Regulating cancer risk prediction: legal considerations and stakeholder perspectives on the Canadian context.

Risk prediction models hold great promise to reduce the impact of cancer in society through advanced warning of risk and improved preventative modalities. These models are evolving and becoming more complex, increasingly integrating genetic screening data and polygenic risk scores as well as calculating risk for multiple types of a disease. However, unclear regulatory compliance requirements applicable to these models raise significant legal uncertainty and new questions about the regulation of medical devices. This paper aims to address these novel regulatory questions by presenting an initial assessment of the legal status likely applicable to risk prediction models in Canada, using the CanRisk tool for breast and ovarian cancer as an exemplar. Legal analysis is supplemented with qualitative perspectives from expert stakeholders regarding the accessibility and compliance challenges of the Canadian regulatory framework. While the paper focuses on the Canadian context, it also refers to European and U.S. regulations in this domain to contrast them. Legal analysis and stakeholder perspectives highlight the need to clarify and update the Canadian regulatory framework for Software as a Medical Device as it applies to risk prediction models. Findings demonstrate how normative guidance perceived as convoluted, contradictory or overly burdensome can discourage innovation, compliance, and ultimately, implementation. This contribution aims to initiate discussion about a more optimal legal framework for risk prediction models as they continue to evolve and are increasingly integrated into landscape for public health.

Scope of coverage of medical genetics and genomics in pre-clerkship programs of Canadian faculties of medicine: A curriculum analysis.

We appraised the scope of medical genetics and genomics concepts covered in the pre-clerkship programs of Canadian faculties of medicine through an analysis of course objectives. All course objectives linked to medical genetics and genomics in pre-clerkship programs of Canadian faculties of medicine were compiled. From this, the fraction of objectives dedicated to medical genetics and genomics was calculated. Course objectives were also categorized according to a curriculum and a competency classification. Of the 17 Canadian faculties of medicine, the complete set of course syllabi (5 faculties) or the listing of learning objectives (4 faculties) were obtained and reviewed. The fraction of learning objectives dedicated to medical genetics and genomics varied between 0.65% and 5.05%. From the objectives classification, "foundational knowledge" was most frequently covered (64% of the compiled objectives), while topics such as: "ethics and professionalism," "communicate genetics information," and "obtain specialist help" were covered by less than 5%. Coverage of medical genetics and genomics in pre-clerkship programs of Canadian faculties of medicine appears to be low. Genetics and genomics are playing a rapidly expanding role in healthcare and clinical practice and educational programs should consider this new reality.

Polygenic risk scores and risk-stratified breast cancer screening: Familiarity and perspectives of health care professionals.

PURPOSE: Health care professionals are expected to take on an active role in the implementation of risk-based cancer prevention strategies. This study aimed to explore health care professionals' (1) self-reported familiarity with the concept of polygenic risk score (PRS), (2) perceived level of knowledge regarding risk-stratified breast cancer (BC) screening, and (3) preferences for continuing professional development. METHODS: A cross-sectional survey was conducted using a bilingual-English/French-online questionnaire disseminated by health care professional associations across Canada between November 2020 and May 2021. RESULTS: A total of 593 professionals completed more than 2 items and 453 responded to all questions. A total of 432 (94%) participants were female, 103 (22%) were physicians, and 323 (70%) were nurses. Participants reported to be unfamiliar with (20%), very unfamiliar (32%) with, or did not know (41%) the concept of PRS. Most participants reported not having enough knowledge about risk-stratified BC screening (61%) and that they would require more training (77%). Online courses and webinar conferences were the preferred continuing professional development modalities. CONCLUSION: The study indicates that health care professionals are currently not familiar with the concept of PRS or a risk-stratified approach for BC screening. Online information and training seem to be an essential knowledge transfer modality.

Issues associated with a hereditary risk of cancer: Knowledge, attitudes and practices of nurses in oncology settings.

Documenting a patient's family history of cancer is useful in assessing their predisposition to some types of hereditary cancers. A group of nurses working with cancer patients were surveyed, by way of a questionnaire, to determine their level of knowledge about oncogenetics, describe various issues related to their capacity to identify, refer and support individuals with a hereditary risk of cancer, and explore their interest in continuing education on this topic. The findings show limited knowledge and a low sense of competence among the participating nurses, as well as a lack of access to university and continuing education programs in this field. Training focused on competency development would enhance their capacity to carry out an initial assessment of individuals who are potentially at risk for cancer and refer them to specialized resources.

Theoretical conceptions of intervention research addressing cancer control issues.

Population health intervention research (PHIR) involves the use of scientific methods to produce knowledge about policy and program interventions that operate within or outside of the health sector and have the potential to impact health at the population level. PHIR is a relatively new research field that has gained momentum internationally. When developing PHIR, it is important to have a program theory with the potential to increase intervention success by identifying underlying mechanisms, areas of failure and unintended outcomes. Since 2010, the French National Cancer Institute (Institut National du Cancer-INCa) has supported a national, competitive, dedicated call for proposals in PHIR to tackle cancer control issues. After 5 years of activity, specific analysis of the proposals submitted for funding and/or funded (n = 63) from descriptive and analytic perspectives was called for. Analysis of the data revealed diversity in terms of targeted populations, partnerships engaged and methodological approaches. Projects were more likely to be funded (n = 15) if presented with a robust methodological approach and diversity in methodology, and/or with research objectives at different levels of action. The analysis also revealed that researchers do not explicitly describe theoretical constructs underpinning their interventions to combat cancer. PHIR still needs improvement to better incorporate social, institutional and policy approaches to cancer control. Researchers should apply a theory-driven approach to distinguish between 'program failure' and 'theory failure'. Following up the funded projects will allow successes and failures to be evaluated with respect to the use (or non-use) of theory-driven approaches.

Survey of palliative care providers' needs, perceived roles, and ethical concerns about addressing cancer family history at the end of life.

OBJECTIVE: Palliative care providers may face questions from patients and relatives regarding the heritability of cancers. Implications of such discussions for providers have been little explored. This study aimed to gather palliative care providers' views on their main needs, roles, and ethical concerns regarding cancer family history discussions. METHOD: The palliative care providers who participated in the 2015 and 2017 annual meetings of the Quebec Palliative Care Association were approached to complete a web-based questionnaire. Study participants answered the questionnaire between November 2016 and July 2017. They were asked to identify the most facilitating factor for cancer family history discussions, as well as their most important knowledge needs, potential role, and ethical concerns. Descriptive analyses were conducted. RESULTS: Ninety-four palliative care providers answered the questionnaire. Access to specialized resources to obtain information and protocols or guidelines were considered the most facilitating factors for cancer family history discussions by 32% and 20% of providers, respectively. Knowledge of hereditary cancers was the most relevant educational need for 53%. Thirty-eight per cent considered essential to be informed about their rights and duties regarding cancer family history discussions. Being attentive to patients' concerns and referring families to appropriate resources were identified as the most relevant roles for palliative care providers by 47% and 34% of respondents, respectively. Fifty-eight per cent agreed that cancer family history discussions should be initiated only if beneficial to family members. SIGNIFICANCE OF RESULTS: Education on hereditary cancers made consensus among palliative care providers as the most important knowledge need regarding discussing cancer family history at the end of life. Nonetheless, other less commonly expressed needs, including access to genetics specialists, protocols, or guidelines, and awareness of provider rights and duties concerning such discussions, deserve attention. Answering providers' needs might help optimize cancer predisposition management in palliative care.

Progesterone receptor status modifies the association between body mass index and prognosis in women diagnosed with estrogen receptor positive breast cancer.

The role of progesterone receptor (PR) status on the association between obesity and prognosis of estrogen receptor positive (ER+) breast cancer (BC) remains poorly understood. We aim to examine whether this association varies according to the tumor PR status. Data for 3,747 women diagnosed with nonmetastatic ER+ invasive BC between 1995 and 2010 were analyzed. Women were classified according to their body mass index (BMI) (<18.5, 18.5-24.9, 25.0-29.9 or ≥30.0 kg/m2 ). Tumor PR status (PR-, PR+) was evaluated by immunohistochemistry. Hazard ratios (HR) for survival outcomes were estimated using multivariable Cox regression models. Effect modification was assessed on both additive and multiplicative scales using relative excess risk due to interaction and ratio of HRs, respectively. After a median follow-up of 5.9 years (range: 3.4-9.2), women with PR- tumors and underweight (HR = 2.76, 95% CI: 1.40-4.91), overweight (HR = 2.02, 95% CI: 1.43-2.81) or obese (HR = 2.51, 95% CI: 1.67-3.65) had increased risk of all-cause mortality, when compared to normal weight women with PR+ tumors. A similar pattern of associations was observed for BC-specific mortality. In contrast, women with PR+ tumors had similar risks for both mortality outcomes, regardless of BMI. On the additive scale, all-cause mortality was modified by PR status for overweight and obese women, whereas for BC-specific mortality, it was only modified for underweight women. The same observations were found on the multiplicative scale. These results suggest that poorer survival associated with low and high BMI among women diagnosed with ER+ BC may depend on the tumor PR status.

Metabolically healthy obesity and the risk of cardiovascular disease and type 2 diabetes: the Whitehall II cohort study.

AIM: The metabolically healthy obese (MHO) phenotype refers to obese individuals with a favourable metabolic profile. Its prognostic value is unclear and may depend on the health outcome being examined. We examined the association of MHO phenotype with incident cardiovascular disease (CVD) and type 2 diabetes. METHODS AND RESULTS: Body mass index and metabolic health, assessed using the Adult Treatment Panel-III (ATP-III) criteria, were assessed on 7122 participants (69.7% men) from the Whitehall II study, aged 39-63 years in 1991-93. Incident CVD (coronary heart disease or stroke) and type 2 diabetes were ascertained from medical screenings (every 5 years), hospital data, and registry linkage until 2009. A total of 657 individuals (9.2% of the cohort) were obese and 42.5% of these were classified as MHO in 1991-93. Over the median follow-up of 17.4 years, there were 828 incident cases of CVD and 798 incident cases of type 2 diabetes. Compared with metabolically healthy normal weight individuals, MHO subjects were at increased risk for CVD (HR = 1.97, 95% CI: 1.38-2.80) and type 2 diabetes (3.25, 95% CI: 2.32-4.54). There was excess risk in metabolically unhealthy obese compared with MHO for type 2 diabetes (1.98, 95% CI: 1.39-2.83) but not CVD (1.23, 95% CI: 0.81-1.87). Treating all measures as time varying covariates produced similar findings. CONCLUSION: For type 2 diabetes, the MHO phenotype is associated with lower risk than the metabolically unhealthy obese, but for CVD the risk is as elevated in both obesity phenotypes.

Sleep duration and sleep disturbances partly explain the association between depressive symptoms and cardiovascular mortality: the Whitehall II cohort study.

Depressive symptoms are associated with an increased risk of death, but most of this association remains unexplained. Our aim was to explore the contribution of sleep duration and disturbances to the association between depressive symptoms, all-cause and cardiovascular disease mortality. A total of 5813 (4220 men and 1593 women) aged 50-74 years at baseline, participants of the British Whitehall II prospective cohort study, were included. Depressive symptoms, sleep duration and disturbances were assessed in 2003-04. Mortality was ascertained through linkage to the national mortality register until August 2012, with a mean follow-up of 8.8 years. Depressive symptoms were associated with an increased risk of mortality from all causes [hazard ratio (HR) = 1.51; 95% confidence interval (CI): 1.16-1.97)] and cardiovascular diseases (HR = 1.63; 95% CI: 1.01-2.64) after adjustment for sociodemographic characteristics. Further adjustment for sleep duration and disturbances reduced the association between depressive symptoms and cardiovascular mortality by 21% (HR = 1.53; 95% CI: 0.91-2.57). Sleep seems to have a role, as a mediator or confounder, in explaining the association between depressive symptoms and cardiovascular mortality. These findings need replication in larger studies with longer follow-up.

Increased risk of coronary heart disease among individuals reporting adverse impact of stress on their health: the Whitehall II prospective cohort study.

AIM: Response to stress can vary greatly between individuals. However, it remains unknown whether perceived impact of stress on health is associated with adverse health outcomes. We examined whether individuals who report that stress adversely affects their health are at increased risk of coronary heart disease (CHD) compared with those who report that stress has no adverse health impact. METHODS AND RESULTS: Analyses are based on 7268 men and women (mean age: 49.5 years, interquartile range: 11 years) from the British Whitehall II cohort study. Over 18 years of follow-up, there were 352 coronary deaths or first non-fatal myocardial infarction (MI) events. After adjustment for sociodemographic characteristics, participants who reported at baseline that stress has affected their health 'a lot or extremely' had a 2.12 times higher (95% CI 1.52-2.98) risk of coronary death or incident non-fatal MI when compared with those who reported no effect of stress on their health. This association was attenuated but remained statistically significant after adjustment for biological, behavioural, and other psychological risk factors including perceived stress levels, and measures of social support; fully adjusted hazard ratio: 1.49 (95% CI 1.01-2.22). CONCLUSIONS: In this prospective cohort study, the perception that stress affects health, different from perceived stress levels, was associated with an increased risk of coronary heart disease. Randomized controlled trials are needed to determine whether disease risk can be reduced by increasing clinical attention to those who complain that stress greatly affects their health.

Optimism and pessimism as predictors of initiating and ending an antidepressant medication treatment.

BACKGROUND: The personality variables optimism and pessimism are potential risk factors for disorders commonly treated with antidepressants. AIMS: To evaluate optimism and pessimism as predictors of initiating and ending an antidepressant treatment. METHODS: Data consisted of 29,930 public sector employees with no record of diagnosed depression. Optimism and pessimism were measured using the Revised Life Orientation Test (LOT-R) at baseline. The data of purchases of antidepressants were from the national Drug Prescription Register. RESULTS: During the mean follow-up of 4.4 years, 1681 participants initiated and of them 1288 ended an antidepressant treatment lasting at least 100 days. In the adjusted model, high optimism was associated with a lower likelihood of starting antidepressant medication treatment (hazard ratios, HR, 0.67, 95% CI 0.62-0.73) and a higher likelihood of stopping the treatment (HR = 1.18, 95% CI 1.08-1.30). High pessimism was associated with a higher likelihood of starting antidepressant medication treatment (HR = 1.27, 95% CI 1.16-1.38) and a lower likelihood of stopping it (HR = 0.89, 95% CI 0.80-0.98). These associations remained after optimism score was adjusted for pessimism and vice versa or those with symptoms of mental health problems at baseline were removed from the analyses. CONCLUSIONS: Low optimism and high pessimism are independently associated with an increased likelihood of initiating antidepressant medication treatment, but with a decreased likelihood of ending it during the follow-up.

Mapping inter-professional collaboration in oncogenetics: Results from a scoping review.

Inter-professional collaboration could improve timely access and quality of oncogenetic services. Here, we present the results of a scoping review conducted to systematically identify collaborative models available, unpack the nature and extent of collaboration proposed, synthesize evidence on their implementation and evaluation, and identify areas where additional research is needed. A comprehensive search was conducted in four journal indexing databases on June 13th, 2022, and complemented with searches of the grey literature and citations. Screening was conducted by two independent reviewers. Eligible documents included those describing either the theory of change, planning, implementation and/or evaluation of collaborative oncogenetic models. 165 publications were identified, describing 136 unique interventions/studies on oncogenetic models with somewhat overlapping collaborative features. Collaboration appears to be mostly inter-professional in nature, often taking place during risk assessment and pre-testing genetic counseling. Yet, most publications provide very limited information on their collaborative features, and only a few studies have set out to formally evaluate them. Better quality research is needed to comprehensively examine and make conclusions regarding the value of collaboration in this oncogenetics. We propose a definition, logic model, and typology of collaborative oncogenetic models to strengthen future planning, implementation, and evaluation in this field.

Disruptions in Cancer Care Due to the COVID-19 Pandemic and Fear of Cancer Recurrence in Women with Breast Cancer: A Mixed-Methods Study.

OBJECTIVE: This study investigated if fear of cancer recurrence (FCR) levels and the proportion of women having a clinical level of FCR differed by whether women had or had not experienced disruptions in their cancer tests and treatments due to the pandemic. METHODS: We conducted a mixed-methods study between November 2020 and March 2021 among women diagnosed with breast cancer in the previous five years at the time of their entry in the study. Women completed a questionnaire online assessing disruptions in breast cancer tests and treatments due to the pandemic and the severity subscale of the Fear of Cancer Recurrence Inventory. Semi-structured interviews were also conducted with a subsample of 24 participants and were thematically analyzed. RESULTS: The proportion of patients with a clinical level of FCR was significantly higher among those who experienced the postponement or cancellation of diagnostic and disease progression tests (e.g., blood tests, X-rays, or magnetic resonance imaging; adjusted PR = 1.27 95% CI = 1.13-1.43). Qualitative findings suggest that FCR was exacerbated by the pandemic context. In particular, perceived or actual barriers to care access due to the pandemic were identified as significant FCR-enhancing factors. CONCLUSIONS: These results highlight the need to keep diagnostic and progression tests as timely as possible to prevent increases in FCR levels and offer counselling about FCR when postponing or cancellation are inevitable.

Implementing Multifactorial Risk Assessment with Polygenic Risk Scores for Personalized Breast Cancer Screening in the Population Setting: Challenges and Opportunities.

Risk-stratified breast screening has been proposed as a strategy to overcome the limitations of age-based screening. A prospective cohort study was undertaken within the PERSPECTIVE I&I project, which will generate the first Canadian evidence on multifactorial breast cancer risk assessment in the population setting to inform the implementation of risk-stratified screening. Recruited females aged 40-69 unaffected by breast cancer, with a previous mammogram, underwent multifactorial breast cancer risk assessment. The adoption of multifactorial risk assessment, the effectiveness of methods for collecting risk factor information and the costs of risk assessment were examined. Associations between participant characteristics and study sites, as well as data collection methods, were assessed using logistic regression; all p-values are two-sided. Of the 4246 participants recruited, 88.4% completed a risk assessment, with 79.8%, 15.7% and 4.4% estimated at average, higher than average and high risk, respectively. The total per-participant cost for risk assessment was CAD 315. Participants who chose to provide risk factor information on paper/telephone (27.2%) vs. online were more likely to be older (p = 0.021), not born in Canada (p = 0.043), visible minorities (p = 0.01) and have a lower attained education (p < 0.0001) and perceived fair/poor health (p < 0.001). The 34.4% of participants requiring risk factor verification for missing/unusual values were more likely to be visible minorities (p = 0.009) and have a lower attained education (p ≤ 0.006). This study demonstrates the feasibility of risk assessment for risk-stratified screening at the population level. Implementation should incorporate an equity lens to ensure cancer-screening disparities are not widened.

Personality and all-cause mortality: individual-participant meta-analysis of 3,947 deaths in 76,150 adults.

Personality may influence the risk of death, but the evidence remains inconsistent. We examined associations between personality traits of the five-factor model (extraversion, neuroticism, agreeableness, conscientiousness, and openness to experience) and the risk of death from all causes through individual-participant meta-analysis of 76,150 participants from 7 cohorts (the British Household Panel Survey, 2006-2009; the German Socio-Economic Panel Study, 2005-2010; the Household, Income and Labour Dynamics in Australia Survey, 2006-2010; the US Health and Retirement Study, 2006-2010; the Midlife in the United States Study, 1995-2004; and the Wisconsin Longitudinal Study's graduate and sibling samples, 1993-2009). During 444,770 person-years at risk, 3,947 participants (54.4% women) died (mean age at baseline = 50.9 years; mean follow-up = 5.9 years). Only low conscientiousness-reflecting low persistence, poor self-control, and lack of long-term planning-was associated with elevated mortality risk when taking into account age, sex, ethnicity/nationality, and all 5 personality traits. Individuals in the lowest tertile of conscientiousness had a 1.4 times higher risk of death (hazard ratio = 1.37, 95% confidence interval: 1.18, 1.58) compared with individuals in the top 2 tertiles. This association remained after further adjustment for health behaviors, marital status, and education. In conclusion, of the higher-order personality traits measured by the five-factor model, only conscientiousness appears to be related to mortality risk across populations.

Depression and the risk of cancer: a 15-year follow-up study of the GAZEL cohort.

Depression has long been hypothesized to be associated with cancer incidence. However, there is evidence for a positive publication bias in this field. In the present study, we examined the association between various measures of depression and cancer incidence at several sites. A total of 14,203 members of the French GAZEL (Gaz et Electricité) cohort (10,506 men, 3,697 women) were followed up for diagnoses of primary cancers from January 1, 1994, to December 31, 2009. All medically certified sickness absences for depression recorded between January 1, 1990, and December 31, 1993, were compiled. Depressive symptoms were self-reported in 1993, 1996, and 1999 with the Center for Epidemiologic Studies Depression Scale. During a mean follow-up period of 15.2 years, 1,119 participants received a cancer diagnosis, excluding nonmelanoma skin cancer and in situ neoplasms. Considering 6 cancer sites (prostate, breast, colorectal, smoking-related, lymphoid and hematopoietic tissues, other sites) and 4 measures of depression, we found 1 positive association and 1 negative association. Overall, there was no compelling evidence for an association between depression and cancer incidence. Such null results should be considered when addressing concerns of cancer patients and their relatives about the role of depression in cancer onset.