree that led to a revised probability estimate for having a BRCA1 or BRCA2 mutation and 5% acquired changes that altered their eligibility for genetic testing. No statistically significant difference existed between the eligibility for genetic testing prior to and post counseling. This suggests that family history questionnaires can be effective at obtaining a family history and accurately assessing eligibility for genetic testing. Based on the variables that were significantly associated with a change in probability estimate, we further present recommendations for improving the clarity of such questionnaires and therefore the ease of use by patients.