Breast cancer and polygenic risk scores: An assessment of the psychosocial and behavioral impact of a novel genomic technology

Breast cancer polygenic risk scores (PRS) are increasingly being implemented in clinical and research settings to stratify women according to genetic risk and to inform risk management strategies. Despite clinical implementation, there is a lack of literature regarding the outcomes of PRS testing. This thesis comprises of mix-method study that aimed to investigate the psychosocial and behavioral impact of returning breast cancer PRS to women at increased of the disease for whom previous genetic testing for monogenic risk genes had been uninformative. Study 1 was a qualitative assessment of women’s experiences receiving their personal breast cancer PRS. Twenty-one women participated in an in-depth semi-structured interview after receiving their PRS. Women’s lived experience with breast cancer informed how they responded to their personal PRS. Receiving PRS did not appear to negatively impact women’s self-reported distress levels or breast cancer risk management decisions. Study 2 was a quantitative assessment of uptake of breast cancer PRS. Out of the 208 women who participated in this study, 165 opted to receive their personal PRS. Multivariate logistic regression identified that women were more likely to receive their PRS if they reported greater benefits and fewer barriers to receiving their PRS, had completed higher level education, and did not have daughters. Studies 3 and 4 were part of a prospective, longitudinal assessment that examined the psychosocial and behavioral outcomes associated with receiving breast cancer PRS (n=165). Outcomes associated with declining to receive PRS were also assessed (n=45). There was no evidence of adverse psychological outcomes associated with receiving PRS up to one year after receipt of results. Similarly, there was no evidence of increased negative health behaviour or negative impact risk breast cancer risk management behaviors, including among women who received a reduced risk PRS. Overall, these studies demonstrate that receiving breast cancer PRS was well-received by women and did not lead to negative psychological or behavioral outcomes. Findings from this thesis suggest that breast cancer PRS can be safely implemented in clinical practice to inform risk for women with previous uninformative genetic testing results

The emerging field of polygenic risk scores and perspective for use in clinical care

Genetic testing is used widely for diagnostic, carrier and predictive testing in monogenic diseases. Until recently, there were no genetic testing options available for multifactorial complex diseases like heart disease, diabetes, and cancer. Genome wide association studies (GWAS) have been invaluable in identifying single nucleotide polymorphisms (SNPs), associated with increased or decreased risk for hundreds of complex disorders. For a given disease, SNPs can be combined to generate a cumulative estimation of risk known as a polygenic risk score (PRS). After years of research, PRSs are increasingly used in clinical settings. In this article we will review the literature on how both genome-wide and restricted PRSs are developed and the relative merit of each. The validation and evaluation of PRSs will also be discussed, including the recognition that PRS validity is intrinsically linked to the methodological and analytical approach of the foundation GWAS together with the ethnic characteristics of that cohort. Specifically, population differences may affect imputation accuracy, risk magnitude and direction. Even as PRSs are being introduced into clinical practice, there is a push to combine them with clinical and demographic risk factors to develop a holistic disease risk. The existing evidence regarding the clinical utility of PRSs is considered across four different domains: informing population screening programs; guiding therapeutic interventions; refining risk for families at high-risk; and facilitating diagnosis and predicting prognostic outcomes. The evidence for clinical utility in relation to five well-studied disorders is summarized. The potential ethical, legal and social implications are also discussed

Clinical applications of polygenic breast cancer risk: a critical review and perspectives of an emerging field

Polygenic factors are estimated to account for an additional 18% of the familial relative risk of breast cancer, with those at the highest level of polygenic risk distribution having a least a twofold increased risk of the disease. Polygenic testing promises to revolutionize health services by providing personalized risk assessments to women at high-risk of breast cancer and within population breast screening programs. However, implementation of polygenic testing needs to be considered in light of its current limitations, such as limited risk prediction for women of non-European ancestry. This article aims to provide a comprehensive review of the evidence for polygenic breast cancer risk, including the discovery of variants associated with breast cancer at the genome-wide level of significance and the use of polygenic risk scores to estimate breast cancer risk. We also review the different applications of this technology including testing of women from high-risk breast cancer families with uninformative genetic testing results, as a moderator of monogenic risk, and for population screening programs. Finally, a potential framework for introducing testing for polygenic risk in familial cancer clinics and the potential challenges with implementing this technology in clinical practice are discusse

Psychosocial and behavioral outcomes of genomic testing in cancer: a systematic review

Psychosocial and behavioral outcomes of genetic testing in oncology are well known, however, it is unclear how these findings will generalize to more complex genomic testing. The aim of this systematic review was to assess the psychosocial and behavioral outcomes of cancer genomic testing. Studies were selected for inclusion if they were published from January 2003 to January 2017 and addressed psychological and behavioral outcomes of cancer genomic testing in adults. A review of four databases identified 9620 abstracts, with 22 publications meeting the inclusion criteria. Of the included articles, 11 studies reported on outcomes of germline testing, with three articles assessing panel testing and eight SNP testing. No studies assessed the outcomes of WGS or WES. Eleven articles assessed the outcomes of somatic testing, including testing for cancer prognosis and for personalized therapies. Studies were biased toward breast cancer and Caucasian women with high education and socioeconomic status. While studies demonstrated limited adverse psychological outcomes associated with genomic testing, a lack of consistency in psychosocial measures precluded any meta-analysis. Changes in health behavior following positive results were limited, and in some cases risk perception was not altered following genomic testing. There is limited evidence of adverse psychosocial outcomes and changes in health behavior following genomic testing to assess cancer risk. Findings from this review highlight the need for longitudinal research with superior methodological and theoretical design

Protocol to evaluate a pilot program to upskill clinicians in providing genetic testing for familial melanoma.

IntroductionGenetic testing for hereditary cancers can improve long-term health outcomes through identifying high-risk individuals and facilitating targeted prevention and screening/surveillance. The rising demand for genetic testing exceeds the clinical genetic workforce capacity. Therefore, non-genetic specialists need to be empowered to offer genetic testing. However, it is unknown whether patient outcomes differ depending on whether genetic testing is offered by a genetics specialist or a trained non-genetics clinician. This paper describes a protocol for upskilling non-genetics clinicians to provide genetic testing, randomise high-risk individuals to receive testing from a trained clinician or a genetic counsellor, and then determine whether patient outcomes differed depending on provider-type.MethodsAn experiential training program to upskill dermatologically-trained clinicians to offer genetic testing for familial melanoma is being piloted on 10-15 clinicians, prior to wider implementation. Training involves a workshop, comprised of a didactic learning presentation, case studies, simulated sessions, and provision of supporting documentation. Clinicians later observe a genetic counsellor led consultation before being observed leading a consultation. Both sessions are followed by debriefing with a genetic counsellor. Thereafter, clinicians independently offer genetic testing in the clinical trial. Individuals with a strong personal and/or family history of melanoma are recruited to a parallel-group trial and allocated to receive pre- and post- genetic testing consultation from a genetic counsellor, or a dermatologically-trained clinician. A mixed method approach measures psychosocial and behavioural outcomes. Longitudinal online surveys are administered at five timepoints from baseline to one year post-test disclosure. Semi-structured interviews with both patients and clinicians are qualitatively analysed.SignificanceThis is the first program to upskill dermatologically-trained clinicians to provide genetic testing for familial melanoma. This protocol describes the first clinical trial to compare patient-reported outcomes of genetic testing based on provider type (genetic counsellors vs trained non-genetic clinicians)

Protocol to evaluate a pilot program to upskill clinicians in providing genetic testing for familial melanoma

Introduction Genetic testing for hereditary cancers can improve long-term health outcomes through identifying high-risk individuals and facilitating targeted prevention and screening/surveillance. The rising demand for genetic testing exceeds the clinical genetic workforce capacity. Therefore, non-genetic specialists need to be empowered to offer genetic testing. However, it is unknown whether patient outcomes differ depending on whether genetic testing is offered by a genetics specialist or a trained non-genetics clinician. This paper describes a protocol for upskilling non-genetics clinicians to provide genetic testing, randomise high-risk individuals to receive testing from a trained clinician or a genetic counsellor, and then determine whether patient outcomes differed depending on provider-type. Methods An experiential training program to upskill dermatologically-trained clinicians to offer genetic testing for familial melanoma is being piloted on 10–15 clinicians, prior to wider implementation. Training involves a workshop, comprised of a didactic learning presentation, case studies, simulated sessions, and provision of supporting documentation. Clinicians later observe a genetic counsellor led consultation before being observed leading a consultation. Both sessions are followed by debriefing with a genetic counsellor. Thereafter, clinicians independently offer genetic testing in the clinical trial. Individuals with a strong personal and/or family history of melanoma are recruited to a parallel-group trial and allocated to receive pre- and post- genetic testing consultation from a genetic counsellor, or a dermatologically-trained clinician. A mixed method approach measures psychosocial and behavioural outcomes. Longitudinal online surveys are administered at five timepoints from baseline to one year post-test disclosure. Semi-structured interviews with both patients and clinicians are qualitatively analysed. Significance This is the first program to upskill dermatologically-trained clinicians to provide genetic testing for familial melanoma. This protocol describes the first clinical trial to compare patient-reported outcomes of genetic testing based on provider type (genetic counsellors vs trained non-genetic clinicians)

How is health literacy addressed in primary care?: strategies that general practitioners use to support patients

Background: Low health literacy is associated with adverse health outcomes and raises healthcare costs. General practitioners (GPs) are the first point of access to health care services and play a key role in building patients’ health literacy level. This study aimed to explore: (1) GPs’ understanding of health literacy, (2) their perceived challenges to addressing health literacy, and (3) the strategies they used to support patients with health literacy difficulties. Method: This qualitative study was conducted in South Western Sydney, New South Wales, Australia. Semi-structured interviews were audio-recorded and transcribed verbatim. Interview data were analyzed using the Framework method, a matrix-based approach to thematic analysis. Results: Eighteen participants took part in the study. Four key themes were identified: (1) identifying patients with health literacy difficulties; (2) perceived consequences of low health literacy; (3) being sensitive to developing health literacy skills; and (4) strategies used to build health literacy. Intuitive skills were used to identify the patient’s health literacy skills through recurring encounters with patients over time. A range of communication techniques were used to build health literacy. The value of a long-term relationship with patients and support from relatives were reported (Please eliminate this comma and the one right before this) to be important in helping patients build their health literacy skills. Conclusions: A number of challenges in health literacy exist in general practice. General practitioners can play a role in overcoming these challenges by placing an increased focus on health literacy, including self-education on this topic, identification of patients with low health literacy skills and helping build patients' level of health literacy

Research participants' attitudes towards the confidentiality of genomic sequence information

Respecting the confidentiality of personal data contributed to genomic studies is an important issue for researchers using genomic sequencing in humans. Although most studies adhere to rules of confidentiality, there are different conceptions of confidentiality and why it is important. The resulting ambiguity obscures what is at stake when making tradeoffs between data protection and other goals in research, such as transparency, reciprocity, and public benefit. Few studies have examined why participants in genomic research care about how their information is used. To explore this topic, we conducted semi-structured phone interviews with 30 participants in two National Institutes of Health research protocols using genomic sequencing. Our results show that research participants value confidentiality as a form of control over information about themselves. To the individuals we interviewed, control was valued as a safeguard against discrimination in a climate of uncertainty about future uses of individual genome data. Attitudes towards data sharing were related to the goals of research and details of participants' personal lives. Expectations of confidentiality, trust in researchers, and a desire to advance science were common reasons for willingness to share identifiable data with investigators. Nearly, all participants were comfortable sharing personal data that had been de-identified. These findings suggest that views about confidentiality and data sharing are highly nuanced and are related to the perceived benefits of joining a research study

Psychosocial implications of living with familial risk of a psychiatric disorder and attitudes to psychiatric genetic testing: A systematic review of the literature

The aim of this systematic review was to synthesize the existing evidence documenting the psychosocial implications of living with a familial risk of an adult-onset psychiatric disorder. Six databases were searched systematically to identify qualitative and quantitative studies, which explored perspectives of those at increased risk for psychiatric disorders, as well as the general public. Thematic analysis was used to identify major themes. Thirty-five articles met the eligibility criteria and reported on the views of 4,896 participants. The literature demonstrates strong interest in psychiatric genetic testing of adults as well as children, whereas attitudes toward prenatal testing were much less positive. Predictors of interest in testing, as well as perceived advantages and disadvantages were identified. Very few studies are available on anticipated and actual reactions to receiving results. Studies show that the majority of participants feel that having a genetic explanation would alleviate some of the stigma associated with mental illness. This review shows that interest in, and predictors of attitudes toward, psychiatric genetic testing are well researched, but the extent to which attitudes will translate into actual testing uptake is unknown. Future research also needs to assess the actual behavioral and psychological impact of genetic testing