Considering Clinical Implementation of Polygenic Scores in Hereditary Cancer Risk Assessment: Recipients’ Perspectives on Influencing Factors and Strategies

Abstract

Background

Polygenic scores (PGS) capture a proportion of the genomic liability for cancer in unselected and high-risk cohorts, with meaningful application in improving risk-stratified screening and management. However, there are significant evidence gaps regarding future clinical implementation. Despite being key interest-holders, recipient views are underrepresented. The objective of this study was to explore recipients’ views on the clinical implementation of PGS for hereditary cancer risk assessment in Australian cancer genetics clinics.

Methods

Three video-conferenced focus groups were conducted with recipients who had been given their breast and ovarian cancer PGS through the PRiMo trial. Nominal Group Technique was used to enable evaluation of implementation determinants and strategies, and priority setting. Descriptive and deductive content analyses were conducted utilising the Consolidated Framework for Implementation Research and the Expert Recommendations for Implementing Change compilation of facilitative strategies.

Results

Participants (N = 10) were female, with an average age of 36 years (range 18–70 years). Of these, 50% (N = 5) experienced a change in their hereditary cancer risk assessment due to their PGS. Participants prioritised the positive value and impact of PGS, and the behavioural characteristics of recipients, notably their knowledge and expectations of PGS and cancer genetics clinics, as major determinants of implementation success. Implementation strategies that prepared and supported recipients to access, engage, and use PGS were emphasised, with a focus on a clear results report, educational resources, in-clinic resources, and delivery of ongoing good clinical follow-up.

Conclusion

Evidence-based strategies should be deployed to address recipients’ priority barriers to the clinical implementation of PGS for hereditary cancer risk assessment. Centralising recipient voices in implementation design will improve effectiveness and success.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40271-025-00747-5.

Key Points for Decision Makers

Decision-makers must promote opportunities for recipients to access and meaningfully engage with PGS for hereditary cancer risk assessment, investing in community education and supportive materials to improve preparedness and overall benefit.

Operationalising recipients’ perspectives within theory-informed implementation frameworks provides a structured and recipient-centred approach to planning, testing, and evaluating a national implementation approach for PGS for hereditary cancer risk assessment.

The eventual model of care for PGS for hereditary cancer risk assessment should be tailored to recipients as key interest-holders, incorporating genetic counselling, clear correspondence and a follow-up care program, and prioritising timeliness and efficiency.

Introduction

Breast and ovarian cancer are complex diseases, with multi-layered genomic risk architectures. Individuals with hereditary breast and ovarian cancer (HBOC) have an increased lifetime risk of developing breast, ovarian and other malignancies compared with general population owing to germline pathogenic and likely pathogenic variants (PV) in cancer susceptibility genes, such as BRCA1/2, PALB2, CHEK2 and ATM [1]. Each susceptibility gene has variable expressivity and penetrance, meaning women with HBOC are currently given generalised, categorised risk management recommendations [2]. As these cancers are multi-factorial in nature, risk management based solely on the binary outcomes of the presence or absence of a PV lacks comprehensiveness and accuracy.

Polygenic risk scores (PGS) have emerged as a tool to improve the personalisation of breast and ovarian cancer risk assessment, helping to explain some of the variance in phenotype amongst women with HBOC. Originating from genome wide association studies (GWAS), a PGS consists of many common, disease-associated single nucleotide polymorphisms (SNPs) that are weighted for their individual low risk contribution and combined, providing a summative, quantitative measure of an individual’s genomic liability. PGS are estimated to explain 18% of the familial risk for breast cancer [3] and have significant clinical potential for application in risk prediction, stratification, diagnosis, prognostication, and treatment planning [4].

Adding PGS to the outcomes of a HBOC genetic test has been shown to improve risk discrimination for unaffected women testing positive or negative for germline PVs, particularly if the variant is within a moderate penetrance gene, such as PALB2, CHEK2 or ATM [5–11] or where the PGS is within the higher or lower deciles of the risk distribution [7, 9]. These improvements in risk stratification have been seen irrespective of family history of breast cancer [7, 12]. PGS also has a role in predicting cancer subtype and tumour pathology, with improvements in risk prediction around oestrogen-receptor status in breast cancer and high-grade serous type epithelial ovarian cancer for BRCA1/2 carriers [7, 9, 13]. Through improving accuracy and personalisation, PGS can refine risk management recommendations, progressing breast and ovarian cancer prevention and improving health outcomes [11, 14], with current economic modelling also supporting better cancer healthcare cost-effectiveness [15, 16].

Debate exists on the utility and readiness of PGS across different use-cases, particularly centring around the true predictive validity and impact on long-term clinical outcomes [12, 17, 18], lack of consensus on optimal PGS development, construction, and validation [19, 20], concerns for inequity of benefit due to poorer predictive performance of PGS in non-European ancestries [21, 22] and consideration of other potential ethical, legal, and social harms. Many of these challenges are inherent to other clinical risk factors and genomic innovations [23]. Integration into HBOC risk assessment is one of the most well-researched and supportable use-cases of PGS [24, 25], with several studies currently evaluating utility and potential implementation [26, 27].

Genetic healthcare recipients (here defined as patients and families accessing clinical cancer genetics services) are key interest-holders in the potential future clinical implementation of PGS for integrated HBOC risk assessment. Women with and without clinically actionable PVs have reported being accepting of, and interested in, receiving breast cancer risk assessments including PGS information [28]. General community members have expressed interest in receiving PGS results [29]. Incorporating PGS into breast cancer risk assessments for potentially high-risk women has not been shown to cause significant adverse psychological outcomes, including depression and anxiety [30, 31].

Recipient acceptability and interest are precursors to successful implementation of any innovation [32]. However, they are not enough to guarantee implementation success. Significant evidence gaps remain, including recipient perspectives on implementation, and their perceived needs, determinants of implementation success and priority strategies. As PGS are intended to improve outcomes for recipients, recipient preferences must inform the design and delivery of this innovation [33]. Capturing recipient perspectives will help ensure a more recipient-focused approach to implementation, helping to improve patient uptake and overall effectiveness of PGS in practice [33]. Better engaging communities in the delivery design for PGS may ensure translation is fair and equitable, as well as bringing improved understanding around the social factors likely to accompany and influence PGS implementation [34]. Additionally, it has been noted that the cost-effectiveness of integrating PGS into risk-stratified cancer screening may be improved with better engagement of the public in decision-making around changes to current programs [15].

The aim of this study was to meaningfully engage with recipients, to investigate their shared perspectives towards the future implementation of PGS for hereditary breast and ovarian cancer risk assessment in Australian clinical cancer genetics practice. These data will begin to bridge the evidence gap and be instrumental in promoting recipient representation in a future national implementation trial.

Methods

A participatory action paradigm was used to examine implementation determinants, and co-design and prioritise implementation strategies. Participatory action research embraces critical theory and constructivism, centralising the value of experiential and co-created knowledge to address system barriers and make change [35]. Focus groups were chosen to promote interaction and collaboration between participants with different experiences of PGS and clinical cancer genetics [36], ensuring collection of a diverse and representative range of opinions and understandings [37]. This study was approved by the Human Research Ethics Committee at the Peter MacCallum Cancer Centre, Victoria, Australia (HREC 64060/PMCC).

Participant Recruitment

Participants were recruited from the cross-over arm of the PRiMo Trial [27], as these participants receive a personalised breast and ovarian cancer risk assessment incorporating their predictive genetic test result for a familial germline PV and their PGS, alongside other clinical risk factors within the clinical cancer genetics setting. This experience of receiving integrated risk assessment was vital as it enabled discussion regarding the specific implementation determinants and strategies for PGS. Cross-over PRiMo participants who had indicated willingness to participate in a focus group were contacted by RP to discuss this study, give verbal consent and organise a convenient time to participate. Focus groups were assembled based on scheduling availability.

Data Collection

Data were collected using a semi-structured guide comprised of three sections, the development of which was informed by the Consolidated Framework for Implementation Research (CFIR) [38]. Section one used open-ended questions to facilitate discussion about participants’ experiences and decision-making with PGS. This open exploration was followed by two rounds of a modified Nominal Group Technique, a structured, multi-stage procedure which enabled priority-setting and established consensus among participants [39]. Participants were invited to generate and share their own intuitive ideas in a round-robin approach, participate in discussion to clarify, refine and group ideas, and then finally prioritise those ideas through a scoring process, ranking ideas in order of their perceived importance and value [40]. In the first round, participants were encouraged to discuss and prioritise determinants of implementation success. In the second round, the focus was on implementation strategies. The focus groups were facilitated online, via videoconference, by R.P. and L.E.F. R.P. is a certified genetic counsellor and PhD student, who observed the focus groups, provided prompts, and took field notes. L.E.F. is a genetic counsellor, senior research fellow and qualitative methodology expert, providing primary supervision to RP and facilitation of the focus groups. Both researchers are cis-gendered, able-bodied women, with no personal history of cancer or genetic testing. Their positioning was influenced by training in genetic counselling and health services research. Prior to starting the recording, participants were informed of R.P.’s and L.E.F.’s roles. Focus groups were audio-recorded, transcribed verbatim using a secure online platform (Rev.com), quality-controlled to ensure accuracy, and de-identified.

Data Analysis

Following familiarisation, data were analysed using iterative and deductive content analyses [41]. Participants’ scores from the rounds of Nominal Group Technique were collated to identify the most prioritised implementation determinants and strategies. Participants’ implementation determinants were coded to the CFIR [38], to enable a systematic evaluation of the multi-level factors that may influence a recipient-informed implementation approach. The CFIR includes five domains: innovation, inner setting, outer setting, individuals and the implementation process. Under the individuals domain, there is a sub-domain incorporating the Capability, Opportunity, and Motivation Behaviour Model (COM-B) [42]. Behavioural determinants were further interrogated using the linked Theoretical Domains Framework (TDF) [43, 44]. The strategies raised by participants to facilitate implementation of PGS were coded to the Expert Recommendations for Implementing Change (ERIC) compilation of implementation strategies [45], consisting of 73 different strategies bought together through expert consensus, providing a compendium of approaches which can be prioritised and selected to address specific contextual implementation barriers [46]. This approach of analysing participants’ intuitive determinants and strategies and mapping them to evidence-based theoretical implementation frameworks was guided by previous work in the translation of genomics [47–49]. Aligning intuition to theory in this way, blending lived experience with operationalizable, standardised terminology, optimises the likelihood of the future clinical approach with PGS being transparent, comprehensive, efficient, and effective [47–49]. All coding was completed by R.P., in consultation with L.E.F. and N.T. Although inter-rater reliability was not formally assessed, a series of coding meetings ensured coding rigour and iteratively contextualised and refined the frameworks’ constructs for this use-case and context, resulting in two codebooks. Codebooks are available in Supplementary Table 1 and Supplementary Table 2. The focus group operating procedures is available in Supplementary Table 3.

Results

Participants

Twenty eligible participants were identified at the time of recruitment, with ten consenting to participate. Three online focus groups were conducted. Participants’ average age was 36 years old (range 18–70 years). Six participants had negative predictive genetic test results. The average time between receiving PGS-integrated personal risk assessment and participating in a focus group was 30 weeks (range 13–55 weeks). Five participants experienced a clinically meaningful change in their breast and ovarian cancer risk assessment through the addition of their PGS, with their PGS altering their follow-on risk management recommendations according to national guidelines; four participants’ risk changed from population risk to moderate risk recommendations, and one participant’s risk changed from moderate risk to high-risk recommendations. Participant demographics are presented in Table 1.

Table 1.

Participant demographics (^aRisk assessment not completed owing to participant having risk-reducing prophylactic surgery)

Focus group	Sex	Age (years)	State	Time between integrated results and focus group (weeks)	Familial variant predictive results	Standard risk assessment category		Integrated lifetime risk (%)		Integrated risk assessment category
						Breast cancer	Ovarian cancer	Breast cancer (%)	Ovarian cancer (%)	Breast cancer	Ovarian cancer	Change in risk category due to integration
1	F	32	VIC	21.3	BRCA2 negative	Population	Population	10.2	3.5	Population	Moderate	Increased
1	F	38	VIC	41.0	BRCA2 positive	High	High	NA	9.8	NAa	High	Nil
1	F	41	VIC	21.7	CHEK2 positive	Moderate	Population	42.4	1.7	High	Population	Increased
2	F	30	VIC	43.6	BRCA2 negative	Population	Population	21.3	1.5	Moderate	Population	Increased
2	F	27	VIC	13.0	BRCA2 positive	High	High	79.7	7.7	High	High	Nil
2	F	70	VIC	29.3	CHEK2 positive	Moderate	Population	22.4	NA	Moderate	NAa	Nil
2	F	18	VIC	11.4	PALB2 negative	Population	Population	22.7	1.3	Moderate	Population	Increased
3	F	37	VIC	37.4	BRCA2 negative	Population	Population	4.7	0.5	Population	Population	Nil
3	F	30	VIC	25.4	BRCA1 negative	Population	Population	19.9	0.7	Moderate	Population	Increased
3	F	41	VIC	55.4	BRCA2 negative	Population	Population	8.7	0.5	Population	Population	Nil

Implementation Determinants

Fourteen unique determinants were discussed and prioritised (Table 2). Three determinants were common across all groups: (1) recipients’ expectations, knowledge and understanding of PGS and cancer genetics clinics, (2) the availability of good clinical follow-up care (including screening) and support following receipt of PGS and (3) the potential positive impact and value of PGS.

Table 2.

The 14 unique implementation determinants intuitively identified by participants, with three determinants common across all focus groups (shown in bold typeface), interrogated with the CFIR and TDF. Availability of good follow-up care (including screening) and support has been included twice due to applicability across the inner setting (the FCC) and outer setting (community cancer prevention and risk management services)

CFIR domain	Times discussed	Implementation determinant	Quote	CFIR construct	TDF domain
Individuals: recipients	3	Consumers’ baseline expectations, knowledge and understanding	“I think knowledge is power and the more that I feel like I can understand, the safer I feel, the safer my family members can be in the future. So that’s important.” -Participant 12	Capability	Knowledge Beliefs about consequences
	1	Consumer readiness for PGS/life stage of the consumer	“Readiness of the patient to actually take on the test in the first place. Because readiness to actually get that information is very reliant on what stage in your life you are. I know some of my cousins won’t do it because they’ve had kids and the guilt factor is there and they don’t want to know. But then there’s others who want to know because they want to equip the next generation. So I think that’s a big influencing factor in whether someone would do the PGS or not.” -Participant 5	Motivation	Beliefs about capabilities Emotions Goals
	1	Resources (staff, time, funding) in considering availability of PGS and the genetics provider	"I thought firstly the availability of the provider is pretty important. So actually having access to someone who can do a polygenic risk assessment for you and genetic risk assessment for you in the first place." Participant 10	Opportunity	Environmental context and resources
	1	Timing of the appointment/fit with the consumer schedule	"I was lucky that I wasn’t in the process of doing anything else health-wise at the time, but I can imagine if you added it to something else health-wise, it’s just another phone call and it really does blur into the background when you’ve got multiple health things going on at the same time.” -Participant 1	Opportunity	Environmental context and resources
	1	Consumer access to information and education	“Having more information, especially about the [PGS] test, for the general public. I’ve had to do a lot of explaining to friends and other family members. More people would be more engaged in wanting this information. Everyone I’ve spoken to has said that it’s fantastic and they want to get involved, but they don’t know how.” - Participant 7	Opportunity	Environmental context and resources
Individuals: deliverers	1	The knowledge and capability of the genetics provider around PGS	“I thought support skills of the provider was quite important because having the ongoing support and the chats with genetic counsellors in our meetings, it made me more comfortable sharing any concerns I had or any questions [about PGS], knowing that everything I said was valid and I was heard. I think that would help a lot of people going into this knowing the same thing, that their voice is valid, how they’re feeling, it’s okay to feel like that and the providers can support us. I think that’s important. More people would want to do it knowing the positive outcomes that people have had.” -Participant 7	Capability	Knowledge Cognitive and interpersonal skills
	1	Level/quality of support given by the genetics provider		Capability	Cognitive and interpersonal skills
Innovation	3	The potential positive impact and benefit/value of the PGS	“Even though it [PGS] is only slightly elevated, it’s something I definitely wanted to know. I walked away from that second appointment feeling really on top of things and like, okay, I’m prepared. I know that I have to go get screened early. I know what I need to do. It gave me that confidence for the rest of my life, as a big planner." -Participant 11	Relative advantage
	1	How confusing/overwhelming the information about PGS is	“I’m not sure how strong the evidence is for the data. And I didn’t understand what tests had been really done and where the information had come from. So it was difficult for me to understand it entirely.” -Participant 16	Complexity
	1	The strength/quality of the evidence supporting PGS	“I think probably the strength of the evidence for me is the most important because for these things to be useful, we need good evidence to inform action....Strength of the evidence is really important because it clarifies for the counselor, but also the patient about what are the steps now and it makes the information clearer.” -Participant 4	Evidence base
	1	The PGS test having information about other/all cancer risks	I kind of thought that that appointment would have that other information. As someone like non-medical, like myself, knowing that a lot of these [cancers] can be related, I just kind of assumed [the PGS] would include other types, other types of cancers. And then when it wasn’t, it was fine, and I got the information I got...I just assumed there would be more information." -Participant 15	Design
Inner setting	3	Availability of good follow-up care (including screening) and support	“The more resources you have, the more administration you can do, the more follow-up you can do, the more pre-call you can do. And I’d imagine that to an extent the whole process was governed by your resources and what you could manage” -Participant 1	Available resources
	1	Resources (staff, time, funding) in considering availability of PGS and the genetics provider		Available resources
Outer setting	3	Availability of good follow-up care (including screening) and support	"Trying to relay that [PGS] information to my GP and what that meant for me, and saying, oh, I’ve been told that I should consider this and this...They didn’t necessarily have what I would call a good knowledge of what should be done or what the recommendations were to help me." -Participant 10	Local conditions
	1	GP knowledge & awareness of PGS		Local conditions

Participants reflected on how a lack of knowledge negatively impacts understanding, as participant 10 stated, “If you don’t know what it actually is, or you don’t have any knowledge of genetics or polygenic scores, it’s very difficult to understand what that information means.” A high drive for knowledge was a significant enabler of engagement with PGS, as participants felt more information was better than less, and PGS can provide an update to personal risk as well as answering unexplained family history.

“I’m a person who really wants to know or wants all the information. I knew that the BRCA2 gene was coming from my father’s side of the family, but I also had a really strong history of breast cancer and ovarian cancer on my mother’s side of the family. We didn’t know necessarily what was coming from that side. I thought this might be interesting or add more information to the picture.” (Participant 1).

Good clinical follow-up was defined by participants as supportive ongoing contact by the clinical cancer genetics service to help patients by answering questions, reminding them of the information, making next steps clear for them and their family members, and ensuring compliance with risk management recommendations. Participant 15 shared, “Generally speaking, it’s a lot of information and understanding everything that’s going on and the emotional factors in the appointments. Having time to pass and understand all that information and then really be able to take it on board [is needed]. Follow-up is really important. It’s all well and good for doctors to say, this is your risk, this is what you should do…But if there’s no follow-up, people might not follow the recommendations.”

Positive impact and value of PGS was discussed in several ways, including: the potential for PGS to influence recipient risk management decision-making and behaviour, the potential for PGS to influence the risk management decision-making of family members, the impact PGS results may have on life planning, such as when to have children, and the potential of PGS results to provide recipients with peace of mind or reassurance regarding their hereditary breast and ovarian cancer risk. Illustrative quotes are presented in Table 3.

Table 3.

Participants considerations of value and impact of PGS for HBOC risk assessment

Positive impact and value of PGS for HBOC risk assessment
The potential for PGS to influence recipient risk management decision-making and behaviour	“I wanted the numbers. I like numbers, I like to know specifics, but also it would have shaped my plan going forward for my own health in terms of, we are not planning to have kids, but whether it would shape a hysterectomy earlier or later. And so those numbers were important to me because I had a threshold in my brain that I was like, if it’s this, then I’m doing plan A, and if it’s not this, it’s plan B.” -Participant 1
	“I don’t know that it impacted my decision-making process too much, having the additional information…I think it hasn’t ultimately changed what choices I was going to make.” -Participant 10
The potential for PGS to influence the risk management decision-making of family members	“I took it as it can help influence my family members to also want to do [PGS] genetic testing to...know what their result is and know how it’s going to affect them. I think, hopefully, [me having testing ] will have a positive influence upon them to want to do it just to see for themselves what their future might look like or anything like that.” -Participant 3
The potential impact PGS results may have on life planning, such as when to have children	“Influencing decisions, specifically around family planning. I’m pregnant at the moment [and] personalized risk really helped me think what order do I do things in knowing that I have this (risk). What I decided is let’s do that [pregnancy] now, and then I can have my surgeries if I need to. Aalso thinking about preparing my children to have the same results as I do. So I’ve had ideas like having a savings fund if they want to do IVF for their children or something that I couldn’t quite afford to do.” -Participant 7
The potential of PGS results to provide recipients with peace of mind or reassurance regarding their hereditary breast and ovarian cancer risk	“I want to know what’s to come, what I can do to prevent these things, what would happen, how I will act if these things do appear in my life. So it’s reassuring to know what I can do, get screened early and where I can go, where I can access help, who I can go to.” -Participant 11
	“I didn’t have the gene, which was a very pleasing result and unexpected...I kind of thought when I left the appointment, cool, I’m in the clear, I’m just a normal population risk. But then, getting the PGS, they were like, you’re actually at moderate risk compared to the population. And it was quite different to just a yes or no, you have the gene or not. So that was disappointing. Not disappointing, but a bit fear-mongering, like, get your life together and do what you can in terms of managing that slightly increased risk.” -Participant 15

Other implementation determinants included recipient readiness to receive their PGS, general practitioners’ awareness and knowledge of PGS, cancer genetics clinics’ resources (including staff, time, and funding) in considering access to PGS, the strength and/or quality of the evidence supporting PGS, how confusing the information about PGS is, and the knowledge and capability of genetics providers to deliver PGS.

Interrogating these determinants with the CFIR and TDF revealed that behavioural determinants relating to recipients were most frequently discussed by all groups, with the focus spread across all three conditions of behavioural change under the COM-B. Opportunity was an important condition, reflecting the focus on recipients being within the right environmental context with the right resourcing to access and use PGS effectively. As was deliverer capability, in considering their knowledge and cognitive and interpersonal skills to deliver PGS in a competent and supportive manner. Determinants related to PGS as an innovation, notably relative advantage, evidence base, complexity, and design were prioritised. In the inner setting, available resources were highlighted. Finally, in the outer setting, local conditions was the only determinant construct discussed, referring to the economic, environmental, political, or technological conditions that would influence recipients accessing PGS and the recommended medical follow-up.

Implementation Strategies

Ten intuitive strategies were identified (Table 4), with four being common across all groups. All participants prioritised: (1) a clear PGS results report that could be used with patients in their genetics appointment and/or afterwards, (2) resources (including advertisements) being distributed to the general community to raise awareness of PGS and the cancer genetics clinics where PGS is available, (3) provision of educational and supportive resources to patients during engagement with the cancer genetics clinic and (4) cancer genetics clinics providing a follow-up care program.

Table 4.

The ten unique implementation- and PGS-focussed strategies intuitively identified by participants, with four strategies common across all focus groups (shown in bold type face), interrogated with the ERIC compilation of facilitative implementation strategies

Times discussed	Implementation strategy	Implementation-focused	PGS-focused	ERIC compilation category	ERIC compilation strategy
3	A clear PGS result report to be provided to/used with patients	X	X	Engage consumers	Intervene with consumers to enhance uptake and adherence
				Support clinicians	Facilitate relay of clinical data to providers
3	Providing resources (including advertisements) about PGS and FCCs to the general community/clinical centres/GP offices	X	0	Engage consumers	Intervene with consumers to enhance uptake and adherence
					Prepare consumers to be active participants
				Train and educate stakeholders	Develop and distribute educational materials
3	Directly providing the patient with educational and supportive resources	X	0	Engage consumers	Intervene with consumers to enhance uptake and adherence
					Prepare consumers to be active participants
				Train and educate stakeholders	Develop and distribute educational materials
3	Have a follow-up care program	0	X
2	Provide a clear summary letter following the genetics appointment	X	X	Engage consumers	Intervene with consumers to enhance uptake and adherence
2	Ensure the genetics appointment is timely/within an efficient care pathway	0	X
1	Train the deliverers for PGS	X	0	Train and educate stakeholders	Conduct ongoing training
1	Provide patient testimonials/examples/advocate stories	X	0	Engage consumers	Intervene with consumers to enhance uptake and adherence
1	Ensure PGS is delivered with genetic counselling	0	X
1	Provide a peer-support group option for patients going through PGS testing	X	0	Engage consumers	Intervene with consumers to enhance uptake and adherence

Participants discussed how resources throughout the PGS results appointment would be helpful. Some participants were shown their research PGS results report and had a favourable response, with Participant 7 stating that the report enabled her to “walk away feeling like I really knew what was going on”. Conversely, other participants wanted further supportive resources, such as a plain language summary, as Participant 4 describes, “I think it’d be good to have something to follow along with while it’s being explained to you so you can read along. And for me, it’s good to have the visual and to hear someone explaining to me at the same time, maybe some graphs and some other visual aids might help.”

With the patient resources, one group emphasised that these needed to be culturally appropriate and tailored for different language groups and comprehension levels. Two groups felt that the patient resources needed to contain information about how to speak to family members about PGS and family support pathways. There was a focus on increasing the volume of educational resources to the general public, as Participant 5 summarises, “I think a lot of people who do the genetic test have some idea of why it’s important for them, but I think probably in the community there needs to be more awareness and almost advertising about the pros and cons of doing it, because a lot of people don’t realize why, don’t know why, don’t know that these tests are available and if they are eligible.”

Of note, participants discussed strategies for facilitating clinical implementation, strategies which were focussed on PGS to improve implementability, and strategies that could be categorised as both. In considering PGS, participants highlighted that PGS should be delivered with a clear results report and summary letter, within a timely and efficient care pathway, which includes genetic counselling and an established follow-up care program. Timing was a focus. Delays receiving results due to the research processes resulted in anxiety, with wait time being seen as, “the only downside of it [PGS]” (Participant 7). Anxiety was felt more in advance of the predictive genetic test result than the PGS results, with many participants describing feeling no anxiety about their integrated risk assessment appointment, as Participant 1 reflected, “The first time around I was a bit anxious. I guess I also knew it would come out the way it did. I was 50/50 chance. I also knew that it would upset my mother because she’s still experiencing her own sense of guilt, as nonsensical as we all know that is, about passing on the gene. The second time around it was more a little bit of clarification, a little bit more of extra information. It was just more interesting to know.”

Overall, the implementation-focused strategies had little variance, predominantly focusing on either engaging recipients or training and educating interest-holders. Engaging recipients involved different resources designed to increase patient awareness and feelings of support, such as through patient testimonials or support groups, or to better enable patients to be active participants with PGS. Training and educating interest-holders focused on the development and distribution of educational materials and conducting ongoing training.

Discussion

This study utilised evidence-based implementation frameworks to explicitly identify determinants and strategies for the implementation of PGS for personalised HBOC risk assessment in the Australian cancer genomics setting. Participants identified key determinants that will influence the success of national implementation, including perceived utility or value of the information, knowledge and expectations of PGS, and opportunity to access and meaningfully engage with PGS. These determinants will need to be accounted for, and addressed, in any future implementation approach. Additionally, participants’ discussion of strategies should contribute to the eventual delivery model of PGS in practice, where the model should be timely and efficient, incorporate a results report and correspondence, and include genetic counselling and a follow-up care program. Implementation strategies which require resourcing include community education materials to raise awareness of, and preparedness for, PGS, and educational and supportive resources for use within the cancer genetics clinics themselves.

The implementation determinants and strategies raised by participants overlap with those described in other focus group studies examining PGS in different use-cases and contexts. Sabatello et al. identified that time management and juggling competing priorities, motivation, low health literacy in the community, and structural challenges such as financial instability, insurance, and lack of community resources and health-supporting infrastructure, are core barriers to recipient access to PGS and behavioural change in response to PGS results [29]. The same recipients also highlighted having genetic counselling, resources, and follow-up care, including ongoing hands-on interaction and correspondence with a multi-specialist clinical team, as supportive for behaviour change [29]. Research into risk-stratified breast cancer screening in general population programs has cited low recipient knowledge and understanding, and financial and insurance concerns, as implementation barriers [28, 50], with facilitative strategies including multi-interest-holder education and communication aids [51]. In a more diverse recipient group, financial and insurance barriers were again reiterated, as well as low understanding of PGS, and other socioeconomic factors affecting access, citing race, ethnicity, and language as challenges to patient-centred clinical implementation [52].

Our participant group focussed on the potential positive value of PGS as a major determinant, value that was described predominantly outside of the typical representation of clinical utility in terms of improved medical outcomes or reduced cancer mortality and morbidity. Establishing clinical utility of an innovation is considered to be essential before progressing wider clinical implementation [53]. However, clinical utility can be subjective and summative measure of healthcare value [54], open to bias and inconsistent definition [55].

Venning et al., in their study of multi-cancer PGS in the Australian general population, found PGS results changing a person’s cancer screening to be a minimally important attribute, with PGS accuracy and cost perceived as being much more valuable in implementation [56]. This highlights the importance of other factors or forms of utility being relevant evidence in decision-making around implementing PGS, such as personal utility (the broad value of knowledge gained from PGS) or public health utility (socio-economic value) [24].

Personal utility can capture non-clinic or non-medical outcomes or benefits from an innovation [57]. As co-design is increasingly emphasised in healthcare research to enhance patient-centeredness and shared decision-making in clinical practice, personal utility is becoming increasingly discussed [24]. Whilst notions of what personal utility means in the monogenic setting have been shown to be influenced by several factors, including perceived severity of the condition [58] and impact of the condition on the family [59, 60], this is an under-researched area in considering PGS integration, including consideration of whether recipients’ beliefs or expectations of PGS accurately reflect the possible outcomes from the test. Further research into how personal utility of PGS is defined and experienced for recipients is needed so that future approaches towards informing recipients and communities about the value of PGS are holistic and representative, and therefore more likely to facilitate uptake. However, there is a clear tension here between delaying implementation of PGS whilst waiting for the evidence of personal and clinical utility to mature, and the opportunity costs incurred by not delivering an innovation perceived to bring value and benefit to patients and families.

The behavioural determinants of recipients, notably their knowledge, understanding and expectations, were highlighted. Recipient genomic literacy has been discussed as a major barrier to successful implementation, with commentaries raising concern that PGS information is complex in nature, and therefore difficult for recipients to adequately understand [23, 61]. Preliminary evidence suggests there are recipient knowledge gaps with breast cancer PGS [62]. In the same disease context, other studies have demonstrated women having good understanding of PGS information [30, 31, 63, 64]. Effective deliverer communication has been emphasised to mitigate risks from recipients’ incorrect interpretation of PGS [65], as well as beliefs of genetic determinism or essentialism [66]. This connects with the consistent recommendation of developing co-designed, educational and clinical decision-support resources and tools for deliverers and recipients [67], and the adaption of current training programs to ensure adequate deliverer competency [61].

Alongside this concern, there is an ongoing discussion on whether PGS information will indeed impact recipients’ cancer risk management decision-making. Achieving a level of proven clinical utility and effectiveness of PGS in this HBOC use-case will be determined by recipient’s ability and willingness to adopt the consequential recommended risk management strategies [29, 52]. Risk management decisions around HBOC are innately complex owing to the recommended interventions carrying significant and multi-layered physical and psychosocial risks [67]. Providing a more refined assessment may enable women to change or delay risk management timing. For example, an unaffected woman with a pathogenic variant in PALB2, who has a low-risk breast PGS, may be stratified to moderate risk of breast cancer rather than high risk, removing the recommendation for prophylactic bilateral mastectomy. However, there is little available evidence on real-world, actual short- and long-term behavioural change following receipt of PGS information alone, or within an HBOC risk assessment.

One systematic review of behavioural outcomes of recipients following receipt of PGS information showed that positive behavioural changes were seen, including changes to lifestyle (such as lowering alcohol), increased communication with healthcare providers, and adherence to recommended risk management [68]. Women with BRCA1 and BRCA2 PVs have stated that PGS information would influence their screening, lifestyle, and risk management decision-making, including their decisions around prophylactic risk-reducing surgeries [28]. Women who have received a high PGS for breast cancer have reported feeling more aware of risk and empowered to act on risk management recommendations [30]. Women with or without an identified HBOC PV, who were then given PGS results, have demonstrated risk management decisions concordant with their integrated risk assessment [62, 69]. One of the difficulties in examining recipient behavioural change following receipt of an integrated HBOC risk assessment is determining which factor(s) within the risk assessment are impacting behaviour. Women have reported not using PGS to guide their cancer screening or risk management and prevention behaviours when other risk factors, such as family history, exercise level, or alcohol intake, were presented to them [50]. These factors impacted their risk perception (and resulting behaviour) more dramatically than their PGS [70].

There is mixed evidence as to whether genetic results impact risk management and lifestyle changes, and therefore lower disease risks [71–73]. A deeper understanding of the impact of PGS information on patient behaviour is needed [74]. Removing barriers to behavioural change will also be vital if improved outcomes are to be had [29]. Finally, using behavioural change theories (BCTs) to design interventions may also be an enabler [68, 75]. For example, recipient capability was identified as a major implementation determinant. Education is a primary intervention function; providing recipients with information on how to act on PGS, and the health, social, and environmental consequences of acting on PGS, having prompts or cues for action, and providing resources that can give feedback on the outcomes of their risk management behaviours are all evidence-based ways to improve knowledge and overall recipient capability with PGS [44, 76]. Similarly, BCTs relating to the environmental context may assist with recipient opportunity, such as restructuring the physical and social environments (in cancer genetics clinics, general practice offices, and other cancer risk management centres) to remove aversive stimuli or add encouraging stimuli, to better enable recipients to engage with and access PGS [44, 76]. An example of this was raised by all focus groups, in the form of providing educational resources and advertisements about PGS in these locations.

Creating recipient opportunity with PGS may be harder to address due to the complexities and idiosyncrasies inherent in ever-changing healthcare, socio-political and cultural settings, and resourcing bottlenecks [77]. Whilst participants focused on resourcing barriers in the cancer genetics clinic and outer community settings, vital access factors were not discussed, such as presence of policies, regulations and guidelines, or the networking, costs, and systems infrastructure needed to update ongoing clinical follow-up and risk management processes. Participants did raise a key opportunity strategy in educating and training deliverers, but, ultimately, trained deliverers will not be helpful if they are not accessible to recipients [66]. Access to HBOC predictive testing is already negatively impacted by availability of genetic counsellors (particularly in remote areas), inefficient referral processes and financial barriers, with non-English speakers and other marginalised groups experiencing additional systemic challenges [78–80]. These barriers will continue to be relevant in considering the future implementation of PGS [23].

The methodology used in this study is valuable for the next steps in national clinical implementation. Participants raised implementation determinants and strategies based on their personal experiences with PGS. These intuitive strategies are therefore highly authentic and appropriate for the HBOC risk assessment use-case and context. Aligning these determinants and strategies to theory-informed implementation frameworks provides a standardised terminology and structured approach to planning, testing, and evaluating strategies within a national implementation trial [47–49, 81, 82]. Being able to consistently record strategies will optimise the opportunity for researchers and clinicians to understand how strategies have impact, identify where improvements can be made, and enable the transfer of an implementation approach to other use-cases and contexts [47–49].

There were limitations to this study. Although our focus groups had a broad range of ages and experiences with PGS in hereditary cancer risk assessment, our total participant number was small. This means our findings may not be fully representative of the views or priorities of the broader community. Additionally, owing to the focus group methodology and language of the facilitators, only English-speaking individuals were able to participate. It is unknown whether non-English-speaking women would have different views or priorities regarding the clinical implementation of PGS in cancer genetics clinics.

Conclusions

Recipients are interested in, and motivated for, PGS for HBOC risk assessment, and identified key determinants and strategies to facilitate clinical implementation. If the intention is to implement PGS in HBOC risk assessment to better stratify individuals and improve the tailoring of risk prevention and management programs, the Australian clinical cancer genetics sector must integrate and centralise the voices of recipient interest-holders into implementation design and delivery. If delivery is not recipient-centred, uptake will be compromised, resulting in unsatisfactory clinical outcomes and wastage of research and clinical investment [33]. Further research exploring recipient perspectives on implementation determinants, strategies, and priorities is needed to enable successful nationwide delivery. These efforts should involve a bigger, more diverse recipient group, and additionally focus on better elucidating and understanding the behavioural determinants of recipients acting on PGS information, perspectives on PGS’ clinical utility, and preferences for co-designing interest-holder education and supportive resources. These evidence needs call for a national implementation trial to further examine recipient perspectives and behaviours, and the impact of evidence-based implementation strategies in practice.

Supplementary Information

Below is the link to the electronic supplementary material.

Declarations

Funding

Open Access funding enabled and organized by CAUL and its Member Institutions. This research was conducted as part of a postdoctoral research program, funded by a PeterMac Foundation Lester Peters Scholarship and an Australian Government RTP Scholarship.

Conflict of Interest

L.F. is an Editorial Board Member of The Patient. She was not involved in the selection of peer reviewers for the manuscript, nor any of the subsequent editorial decisions. The remaining authors declare no conflicts of interest. 

Data Policy and Availability

The de-identified data supporting the conclusions of this article will be made available by the authors on request.

Ethics Approval

The study was conducted in accordance with the World Medical Association Declaration of Helsinki and approved by the Human Research Ethics Committee at the Peter MacCallum Cancer Centre, Victoria, Australia (HREC 64060/PMCC; approved October 2022). The privacy rights of all participants have been observed.

Consent to Participate and Publish

Informed consent was obtained from all participants involved in this study.

Author Contributions

Conceptualization, R.P., N.T., P.J., M.-A.Y. and L.F.; methodology, R.P., N.T., P.J., M-A.Y., and L.F.; validation, R.P. and L.F.; formal analysis, R.P. and L.F.; investigation, R.P. and L.F.; resources, N.T. and L.F.; data curation, R.P.; writing—original draft preparation, R.P.; writing—review and editing, R.P., N.T., P.J., M.-A.Y. and L.F.; visualization, R.P.; supervision, N.T., P.J., M-A.Y. and L.F.; project administration, R.P.; All authors have read and agreed to the published version of the manuscript.