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

Influence of lived experience on risk perception among women who received a breast cancer polygenic risk score: 'Another piece of the pie'

Polygenic risk scores (PRS) are personalized assessments of disease risk based on the cumulative effect of common low-risk genetic variants. PRS have been shown to accurately predict women's breast cancer risk and are likely to be incorporated into personalized breast cancer risk management programs. However, there are few studies investigating the individual impact of receiving a breast cancer PRS. Existing studies have not demonstrated significant changes in perceived risk or risk management behaviors after receipt of polygenic risk information. The aim of this qualitative study was to explore how women with a family history of breast cancer construct breast cancer risk perceptions after receipt of a breast cancer PRS. Unaffected women with a family history of breast cancer who had not previously received genetic counseling regarding their breast cancer risk were invited to participate in this study. In-depth, semi-structured interviews were conducted with 20 women who attended a familial cancer clinic in the Australian states of Victoria and Tasmania. Data were analyzed using an inductive thematic approach. Women's lived experience played a significant role in the construction and maintenance of their breast cancer risk perception. Women's pre-existing risk perceptions were informed by their family history and their knowledge that breast cancer is a multifactorial disease. Knowing that breast cancer is a multifactorial disease enabled most women to integrate genetic information with their pre-existing notions of risk. Women reported that the information they received was consistent with their existing notions of personal risk and screening advice. Therefore, the PRS did not lead to a change in perceived risk or risk management behaviors for most women. The results of this study provide insight into how polygenic risk information is integrated with pre-existing notions of risk, which will inform its implementation into clinical practice.</p

Influence of lived experience on risk perception among women who received a breast cancer polygenic risk score: 'Another piece of the pie'

Polygenic risk scores (PRS) are personalized assessments of disease risk based on the cumulative effect of common low-risk genetic variants. PRS have been shown to accurately predict women's breast cancer risk and are likely to be incorporated into personalized breast cancer risk management programs. However, there are few studies investigating the individual impact of receiving a breast cancer PRS. Existing studies have not demonstrated significant changes in perceived risk or risk management behaviors after receipt of polygenic risk information. The aim of this qualitative study was to explore how women with a family history of breast cancer construct breast cancer risk perceptions after receipt of a breast cancer PRS. Unaffected women with a family history of breast cancer who had not previously received genetic counseling regarding their breast cancer risk were invited to participate in this study. In-depth, semi-structured interviews were conducted with 20 women who attended a familial cancer clinic in the Australian states of Victoria and Tasmania. Data were analyzed using an inductive thematic approach. Women's lived experience played a significant role in the construction and maintenance of their breast cancer risk perception. Women's pre-existing risk perceptions were informed by their family history and their knowledge that breast cancer is a multifactorial disease. Knowing that breast cancer is a multifactorial disease enabled most women to integrate genetic information with their pre-existing notions of risk. Women reported that the information they received was consistent with their existing notions of personal risk and screening advice. Therefore, the PRS did not lead to a change in perceived risk or risk management behaviors for most women. The results of this study provide insight into how polygenic risk information is integrated with pre-existing notions of risk, which will inform its implementation into clinical practice.</p

Breast cancer polygenic risk scores: A 12-month prospective study of patient reported outcomes and risk management behavior

Purpose: Polygenic risk scores (PRS) for breast cancer risk have emerged as a potential tool for informing disease risk management. However, little is known about women’s responses to receiving this information. This study aimed to prospectively assess patient reported outcomes and risk management behavior of women choosing to receive (receivers) or decline (decliners) their breast cancer PRS. Methods: Eligible women were identified from the Variants in Practice (ViP) cohort. Eligibility included either unaffected or affected by breast cancer and from families with no identified pathogenic variant in a breast cancer risk gene. Genotyping for 62 common variants was performed, from which a PRS and relative risk for breast cancer were calculated. All participants completed a questionnaire at study enrollment. Receivers also completed questionnaires at two-weeks and 12-months after receiving their PRS, and decliners a second questionnaire at 12-months post study enrollment. Results: Of the 208 participants, 165 (79%) received their PRS. Among receivers, there was no change in anxiety or distress (general-and cancer-specific) following testing. In the first year after receiving their PRS, breast screening and uptake of risk-reducing strategies (i.e. bilateral mastectomy and risk-reducing medication) were consistent with current Australian guidelines of breast cancer risk management. Compared to receivers, decliners reported significantly higher decisional regret regarding receipt of their PRS. Reasons for not receiving PRS included being unable to attend the appointment in person and concerns over potential emotional response. Conclusion: These findings provide the first insight into patient reported outcomes and risk management behavior after receiving or declining breast cancer PRS. Our findings provide additional support for the suitability of PRS testing for clinical practice, while highlighting the issues that need to be addressed when providing this information

Women’s Responses and Understanding of Polygenic Breast Cancer Risk Information

It is estimated that polygenic factors can explain up to 18% of familial breast cancer. Clinical implementation of polygenic testing has begun, with several commercial laboratories now testing. Despite commercial implementation, there is little research investigating how women respond and understand polygenic risk information. This study aimed to explore women’s experience receiving their personalized polygenic risk score (PRS) and compare responses of women at different levels of polygenic risk. Eligible participants were affected and unaffected women from families clinically assessed to be at high risk for breast cancer who had received their personalized PRS as part of the Variants in Practice Psychosocial Study (ViPPs). In-depth semi-structured interviews were conducted with 21 women (mean age 53.4 years) up to four weeks after receiving their PRS. Interviews were transcribed verbatim and analyzed using thematic analysis. Eleven women received a PRS that was in the top quartile of PRS distribution and 10 in the lowest quartile. Women’s lived experience with breast cancer informed how they responded to their PRS, constructed and made sense of breast cancer risk following receipt of their PRS, and integrated this new information into their breast cancer risk management. Regardless of polygenic risk level, all participants demonstrated broad knowledge of concepts related to polygenic information and were able to accurately describe the implications of their PRS. Receiving PRS did not appear to negatively impact women’s reported distress levels. Our findings suggest polygenic breast cancer information is well received and understood by women at high-risk for breast cancer

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

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

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

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)

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)