Integrating Tumor Sequencing Into Clinical Practice for Patients With Mismatch Repair-Deficient Lynch Syndrome Spectrum Cancers.

INTRODUCTION: Uninformative germline genetic testing presents a challenge to clinical management for patients suspected to have Lynch syndrome, a cancer predisposition syndrome caused by germline variants in the mismatch repair (MMR) genes or EPCAM. METHODS: Among a consecutive series of MMR-deficient Lynch syndrome spectrum cancers identified through immunohistochemistry-based tumor screening, we investigated the clinical utility of tumor sequencing for the molecular diagnosis and management of suspected Lynch syndrome families. MLH1-deficient colorectal cancers were prescreened for BRAF V600E before referral for genetic counseling. Microsatellite instability, MLH1 promoter hypermethylation, and somatic and germline genetic variants in the MMR genes were assessed according to an established clinical protocol. RESULTS: Eighty-four individuals with primarily colorectal (62%) and endometrial (31%) cancers received tumor-normal sequencing as part of routine clinical genetic assessment. Overall, 27% received a molecular diagnosis of Lynch syndrome. Most of the MLH1-deficient tumors were more likely of sporadic origin, mediated by MLH1 promoter hypermethylation in 54% and double somatic genetic alterations in MLH1 (17%). MSH2-deficient, MSH6-deficient, and/or PMS2-deficient tumors could be attributed to pathogenic germline variants in 37% and double somatic events in 28%. Notably, tumor sequencing could explain 49% of cases without causal germline variants, somatic MLH1 promoter hypermethylation, or somatic variants in BRAF. DISCUSSION: Our findings support the integration of tumor sequencing into current Lynch syndrome screening programs to improve clinical management for individuals whose germline testing is uninformative.

Burden of hereditary cancer susceptibility in unselected patients with pancreatic ductal adenocarcinoma referred for germline screening.

BACKGROUND: Recent guidelines recommend consideration of germline testing for all newly diagnosed pancreatic ductal adenocarcinoma (PDAC). The primary aim of this study was to determine the burden of hereditary cancer susceptibility in PDAC. A secondary aim was to compare genetic testing uptake rates across different modes of genetic counselling. PATIENTS AND METHODS: All patients diagnosed with PDAC in the province of British Columbia, Canada referred to a population-based hereditary cancer program were eligible for multi-gene panel testing, irrespective of cancer family history. Any healthcare provider or patients themselves could refer. RESULTS: A total of 305 patients with PDAC were referred between July 2016 and January 2019. Two hundred thirty-five patients attended a consultation and 177 completed index germline genetic testing. 25/177 (14.1%) of unrelated patients had a pathogenic variant (PV); 19/25 PV were in known PDAC susceptibility genes with cancer screening or risk-reduction implications. PDAC was significantly associated with PV in ATM (OR, 7.73; 95% CI, 3.10 to 19.33, P = 6.14E-05) when comparing age and gender and ethnicity-matched controls tested on the same platform. The overall uptake rate for index testing was 59.2% and was significantly higher with 1-on-1 consultations and group consultations compared to telehealth consultations (88.9% vs 82.9% vs 61.8%, P < .001). CONCLUSION: In a prospective clinic-based cohort of patients with PDAC referred for testing irrespective of family history, germline PV were detected in 14.1%. PV in ATM accounted for half of all PVs and were significantly associated with PDAC. These findings support recent guidelines and will guide future service planning in this population.

Oncology Clinic-Based Hereditary Cancer Genetic Testing in a Population-Based Health Care System.

New streamlined models for genetic counseling and genetic testing have recently been developed in response to increasing demand for cancer genetic services. To improve access and decrease wait times, we implemented an oncology clinic-based genetic testing model for breast and ovarian cancer patients in a publicly funded population-based health care setting in British Columbia, Canada. This observational study evaluated the oncology clinic-based model as compared to a traditional one-on-one approach with a genetic counsellor using a multi-gene panel testing approach. The primary objectives were to evaluate wait times and patient reported outcome measures between the oncology clinic-based and traditional genetic counselling models. Secondary objectives were to describe oncologist and genetic counsellor acceptability and experience. Wait times from referral to return of genetic testing results were assessed for 400 patients with breast and/or ovarian cancer undergoing genetic testing for hereditary breast and ovarian cancer from June 2015 to August 2017. Patient wait times from referral to return of results were significantly shorter with the oncology clinic-based model as compared to the traditional model (403 vs. 191 days; p < 0.001). A subset of 148 patients (traditional n = 99; oncology clinic-based n = 49) completed study surveys to assess uncertainty, distress, and patient experience. Responses were similar between both models. Healthcare providers survey responses indicated they believed the oncology clinic-based model was acceptable and a positive experience. Oncology clinic-based genetic testing using a multi-gene panel approach and post-test counselling with a genetic counsellor significantly reduced wait times and is acceptable for patients and health care providers.

Prophylactic salpingectomy and delayed oophorectomy as an alternative for BRCA mutation carriers.

OBJECTIVE: Prophylactic bilateral salpingo-oophorectomy is advised for women with BRCA mutations, but there are adverse consequences of premature menopause. The majority of BRCA-associated ovarian cancers appear to arise in the fallopian tube; therefore, salpingectomy may be an alternative to bilateral salpingo-oophorectomy. We compared the costs and benefits of salpingectomy with bilateral salpingo-oophorectomy among BRCA mutation carriers. METHODS: We developed a Markov Monte Carlo simulation model to compare three strategies for risk reduction in women with BRCA mutations: 1) bilateral salpingo-oophorectomy; 2) bilateral salpingectomy; and 3) bilateral salpingectomy with delayed oophorectomy. Net health benefits were measured in years-of-life expectancy and quality-adjusted life-year expectancy, and the primary outcome was the incremental cost-effectiveness ratio. The model estimated the number of future breast and ovarian cancers and cardiovascular deaths attributed to premature menopause with each strategy. RESULTS: Bilateral salpingo-oophorectomy was associated with the lowest cost and highest life expectancy compared with the other two strategies. When quality-of-life measures were included, salpingectomy followed by delayed oophorectomy yielded the highest quality-adjusted life expectancy with incremental cost-effectiveness ratios of $37,805 and $89,680 per quality-adjusted life-year for BRCA1 and BRCA2, respectively, relative to salpingectomy alone. Bilateral salpingo-oophorectomy yielded the lowest number of future breast and ovarian cancers compared with the other two strategies. CONCLUSION: Bilateral salpingo-oophorectomy offers the greatest risk reduction for breast and ovarian cancer among BRCA mutation carriers. However, when considering quality-adjusted life expectancy, bilateral salpingectomy with delayed oophorectomy is a cost-effective strategy and may be an acceptable alternative for those unwilling to undergo bilateral salpingo-oophorectomy.

Risk-reducing bilateral salpingo-oophorectomy and sexual health: a qualitative study.

OBJECTIVE: To examine the impact of risk-reducing bilateral salpingo-oophorectomy (RRBSO) on sexual function in BRCA gene mutation carriers, compared with the effect on women undergoing BSO (bilateral salpingo-oophorectomy) for benign indications from a qualitative perspective. METHODS: Our study included 25 women who had undergone either a RRBSO because of BRCA carrier status or a BSO for a benign gynaecologic indication. Women were invited to participate if they were at least six months post-BSO. They took part in an individual, private interview during which they were asked open-ended questions about their sexual health in the context of undergoing BSO. They also completed self-report measures of sexual response, sexual distress, sexual self-image, and mood. RESULTS: Using content analysis of interviews, saturation in themes was reached after 15 interviews and four main themes were identified: (1) preoperative knowledge of sexual side effects, (2) preoperative drive to educate oneself on BSO side effects, (3) partner support, and (4) treatment for sexual side effects. Preoperative awareness of post-BSO sexual side effects was highly correlated with patient satisfaction and inversely correlated with postoperative sexual distress. A majority of participants reported that they did not discuss post-BSO sexual functioning with their physicians, and had to seek out information independently. Satisfaction with RRBSO remained high regardless of whether or not participants reported post-BSO sexual distress. Self-report questionnaires did not reveal any differences between the two groups on measures of sexual function. CONCLUSION: This study provided a nuanced view of sexual health in women following RRBSO that was not captured by self-report questionnaires. Women with preoperative knowledge of post-BSO sexual side effects report being more prepared for surgery, and experience less sexual distress following their BSO.

Evaluation of group genetic counseling for hereditary breast and ovarian cancer.

As demand for genetic counseling regarding hereditary cancer continues to grow, more efficient methods of providing this service must be explored. In this pilot study, group genetic counseling was offered to two different cohorts of women seeking genetic counseling for Hereditary Breast and Ovarian Cancer. Seven group sessions, designed to cover all aspects of an individual genetic counseling appointment, were conducted. Although patients were receptive to group genetic counseling, a significant proportion chose individual counseling when given the option. Advantages of group genetic counseling include shared experience and increased efficiency. Disadvantages include increased frustration at not being eligible for genetic testing, group influence on decision-making, privacy concerns, increased need for follow-up, and difficulty booking group appointments. Overall, the level of patient satisfaction with group genetic counseling was similar to that of individual counseling. The results of this pilot study suggest that further research is needed to determine whether group genetic counseling is an acceptable alternative to individual counseling.

Time to decide about risk-reducing mastectomy: a case series of BRCA1/2 gene mutation carriers.

BACKGROUND: The purpose of this research was to explore women's decision-making experiences related to the option of risk-reducing mastectomy (RM), using a case series of three women who are carriers of a BRCA1/2 gene mutation. METHODS: Data was collected in a pilot study that assessed the response of women to an information booklet about RM and decision-making support strategies. A detailed analysis of three women's descriptions of their decision-making processes and outcomes was conducted. RESULTS: All three women were carriers of a BRCA1/2 gene mutation and, although undecided, were leaning towards RM when initially assessed. Each woman reported a different RM decision outcome at last follow-up. Case #1 decided not to have RM, stating that RM was "too radical" and early detection methods were an effective strategy for dealing with breast cancer risk. Case #2 remained undecided about RM and, over time, she became less prepared to make a decision because she felt she did not have sufficient information about surgical effects. Case #3 had undergone RM by the time of her second follow-up interview and reported that she felt "a load off (her) mind now". CONCLUSION: RM decision making may shift over time and require decision support over an extended period.

Canadian nursing in the genomic era: a call for leadership.

With developments in genomics, there is an urgent need for Canadian nurses in all settings to be informed and involved in the incorporation of this new knowledge into healthcare. The purpose of this paper was to synthesize the literature on genetic nursing roles to provide a foundation for Canadian nursing leaders as they take on the challenges of nursing in the genomic era. A comprehensive review of 98 articles published between 1994 and 2004 revealed strong support for genetic nursing roles and recommendations for levels of genetic nursing practice. The few studies on genetic nursing roles suggested that nurses and other health professionals support the integration of genomics into nursing practice. Issues that need to be addressed related to nursing practice, education and research are offered to engage nursing leaders in advocating for the incorporation of genomics into nursing in Canada.

Establishing roles in genetic nursing: interviews with Canadian nurses.

The purpose of this qualitative study was to describe nurses' roles in providing clinical genetic services related to adult onset hereditary disease and factors that influence genetic nursing practice in Canada. The study involved semi-structured telephone interviews with 22 nurses from 5 Canadian provinces with full-time or part-time roles in providing genetic services. The interviews included open-ended questions to elicit descriptions of genetic nursing roles and factors that support and limit opportunities in genetic nursing practice. Thematic analysis of the transcribed interviews revealed that, in addition to genetic counselling, the nurses reported a wide range of roles and responsibilities related to the provision of genetic services that drew directly on their nursing background (e.g., patient assessment, health promotion). Factors identified as supporting genetic nursing roles included nursing background, being part of a multidisciplinary team, and receiving mentorship. Challenges in establishing roles in genetic nursing were related to role ambiguity, lack of recognition of nursing expertise, limited availability of genetics education, isolation, and instability of nursing positions. Recommendations to support the development and expansion of genetic nursing practice were identified. A coordinated national effort among all stakeholders is needed to provide the resources necessary to support the appropriate and effective use of nursing expertise as genetics is integrated into the Canadian health-care system.

Unraveling women's perceptions of risk for breast cancer.

Inconsistent reports of the prevalence of risk perception accuracy may be related to the use of different classification strategies. The purpose of this study was to compare two approaches for assessing the accuracy of women's breast cancer risk perceptions. A telephone survey was conducted with an age-stratified random sample of British Columbian women 20-79 years of age without a breast cancer diagnosis (n = 761). A comparison of two methods employed to determine perception accuracy revealed substantial differences between the methods with regard to the classification of women as under- and over-estimators. The study highlights the need for researchers to consider the method used to determine the accuracy of risk perceptions and the implications of using different strategies to assess risk perception accuracy when such information is used in research or to guide interventions.

The influence of question wording on assessments of interest in genetic testing for breast cancer risk.

The purpose of this study was to compare the results of different measures of interest in genetic testing for breast cancer risk. A telephone survey of a random sample of women without breast cancer was conducted in British Columbia, Canada. Interest in genetic testing for breast cancer risk was measured in three ways: (1) an unprompted assessment of interest, (2) assessment of interest when prompted with a hypothetical offer of testing, and (3) assessment of interest when provided with supplementary information. Substantial differences in reported levels of interest in genetic testing were observed across the different assessment approaches, with the unprompted assessment of interest resulting in lowest levels of interest. The highest levels of interest were observed when the assessment of interest was prompted with a hypothetical offer of testing. Factors predicting interest in genetic testing varied depending on the assessment measure used. These findings suggest that more attention must be given to measurement issues, including complete reporting of measures used in research, development of standardized approaches to assessing interest in genetic testing, and more rigorous psychometric evaluations of measures of interest in genetic testing.

Finding and interpreting cancer screening guidelines: an oncology nursing challenge.

It is our hope that increased awareness of cancer screening recommendations will initiate a dialogue between individuals and their health care providers. Organizational screening recommendations differ as a result of evolving technology, financial and ethical considerations, and impact on mortality. It is through discussions with informed health care providers that patients and families will determine the most effective personal cancer screening strategies. We are hopeful that this discussion of cancer screening recommendations will encourage other oncology nurses to identify their provincial screening guidelines and to address them in discussions with people living with cancer, family members, community groups, and friendship circles. For those cancers where early detection correlates with improved survival, regular screening may have a direct impact on individual lives. We challenge you to implement strategies to incorporate cancer screening information in your professional and personal relationships.

Women's perceptions of breast cancer risk: are they accurate?

BACKGROUND: The objective was to compare women's personal estimates of their risk with objective breast cancer risk estimates and to describe the risk factors for breast cancer identified by women. METHODS: Telephone survey of a random sample of 761 rural and urban women with no history of breast cancer. Survey instrument included measures of perceptions of lifetime risk for breast cancer for themselves and for the average woman, perceptions of risk factors that influenced their risk and the average woman's risk for breast cancer. Objective estimates of breast cancer risk were calculated using the Gail et al. algorithm. Descriptive statistics and multiple linear regression were used to analyze the data. RESULTS: Women's estimates of their own lifetime risk for breast cancer were significantly higher than their Gail model risk estimates (mean difference = 19%, p < 0.001). The women's personal breast cancer risk estimates were lower than estimates of risk for a hypothetical average woman (mean difference = -8%, p < 0.001). Fifty percent of the sample reported a perceived risk estimate at least 15% above their Gail risk estimate. The risk factors for breast cancer most frequently identified included family history, nutrition/diet, smoking, lifestyle, environment, stress and age. Although the risk factors used to calculate the Gail model risk estimates were reported by some study participants, these women consistently identified only family history as their personal risk factor. CONCLUSION: Women have difficulty accurately estimating their breast cancer risk and identifying known risk factors for breast cancer. Individual risk information may be more useful in enhancing accurate risk perceptions than the "1 in 9" message.

Women's interest in genetic testing for breast cancer risk: the influence of sociodemographics and knowledge.

The objective of this study was to assess women's interest in genetic testing for breast cancer risk. Randomly selected samples of 761 women without breast cancer from the general population of British Columbia, Canada, and 260 women with breast cancer from the provincial cancer registry participated in a telephone survey that assessed interest in genetic testing for breast cancer risk, knowledge of hereditary breast cancer and genetic testing, and sociodemographics. Women with breast cancer did not possess superior knowledge of breast cancer genetics compared with women from the general population. Of the women with breast cancer, 30.8% reported interest in testing or had been tested, compared with 28.5% of women without breast cancer. Controlling for differences in age, education, personal history of breast cancer, and knowledge of genetics, women with at least one relative with breast cancer were 2.3 times more likely to express interest in genetic testing for breast cancer risk than those with no family history. There were significant interactions between breast cancer status and education and between age and knowledge of breast cancer genetics. Women without breast cancer and with a positive family history, who were between 20 and 40 years of age, were most likely to be interested in testing. The women with breast cancer who were interested in testing tended to be approximately 50 years of age, had a positive family history, and had more years of education. Women with a family history of breast cancer, well-educated women with breast cancer, and younger women, particularly those with knowledge of genetic testing, are important target audiences for community-based education on genetic testing for breast cancer risk.