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.

Canadian Healthcare Professionals' Views and Attitudes toward Risk-Stratified Breast Cancer Screening.

Given the controversy over the effectiveness of age-based breast cancer (BC) screening, offering risk-stratified screening to women may be a way to improve patient outcomes with detection of earlier-stage disease. While this approach seems promising, its integration requires the buy-in of many stakeholders. In this cross-sectional study, we surveyed Canadian healthcare professionals about their views and attitudes toward a risk-stratified BC screening approach. An anonymous online questionnaire was disseminated through Canadian healthcare professional associations between November 2020 and May 2021. Information collected included attitudes toward BC screening recommendations based on individual risk, comfort and perceived readiness related to the possible implementation of this approach. Close to 90% of the 593 respondents agreed with increased frequency and earlier initiation of BC screening for women at high risk. However, only 9% agreed with the idea of not offering BC screening to women at very low risk. Respondents indicated that primary care physicians and nurse practitioners should play a leading role in the risk-stratified BC screening approach. This survey identifies health services and policy enhancements that would be needed to support future implementation of a risk-stratified BC screening approach in healthcare systems in Canada and other countries.

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.

Perceptions and Usability of PREVENTION: A Breast Cancer Risk Assessment e-Platform.

BACKGROUND: The PREVENTION e-platform was developed to provide accessible and evidence-based health information tailored to different Breast Cancer (BC) risk levels. The demonstration study objectives were to (1) assess the usability and perceived impact of PREVENTION on women with assigned hypothetical BC risk levels (i.e., near population, intermediate or high) and (2) explore perceptions and recommendations for e-platform improvement. METHODS: Thirty women with no history of cancer were recruited through social media, commercial centers, health clinics, and community settings in Montreal, Qc, Canada. Participants accessed e-platform content tailored to their assigned hypothetical BC risk level, and then completed study e-questionnaires including the user Mobile Application Rating Scale (uMARS), an e-platform quality scale (i.e., in terms of engagement, functionality, aesthetics, and information). A subsample (n = 18) was randomly selected for an individual follow-up semi-structured interview. RESULTS: The e-platform overall quality was high, with mean M = 4.01 (out of 5) and SD = 0.50. A total of 87% (n = 26) agreed or strongly agreed that PREVENTION increased their knowledge and awareness of BC risk, and 80% would recommend it to others while reporting likelihood of following lifestyle recommendations to decrease their BC risk. Follow up interviews indicated that participants perceived the e-platform as a trusted source of BC information and a promising means to connect with peers. They also reported that while the e-platform was easy to navigate, improvements were needed for connectivity, visuals, and the organization of scientific resources. CONCLUSION: Preliminary findings support PREVENTION as a promising means to provide personalized BC information and support. Efforts are underway to further refine the platform, assess its impact in larger samples and gather feedback from BC specialists.

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.

Cultured Autologous Corneal Epithelia for the Treatment of Unilateral Limbal Stem Cell Deficiency: A Case Series of 15 Patients.

Damage to limbal epithelial stem cells can lead to limbal stem cell deficiency (LSCD). Current autologous treatment procedures for unilateral LSCD bear a significant risk of inducing LSCD in the donor eye. This complication can be avoided by grafting a stem cell containing cultured autologous corneal epithelium (CACE). The primary objective of this study was to demonstrate the safety of CACE grafted on eyes with LSCD. The secondary objective was to assess the efficacy of a CACE graft in restoring a self-renewing corneal surface with adequate anatomic structures, as well as improving the best corrected visual acuity (BCVA). Fifteen patients were grafted with a CACE on a fibrin gel produced from a 3 mm2 limbal biopsy harvested from the donor eye. Data were collected at baseline and after grafting. Follow-ups from 1 to 5 years were conducted. No major adverse events related to the CACE graft were observed. For every visit, an anatomic score based on corneal opacity as well as central vascularization and a functional score based on BCVA were determined. Safety was demonstrated by the low occurrence of complications. Anatomical (93%) and functional (47%) results are promising for improving vision in LSCD patients. Combined functional success and partial success rates with inclusion of BCVA were 53% [CI95: 27-79%] one year after CACE grafting. At the last follow-up, 87% [CI95: 60-98%] of the patients had attained corneal clarity. The outcomes demonstrate the safety of our technique and are promising regarding the efficacy of CACE in these patients.

Gynecologic Cancer Risk and Genetics: Informing an Ideal Model of Gynecologic Cancer Prevention.

Individuals with proven hereditary cancer syndrome (HCS) such as BRCA1 and BRCA2 have elevated rates of ovarian, breast, and other cancers. If these high-risk people can be identified before a cancer is diagnosed, risk-reducing interventions are highly effective and can be lifesaving. Despite this evidence, the vast majority of Canadians with HCS are unaware of their risk. In response to this unmet opportunity for prevention, the British Columbia Gynecologic Cancer Initiative convened a research summit "Gynecologic Cancer Prevention: Thinking Big, Thinking Differently" in Vancouver, Canada on 26 November 2021. The aim of the conference was to explore how hereditary cancer prevention via population-based genetic testing could decrease morbidity and mortality from gynecologic cancer. The summit invited local, national, and international experts to (1) discuss how genetic testing could be more broadly implemented in a Canadian system, (2) identify key research priorities in this topic and (3) outline the core essential elements required for such a program to be successful. This report summarizes the findings from this research summit, describes the current state of hereditary genetic programs in Canada, and outlines incremental steps that can be taken to improve prevention for high-risk Canadians now while developing an organized population-based hereditary cancer strategy.

"The Stakes Are Higher"- Patient and Caregiver Perspectives on Cystic Fibrosis Research and Personalized Medicine.

Introduction: Making bench to bedside advances in cystic fibrosis (CF) care requires the sustained engagement and trust of people living with CF. However, there is a scarcity of studies exploring their concerns and priorities regarding research and its end products. The aim of this qualitative study was to generate empirical evidence regarding patient and caregiver perspectives on cystic fibrosis research and personalized medicine to foster developments in translational research in Canada. Methods: A total of 15 focus groups were conducted, engaging 22 adults with CF and 18 caregivers (e.g., parents, siblings and partners) living in Canada. Inductive thematic analysis relied on an iterative process involving themes derived from both participant meaning-making and existing scientific literature. Participant perspectives were considered along intrapersonal, intracommunity, interpersonal, and structural lines. Results: Overall, participants described a relationship to CF research inextricable from the lived experience of CF as a lifelong progressive and terminal disease and from the goal of advancing medical science. They were enthusiastic and excited about the emergence of CFTR modulators, although they had some knowledge gaps regarding the associated research. They largely spoke to positive experiences with researcher communication but had feedback regarding informed consent processes and the return of study results. Participants also voiced concerns about structural access barriers to research and to its end products. Extensive histories of research participation, a relatively small and intercommunicative CF community, and structural overlap between research and care settings contributed to their perspectives and priorities. Conclusion: Study findings are valuable for researchers and policy-makers in CF and rare or progressive diseases more broadly. Continuing to solicit and listen to the voices of patients and caregivers is crucial for research ethics and the translation of new therapies in the area of personalized medicine.

Women's perceptions of PERSPECTIVE: a breast cancer risk stratification e-platform.

BACKGROUND: Breast cancer risk stratification categorizes a woman's potential risk of developing the disease as near-population, intermediate, or high. In accordance, screening and follow up for breast cancer can readily be tailored following risk assessment. Recent efforts have focussed on developing more accessible means to convey this information to women. This study sought to document the relevance of an informational e-platform developed for these purposes. OBJECTIVE: To begin to assess a newly developed breast cancer risk stratification and decision support e-platform called PERSPECTIVE (PErsonalised Risk Stratification for Prevention and Early deteCTIon of breast cancer) among women who do not know their personal breast cancer risk (Phase 1). Changes (pre- and post- e-platform exposure) in knowledge of breast cancer risk and interest in undergoing genetic testing were assessed in addition to perceptions of platform usability and acceptability. METHODS: Using a pre-post design, women (N = 156) of differing literacy and education levels, aged 30 to 60, with no previous breast cancer diagnosis were recruited from the general population and completed self-report e-questionnaires. RESULTS: Mean e-platform viewing time was 18.67 min (SD 0.65) with the most frequently visited pages being breast cancer-related risk factors and risk assessment. Post-exposure, participants reported  significantly higher breast cancer-related knowledge (p < .001). Increases in knowledge relating to obesity, alcohol, breast density, menstruation, and the risk estimation process remained even when sociodemographic variables age and education were controlled. There were no significant changes in genetic testing interest post-exposure. Mean ratings for e-platform acceptability and usability were high: 26.19 out of 30 (SD 0.157) and 42.85 out of 50 (SD 0.267), respectively. CONCLUSIONS: An informative breast cancer risk stratification e-platform targeting healthy women in the general population can significantly increase knowledge as well as support decisions around breast cancer risk and assessment. Currently underway, Phase 2, called PERSPECTIVE, is seeking further content integration and broader implementation .

Ethical challenges of precision cancer medicine.

Amongst common diseases, cancer is often both a leader in self-regulatory policy, or the field for contentious ethical issues such as the patenting of the BRCA1/2 genes. With the advent of genomic sequencing technologies, achieving precision cancer medicine requires prospective norms due to the large and varied sources of data involved. Here, we discuss the ethical and legal aspects of the policy debate around the relevant topics in precision cancer medicine: the return of incidental findings and sequencing raw data to patients, the communication of genetic results to patients' relatives, privacy and communication risks with concomitant oversight strategies, patient participation and consent models. We present the arguments and empirical data supporting specific policy solutions delineating still contested areas. What type of consent and oversight are required to acquire genomic data or to access it where desired, either by the participant/patient or third-party researchers? Most of the raw sequencing data is still uninterpretable and the variants revealed subject to reinterpretation over time. No doubt the ethical challenges of precision cancer medicine are a prototype of what's to come for other diseases. They are also paradigmatic for regulatory and ethical questions of the translational endeavors since the two worlds - basic science and patient care - are governed by different ethical and legal principles that need to be reconciled in precision cancer medicine.

Artificial Intelligence in Cardiovascular Imaging: "Unexplainable" Legal and Ethical Challenges?

Nowhere is the influence of artificial intelligence (AI) likely to be more profoundly felt than in health care, from patient triage and diagnosis to surgery and follow-up. Over the medium-term, these effects will be more acute in the cardiovascular imaging context, in which AI models are already successfully performing at approximately human levels of accuracy and efficiency in certain applications. Yet, the adoption of unexplainable AI systems for cardiovascular imaging still raises significant legal and ethical challenges. We focus in particular on challenges posed by the unexplainable character of deep learning and other forms of sophisticated AI modelling used for cardiovascular imaging by briefly outlining the systems being developed in this space, describing how they work, and considering how they might generate outputs that are not reviewable by physicians or system programmers. We suggest that an unexplainable tendency presents 2 specific ethico-legal concerns: (1) difficulty for health regulators; and (2) confusion about the assignment of liability for error or fault in the use of AI systems. We suggest that addressing these concerns is critical for ensuring AI's successful implementation in cardiovascular imaging.

Should Age-Dependent Absolute Risk Thresholds Be Used for Risk Stratification in Risk-Stratified Breast Cancer Screening?

In risk-stratified cancer screening, multiple risk factors are incorporated into the risk assessment. An individual's estimated absolute cancer risk is linked to risk categories with tailored screening recommendations for each risk category. Absolute risk, expressed as either remaining lifetime risk or shorter-term (five- or ten-year) risk, is estimated from the age at assessment. These risk estimates vary by age; however, some clinical guidelines (e.g., enhanced breast cancer surveillance guidelines) and ongoing personalised breast screening trials, stratify women based on absolute risk thresholds that do not vary by age. We examine an alternative approach in which the risk thresholds used for risk stratification vary by age and consider the implications of using age-independent risk thresholds on risk stratification. We demonstrate that using an age-independent remaining lifetime risk threshold approach could identify high-risk younger women but would miss high-risk older women, whereas an age-independent 5-year or 10-year absolute risk threshold could miss high-risk younger women and classify lower-risk older women as high risk. With risk misclassification, women with an equivalent risk level would be offered a different screening plan. To mitigate these problems, age-dependent absolute risk thresholds should be used to inform risk stratification.

Risk-Stratified Approach to Breast Cancer Screening in Canada: Women's Knowledge of the Legislative Context and Concerns about Discrimination from Genetic and Other Predictive Health Data.

The success of risk-stratified approaches in improving population-based breast cancer screening programs depends in no small part on women's buy-in. Fear of genetic discrimination (GD) could be a potential barrier to genetic testing uptake as part of risk assessment. Thus, the objective of this study was twofold. First, to evaluate Canadian women's knowledge of the legislative context governing GD. Second, to assess their concerns about the possible use of breast cancer risk levels by insurance companies or employers. We use a cross-sectional survey of 4293 (age: 30-69) women, conducted in four Canadian provinces (Alberta, British Colombia, Ontario and Québec). Canadian women's knowledge of the regulatory framework for GD is relatively limited, with some gaps and misconceptions noted. About a third (34.7%) of the participants had a lot of concerns about the use of their health information by employers or insurers; another third had some concerns (31.9%), while 20% had no concerns. There is a need to further educate and inform the Canadian public about GD and the legal protections that exist to prevent it. Enhanced knowledge could facilitate the implementation and uptake of risk prediction informed by genetic factors, such as the risk-stratified approach to breast cancer screening that includes risk levels.

Of Screening, Stratification, and Scores.

Technological innovations including risk-stratification algorithms and large databases of longitudinal population health data and genetic data are allowing us to develop a deeper understanding how individual behaviors, characteristics, and genetics are related to health risk. The clinical implementation of risk-stratified screening programmes that utilise risk scores to allocate patients into tiers of health risk is foreseeable in the future. Legal and ethical challenges associated with risk-stratified cancer care must, however, be addressed. Obtaining access to the rich health data that are required to perform risk-stratification, ensuring equitable access to risk-stratified care, ensuring that algorithms that perform risk-scoring are representative of human genetic diversity, and determining the appropriate follow-up to be provided to stratification participants to alert them to changes in their risk score are among the principal ethical and legal challenges. Accounting for the great burden that regulatory requirements could impose on access to risk-scoring technologies is another critical consideration.

Personalized Risk Assessment for Prevention and Early Detection of Breast Cancer: Integration and Implementation (PERSPECTIVE I&I).

Early detection of breast cancer through screening reduces breast cancer mortality. The benefits of screening must also be considered within the context of potential harms (e.g., false positives, overdiagnosis). Furthermore, while breast cancer risk is highly variable within the population, most screening programs use age to determine eligibility. A risk-based approach is expected to improve the benefit-harm ratio of breast cancer screening programs. The PERSPECTIVE I&I (Personalized Risk Assessment for Prevention and Early Detection of Breast Cancer: Integration and Implementation) project seeks to improve personalized risk assessment to allow for a cost-effective, population-based approach to risk-based screening and determine best practices for implementation in Canada. This commentary describes the four inter-related activities that comprise the PERSPECTIVE I&I project. 1: Identification and validation of novel moderate to high-risk susceptibility genes. 2: Improvement, validation, and adaptation of a risk prediction web-tool for the Canadian context. 3: Development and piloting of a socio-ethical framework to support implementation of risk-based breast cancer screening. 4: Economic analysis to optimize the implementation of risk-based screening. Risk-based screening and prevention is expected to benefit all women, empowering them to work with their healthcare provider to make informed decisions about screening and prevention.

The Equitable Implementation of Cystic Fibrosis Personalized Medicines in Canada.

This article identifies the potential sources of inequity in three stages of integrating cystic fibrosis personalized medicines into the Canadian healthcare system and proposes mitigating strategies: (1) clinical research and diagnostic testing; (2) regulatory oversight and market authorization; and (3) implementation into the healthcare system. There is concern that differential access will cast a dark shadow over personalized medicine by stratifying the care that groups of patients will receive-not only based on their genetic profiles, but also on the basis of their socioeconomic status. Furthermore, there is a need to re-evaluate regulatory and market approval mechanisms to accommodate the unique nature of personalized medicines. Physical and financial accessibility ought to be remedied before personalized medicines can be equitably delivered to patients. This article identifies the socio-ethical and legal challenges at each stage and recommends mitigating policy solutions.

Women's Views on Multifactorial Breast Cancer Risk Assessment and Risk-Stratified Screening: A Population-Based Survey from Four Provinces in Canada.

Risk-stratified screening for breast cancer (BC) is increasingly considered as a promising approach. However, its implementation is challenging and needs to be acceptable to women. We examined Canadian women's attitudes towards, comfort level about, and willingness to take part in BC risk-stratified screening. We conducted an online survey in women aged 30 to 69 years in four Canadian provinces. In total, 4293 women completed the questionnaire (response rate of 63%). The majority of women (63.5% to 72.8%) expressed favorable attitudes towards BC risk-stratified screening. Most women reported that they would be comfortable providing personal and genetic information for BC risk assessment (61.5% to 67.4%) and showed a willingness to have their BC risk assessed if offered (74.8%). Most women (85.9%) would also accept an increase in screening frequency if they were at higher risk, but fewer (49.3%) would accept a reduction in screening frequency if they were at lower risk. There were few differences by province; however, outcomes varied by age, education level, marital status, income, perceived risk, history of BC, prior mammography, and history of genetic test for BC (all p ≤ 0.01). Risk-based BC screening using multifactorial risk assessment appears to be acceptable to most women. This suggests that the implementation of this approach is likely to be well-supported by Canadian women.

Ethical and Analytic Challenges With Genomic Sequencing of Relapsed Hematologic Malignancies Following Allogeneic Hematopoietic Stem-Cell Transplantation.

The implementation of precision medicine and next-generation sequencing technologies in the field of oncology is a novel approach being more widely studied and used in cases of high-risk primary and recurrent malignancies. Leukemias are the second most common cause of cancer-related mortality in children and the sixth most in adults. Relapsed leukemia represents a major component of the population that may benefit from genomic sequencing. However, ethical and analytic challenges arise when considering sequencing of biologic samples obtained from patients with relapsed leukemia following allogeneic hematopoietic stem-cell transplantation. Blood from the recipient after transplantation would include donor-derived cells and thus, genomic sequencing of recipient blood will interrogate the donor germline in addition to the somatic genetic profile of the leukemia cells and the recipient germline. This is a situation for which the donor will not have typically provided consent and may be particularly problematic if actionable secondary or incidental findings related to the donor are uncovered. We present the challenges raised in this scenario and provide strategies to mitigate this risk.

The Provision of Genetic Testing and Related Services in Quebec, Canada.

BACKGROUND: Research in the field of genomics and genetics has evolved in recent years and so has the demand of consumers who are increasingly interested in genomic prediction of diseases and various traits. The aim of this study is to identify genetic service delivery models, policies governing the use of genomics medicine, and measures to evaluate genetic services in the province of Quebec, Canada. METHODS: An ad hoc questionnaire was designed and administered online in 2017 to healthcare workers with good knowledge or experience in the provision of BReast CAncer genes 1 and 2 (BRCA1/2), Lynch syndrome, familial hypercholesterolemia, inherited thrombophilia genetic tests, engaged in policy planning or evaluation of genetic services. A quali-quantitative analysis of the survey results was performed. RESULTS: Thirty professionals participated in the study. The delivery models are classified in five categories according to the leading role of healthcare professionals in patient care pathways: i) the geneticist model; ii) the primary care model; iii) the medical specialist model; iv) the population screening program model; and v) the direct-to-consumer model. Barriers to genetic services are the coverage of genetic tests by the publicly funded healthcare system, the availability of qualified personnel, and the number of genetic centers. Regulatory oversight concerning the provision of genetic services appears to be insufficient. CONCLUSIONS: Integration between genetics and the overall healthcare system in Quebec is in an early phase. Current models of genetic services require good level of genetic knowledge by all medical specialists, collaboration among different healthcare personnel, and work redistribution. The proper implementation of genomics into healthcare can be achieved through education and training, proper regulatory oversight, genomic policies, and public awareness.