Stakeholder attitudes towards establishing a national genomics registry of inherited cancer predisposition: a qualitative study

Abstract

This study aimed to describe the acceptability and perceived barriers and enablers to establish a national registry targeting carriers of pathogenic variants in cancer susceptibility genes from stakeholders’ perspectives. Such a registry may effectively target carriers to translate existing research findings into optimised clinical care and provide a population-level resource for further clinical research and new gene and therapy discovery. In-depth interviews were conducted with individuals from four stakeholder groups: carriers of pathogenic variants, healthcare professionals, data custodians from the field of familial cancer, and heads of molecular pathology laboratories. Interview data were subjected to a qualitative analysis guided by a thematic analysis framework using NVivo software. A total of 28 individuals were interviewed: 11 carriers, 8 healthcare professionals, 5 laboratory heads, and 4 data custodians. All carriers and healthcare professionals were enthusiastic about the potential research applications of the registry. Carriers described that altruistic motivations provided the foundation of their support of the planned registry. Some carriers felt comfortable with a broad consent (consenting once, prospectively), while others preferred a narrow consent approach (consenting each time data is accessed). Some carriers and data custodians and registry developers also expressed a reluctance to link family member data without appropriate consent. Participants’ enthusiasm and support for a national registry herald a productive and responsive research partnership once the registry has been established. Participants’ views can be used to inform the approaches to be taken to develop and manage such a registry as an implicit codesign approach.

Supplementary Information

The online version contains supplementary material available at 10.1007/s12687-021-00559-8.

Introduction

Tracking and monitoring carriers of pathogenic and likely pathogenic variants in cancer susceptibility genes is crucial due to the high cancer risks faced by carriers (Kuchenbaecker et al. 2017) and the availability of effective cancer prevention and surveillance strategies (Evans et al. 2013; Rebbeck et al. 2004, 2009; Jarvinen et al. 2000; Burn et al. 2020). Focussing research efforts and clinical services on carriers of cancer-related pathogenic variants is also likely to have a significant impact on population cancer incidence and outcomes to reduce costs to the health system (D'Andrea et al. 2015) and to accelerate discoveries for the general population due to the opportunity to trial novel agents efficiently in a genetically determined population (Burn et al. 2020; Moore et al. 2018; Puiade-Lauraine et al. 2017; Mirza et al. 2016).

Classic criteria for an offer of genetic testing include a strong family history (Meiser et al. 2008; Trainer et al. 2010), younger age at cancer diagnosis, and membership in an ethnic group with a high incidence of founder pathogenic variants (e.g. Ashkenazi Jewish background) (Meiser et al. 2008; Trainer et al. 2010). A number of factors have led to the increasing use of genetic testing of cancer susceptibility genes. Aside from the falling costs of all types of genetic tests (Aronson 2015), these factors include the expansion of indications to include certain tumour tissue characteristics (Meiser et al. 2008; Trainer et al. 2010) or indeed universal tumour testing for colorectal cancer (Cancer Institute NSW 2018; Clinical Oncological Society of Australasia & Human Genetics Society of Australasia 2018). The utility of genetic testing in determining the suitability of targeted treatments, e.g. poly (ADP-ribose) polymerase (PARP) inhibitor, for BRCA-mutated human epidermal growth factor receptor 2 (HER2)–negative breast cancer (Tutt et al. 2021) and BRCA-mutated platinum-sensitive high-grade epithelial ovarian cancer patients (Moore et al. 2018; Puiade-Lauraine et al. 2017; Mirza et al. 2016; Department of Health 2021a) has also contributed to an increase in the number of patients for whom genetic testing is recommended. In addition, in many countries, the introduction of national or state funding, such as through the National Health Service in the UK or the Medical Benefit Scheme in Australia (Department of Health 2021a, b), for testing for specific cancer predisposition syndromes (Department of Health 2021a, b) has also made it easier for non-genetic healthcare professionals to directly order genetic testing, without involvement of a specialist genetic service.

The increasingly widespread use of genetic testing will inevitably lead to identification of more pathogenic variant carriers in less traditional settings. It is therefore even more important to be able to systematically track and contact carriers regarding new clinical information and research opportunities if their genetic status is to be translated into improved personal and population-based health outcomes. A registry of carriers of pathogenic variants in cancer-related susceptibility genes would appear to be the ideal vehicle to follow up and contact carriers. In Australia, no national registry exists comprising specifically carriers of cancer-related pathogenic variants, although national hereditary cancer registries focusing on people at risk for Lynch syndrome and familial adenomatous polyposis (FAP) have been available in many countries, e.g. in the Netherlands (Vasen et al. 2016), for several decades. Evidence from well-designed cohort or case–control analytic studies demonstrate that registration and coordinated screening in patients with FAP and Lynch syndrome results in a reduction of colorectal cancer incidence and mortality (Barrow et al. 2013a). This lends strong support to the future establishment of registries for carriers of pathogenic variants related to a wide range of cancer syndromes. In particular, the European Reference Network on Genetic Tumour Risk Syndromes (Vos et al. 2019) has a broad focus in that it is aimed at all patients in Europe with a known hereditary cancer predisposition to have their de-identified data included in one or more network database or registry and to be contacted about the possibility to participate in specific research projects (European Reference Network Genetic Tumour Risk Syndromes (ERN GENTURIS) and www.genturis.eu, Accessed 18 April 2021).

Currently in Australia, the only comprehensive centralised information for people with inherited cancer syndromes is the Inherited Cancer Connect (ICCon) database, which is a database of all adult carriers of germline pathogenic variants in cancer predisposition genes identified up to December 2016 through predominantly publicly funded specialist familial cancer clinics. The current ICCon database has enabled, for the first time, data on almost all carriers of pathogenic variants in high-risk cancer predisposition genes in Australia to be held in one place, housed outside of the usual clinical institutional and state data silos. It has generated aggregated/re-identifiable clinical data that can be extracted to (a) offer clinical benefit, (b) provide supportive data for health policy decisions, (c) respond to feasibility enquiries for clinical trials, and (d) identify those carriers who are eligible to participate in specific trials or who may benefit from new advances in therapeutic interventions in partnership with their submitting familial cancer clinic (Tumours and https://www.cart-wheel.org, Accessed on 18 April 2021). Moreover, the ICCon database has established relationships with the international consortia Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (Alleles and https://enigmaconsortium.org, Accessed on 18 April 2021; Spurdle et al. 2012) and the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (Tumours and https://www.insight-group.org, Accessed 18 April 2021) to review the classifications of variants in cancer predisposition genes in the ICCon database for pathogenicity against international gene-specific classification criteria for the purpose of consistent classification of variants across Australia. These efforts facilitated interaction with family cancer clinics to obtain clinical information to support variant interpretation and inclusion of data in research publications.

The current structure of the ICCon database unfortunately limits its utility, primarily because the ethical restrictions associated with the submission of data prevent direct identification of, and contact with, the people entered into the database; currently identification and contacting of carriers on the ICCon database must occur via their familial cancer clinic. The development of the ICCon database into a registry structure, on the other hand, would allow identification of, and contact directly with, the participants and expand opportunities for clinical and research studies. The main difference between a registry and a database is that, in the registry format, participants consent to be included as their data is stored in an identified format. This has a notable/distinct advantage for people in the registry as they can be personally kept up-to-date with recommendations about their clinical care and informed about available research opportunities. The Australian government and state and territory governments fund a range of services, with the Australian government being responsible for Medicare and the Pharmaceutical Benefits Scheme, whereas state and territories are responsible for funding of public hospitals, including laboratories associated with public hospitals, cancer registries, and cancer screening services (Australian Institute of Health and Welfare 2016). The broader advantages for healthcare would come from the ability to have a direct linkage of the registry with these state-based and national datasets. Linkage with such datasets would underpin clinical healthcare decision-making at a local and national level, enable research participation, and provide the most efficient way to guide many research projects in terms of development and implementation.

Given the potential, the ICCon database has already demonstrated for data linkage and meaningful impact for consumers and patients (Forrest et al. 2018); its transition into a formal registry is warranted. This qualitative study aims to describe the acceptability and perceived barriers and enablers to establish a national registry of individuals with a germline pathogenic variant in a cancer syndrome gene from the perspectives of all stakeholders to inform the decisions and plans for developing a registry from the ICCon database.

Methodology

Participants

Interviews were conducted with four stakeholder groups to achieve a comprehensive description of views from all relevant perspectives: (i) carriers of pathogenic variants from the ICCon database, (ii) healthcare professionals from the field of familial cancer, (iii) data custodians and registry developers from the field of familial cancer, and (iv) heads of genetic testing laboratories. Decisions about which stakeholder groups to include were made by the authors while taking into account the relevant literature. Participants were eligible if they were 18 years and above and able to provide informed consent. Exclusion criteria were as follows: cannot communicate in English and cognitive impairment.

Recruitment

Carriers of pathogenic variants and healthcare professionals were recruited through familial cancer clinics across Australia, by letter, while data custodians and registry developers were invited by email. Data managers and data custodians of known registries in Australia and overseas were invited to participate in an interview. Registries were identified through clinical and research networks. Heads of laboratories were invited by asking familial cancer clinics which laboratories performed their clinical testing, and who the heads of laboratories were. Familial cancer clinics also identified other senior laboratory members, who participated when the head of laboratory was unresponsive or declined. Patient, healthcare professionals, and heads of laboratories were sent the invitation letter along with the participant and information and consent form, opt-in response sheet, and a replied-paid envelope, while data managers and data custodians emailed the participant and information and consent form. Participants who opted into the study were contacted by telephone by the interviewer to assess whether they had any additional questions and to answer these questions, to determine their interest in participating, and to arrange a convenient time for a telephone interview. Up to three reminder letters or emails were sent.

Procedure

Sampling was continued until informational redundancy was achieved (Miles et al. 2014). In-depth, semi-structured individual interviews were conducted in-person (two heads of laboratories) or by telephone (remaining interviews). All interviews were conducted by clinical researchers and genetic counsellors with a research background; interviews with carriers were conducted by MM, healthcare professional interviews by RA, data custodian interviews by LS, and interviews with heads of laboratories by EC and CN. All interviewers were trained in interview skills by RK; RK is an experienced qualitative researcher with a background in public health. The interview guides were specific to each stakeholder group, while leaving the specific wording and sequencing of questions open. Table 1 shows the topics covered in interviews with each stakeholder group. The interview guide for carriers, healthcare professionals, data custodians and registry developers, and heads of laboratories are included as Supplementary Files 1, 2, 3, and 4, respectively. Interview guides were modified over the course of the study by including additional lines of questioning to ensure that emerging themes were fully explored. Each interview was audiotaped and transcribed verbatim using a professional transcription service.

Table 1.

Topics covered in interviews with each stakeholder group

Stakeholder group	Topics covered in interviews
Carriers of pathogenic variants	(i) Acceptability of a registry (ii) Benefits of a registry (iii) Who should and should not have access (iv) Concerns about a registry (v) Whether they wished to be asked permission each time access to their records is requested (vi) Information they would prefer not to be shared (vii) Feelings about linkage with other databases including international databases; and (viii) Comfort with the registry contacting their managing specialists directly
Healthcare professionals	(i) Possible uses and benefits of a registry, in particular how a registry can support the management of mutation carriers (ii) Who the best person is to consent carriers to a registry (iii) Concerns about a registry
Data custodians and registry developers	(i) Important functions of a registry (ii) Considerations for a group setting up a national genomic registry (iii) Perceived enablers and barriers to the successful running of a registry (iv) Concerns about a registry
Heads of laboratories	(i) How interviewees thought a registry could assist in workflow at the testing and variant calling level (ii) What variant classifications should be entered into the registry (iii) Who from the laboratory should and should not have access (iv) How data within a registry should be used

Data analysis

Thematic analysis was used to guide data analysis (Braun and Clarke 2006). Transcripts were coded using NVivo 10 qualitative data analysis software to categorise the data and facilitate comparison of subgroups of participants (e.g. affected and unaffected carriers). The qualitative analyses were undertaken by the interviewer of each participant group, except that the data custodian interviews and two of the interviews with carriers were analysed by CN, who is a genetic counsellor. All individuals involved in the qualitative analyses were trained and supervised by RK. The coders for each of the participant groups and RK reviewed the first transcript for each group for early themes and concepts, from which the preliminary coding scheme was constructed, and the coder then coded all transcripts, revising the scheme iteratively to reflect emergent themes from interview responses for each group. The coders for each group drafted the results for each of their participant groups and selected illustrative quotes.

Results

A total of 77 letters of invitation were mailed out (see Fig. 1). Of these, 37 did not respond, 10 declined participation, and 2 were ineligible to participate, leaving 28 who were interviewed. All interviews were transcribed. They were from the following groups: carriers (n = 11), healthcare professionals (n = 8), data custodians and registry developers (n = 4), and heads of laboratory (n = 5).

Fig. 1.

Overview of stakeholder groups interviewed

Interviews with carriers of pathogenic variants

Sociodemographic and medical characteristics of the carrier group are shown in Table 2. There were no differences in views between affected and unaffected carriers.

Table 2.

Sociodemographic background characteristics of carriers of pathogenic variants

Characteristic	Carriers n = 11
Gender
Male	2
Female	9
Age
18–29	0
30–39	2
40–49	2
50–59	5
60 +	2
Familial cancer condition	Gene (n)
Hereditary breast and ovarian cancer	BRCA1 (5); BRCA2 (2)
Lynch syndrome	MLH1 (1)
Birt-Hogg-Dube	FLCN (1)
Familial adenomatous polyposis	APC (1)
Hereditary leiomyomatosis and renal cell cancer	FH (1)
Cancer diagnosis	Type
Yes	8
No	3
Education
High school	3
Vocational training	2
University degree	4
Not specified	2
Employment
Full-time	5
Part-time	1
Retired	3
Not specified	2

A potentially powerful and necessary tool to enable and promote research and clinical care

Carriers expressed their understanding of the need for, and utility of, a national genomics registry and supported it in theory. Many carriers independently came to focus their understanding of the registry on the more altruistic motivations for its existence rather than whether they could personally benefit from it. Altruistic motivations related to future generations in particular were described. Specifically, carriers described being motivated to contribute to research efforts and share their medical/genetic information to reduce the impact of familial cancer conditions on future generations, as exemplified by one carrier who said:

I just think, I think the more info we can supply, I think the better it's going to be for future generations, I think.

However, altruistic motivations were also described in relation to benefiting relatives in the future. In particular, carriers described being motivated to contribute to research to ensure genetic information was accessible and available for relatives in the future and to know that their experience, while difficult, might be used to benefit the lives of others, as described by one carrier:

If there’s some sort of treatments or programs or something you can do to try to help, then yes it good to know those are out there.

Acceptability of accessing registry data depends on the motivation and aim for its use

Carriers were unequivocally supportive of the registry data being accessed by health/medical researchers and clinical services. However, regarding government and pharmaceutical companies, opinions were divided. In particular, some carriers expressed hesitation regarding access by the government (e.g. state/territory health departments) and pharmaceutical companies, as they were concerned that the data may be used to further their own agenda or for financial gain. Some carriers concluded that the most important factor was the goal of improving the lives of the population or developing beneficial therapies, as illustrated by one carrier:

If they’re not going to manipulate the information, they’re going to use it ethically and it’s going to help with medications in the future, making them better because they’ve got the more actual information, I […] would be okay with that.

Provided that improving the lives of the population or developing beneficial therapies was the main motivation, profiting financially was not seen as a reason to prevent access to the registry data.

The possibility of the registry being used to link relatives was considered to have both benefits and limitations. While carriers could see the value in sharing information across geographical boundaries and were supportive of the registry being used to reduce barriers to accessing genetic testing and healthcare, they believed that some relatives may not want to be linked due to fractured families or estrangement. Some carriers expressed reluctance to link family members without appropriate consent, as illustrated by one carrier, who said:

Well, if they are happy to be linked, they need to be - like I’m okay with them to be linked to me but they might not want to be linked you know what I mean?

Most carriers described a preference for minors to not be included to prevent negative implications for their future and to enable them to choose whether to be included on the registry as adults, as exemplified by one carrier who said:

I wouldn’t want my kids to be included in it, so I don’t know if that would be even considered or whatever but I want that to be their choice.

Carriers also considered the type of consent required for inclusion on the registry. Most participants felt comfortable with a blanket (once-for-all) consent, as exemplified by the following participant:

No, no , that would be just a pain in the butt I think […] So I’m quite happy that anybody that wants to access it can.

However, some suggested that additional consent may be desired by registry members when identifiable information is being accessed:

If they’re just doing stats and research on, you know, numbers and demographics all that kind of stuff, that’s what like ‘Go for it’ I wouldn’t want to be contacted for that. If they were able to access that [information] where they could identify me then I would want to know about that.

By contrast, others preferred a more dynamic consent approach with regular consultation when their data is accessed. For example, one carrier said:

I think from the outset I would prefer to be notified of when that information can be accessed and by whom, just to see that I’m still comfortable with who and the purpose, who’s accessing that information and for what purpose because then if for some reason I thought it wasn't in line with what I thought it would be being used for then I would like I guess [request to] pull down my data. So yeah, definitely from the outset it’s just making sure, yeah, I'm comfortable with who and why that's been used.

Responsibility for safeguarding information about carriers lies with the registry committee

Carriers suggested that specific criteria should be established by the overseeing committee for allowing access to the data. They felt it was vital that any groups accessing data were vetted to ensure their motivations and purpose for seeking access are ethical; however, they felt comfortable with placing this responsibility with the registry oversight committee. Interestingly, the interviews with carriers showed an implicit trust in the registry committee to oversee the data governance processes despite not having been given any information on the function or composition of such a committee. As one carrier said:

And I know that you guys won’t let people just take the - like unless they need it pretty much. That’s what I gathered from all the, from what I’ve read and that you know you guys will decide on who is going to access it.

Carriers recommended that serious consideration be given to the storage and security of the data but also expressed confidence in the committee managing the registry to safeguard their information and to make appropriate decisions about permitting data access.

Registry as a conduit to provide updated information to registry members

Carriers recognised the value of a registry being used as a two-way communication tool, where they could contribute to ongoing research but also receive updated information and advice relevant to them. A registry was perceived as creating a central repository of data and a pool of available and interested participants to access for recruitment to clinical trials, as exemplified by one carrier:

But I guess the main thrust of the registry is to, as you said, create a pool of people with the gene issue, or gene abnormality, to be made available for contact around things like clinical trials or tests and that sort of thing.

Carriers also recognised the potential value of the registry in supporting clinical care by improving sharing of family information between states by familial cancer clinics and increasing access to family history information. For example, one carrier said:

But I, I think it’s a, it would be beneficial for, to be linked to them because then each further family member that gets tested can be all, so it’s all linked.

However, carriers also noted that such family health information may not be held by individual family members due to adoption, loss of contact, or estrangement.

Carriers also recognised that the registry could promote mutual collaboration between clinical services and researchers, and sharing data with other registries/research groups could help to consolidate research efforts. Carriers recognised that the registry data could be used to support access to funding for research projects and to help determine allocation of healthcare funding and services. Most carriers felt comfortable with their treating doctors being provided with relevant updates or new risk management advice.

Balancing altruistic motivations with the need to protect self and family

Carriers expressed confidence in the registry management committee to regulate appropriate access to, and storage of, the data and a spirit of generosity in their data being used by various groups (e.g. researchers, pharmaceutical companies, and government healthcare). However, concerns were raised about the potential for personal information to be misused and/or leaked. For example, one carrier said:

And I guess the whole identify theft thing so okay is it too much information in one place, then if there’s a hack, then someone’s got all of that.

Some carriers voiced the concern that if their medical/genetic information were leaked, it could lead to discrimination in relation to employment or insurance. For example:

I guess being aware of the fact that, yes, the information – there could potentially be implications for them in terms of insurance discrimination and so on.

They were also wary of receiving extensive communication from the registry and of unsolicited contact from groups who have accessed their information for marketing or advertising purposes, as exemplified by one carrier, who said:

The only reason it would concern me I guess is, if I started to receive contact from pharmaceutical companies and those sorts of private organisations that were contacting me because they had my details [yes], but it's not actually linked to any sort of tests, trials, or research. If they're contacting me for some sort of other purposes, marketing or you know, all of a sudden, I start getting hammered with emails and phone calls, cold calling trying to flog me something, that would be more of an issue.

Interviews with healthcare professionals from the field of familial cancer

Sociodemographic and professional characteristics of healthcare professionals are shown in Table 3. All healthcare professionals interviewed expressed their support for establishing a national registry and identified several enablers, benefits, uses, and barriers.

Table 3.

Sociodemographic background characteristics of healthcare professionals, data custodians, and registry developers as well as heads of laboratories

Characteristic	Healthcare professionals n = 8	Data custodians and registry developers n = 4	Laboratory heads n = 5
Gender
Male	3	2	1
Female	5	2	4
Age
18–29
30–39	4		2
40–49	2		1
50–59	2		1
60 +		1	1
Missing		3
Professional background
Obstetrician/gynaecologist	1
Clinical geneticist	2
Genetic counsellor	5
Data or registry manager		4
Molecular pathologist/medical			5
Scientist
Type of practice
Public hospital	6	4	4
Private practice
Mixture of public and private practice	2		1
Missing
Location of practicea
Urban	8		5
Rural		4
Both
Missing
Length of time practicing in current field
0–5 years
6–10 years	4		1
11–20 years	3	2	3
More than 20 years	1		1
Missing		2

Enablers to ensure success of the registry

The most common theme was raised by healthcare professionals related to the need for adequate national funding and resources for longevity of the registry needing to be available, as one healthcare professional said:

But then thinking realistically about what sort of funding might be better because the success of a registry, or the survival of a registry, is going to rely on funding, and what staffing levels there are, and what resources are made available to that registry, and so one of us has to [be] realistic about - if you ask for everything the cost of running it is going to be much higher...I mean depending on what sort of registry is envisaged it could require substantial funding and just to run it for two, three, four years, and then run out of funding obviously would be extremely disappointing.

Other enablers mentioned related to acceptability amongst pathogenic variant carriers, utilisation of a user-friendly platform, education of carriers and healthcare professionals on its existence and functions, a clear purpose, and evidence of benefit to carriers.

Data centralisation as the overarching benefit of the registry

Healthcare professionals believed that the availability of accurate and comprehensive data on pathogenic variant carriers across Australia in an easily accessible location could improve clinical utility, patient care, research participation, and coordination. Most healthcare professionals indicated that a national registry could improve clinical utility and patient care because of the potential to identify shared patients and families across separate genetics clinics, thus overcoming the sometimes disjointed nature of clinical care, as one healthcare professional said:

I think it’s a really great initiative. I think to be in a centralised place, all of that information to be stored has the potential to provide a lot of benefits in patient care.

A national registry would save clinicians’ time and provide a single information source to keep carriers engaged and updated on changing information, as illustrated by one healthcare professional, who said:

Families don’t live in little villages like we used to, they’re spread all over the country...Yeah. And so, you know, by the time you sit down and work out where that family is and then potentially what clinic they’re from. So you know in (name of Australian state) we have four familial cancer centres, and technically we have geographical areas but we don’t follow them very strictly. So, you know, every time we have to try and chase up a result we have to email four different clinics.

A registry was thought to be particularly useful to engage patients who had genetic testing outside of the genetic clinic setting. All healthcare professionals were enthusiastic about the research applications of the registry, thus reiterating the enthusiasm expressed by carriers. Healthcare professionals thought that a registry would provide investigators access to a national cohort and provide more carriers with the opportunity to participate in research, as one healthcare professional explained:

I think from the research perspective, just because of how familial cancer centres store their information at the moment, it potentially could be viewed as in silos or in a fractured way. And so, to have it all in one spot, will enable research to be done on the Australian group as a whole.

Several healthcare professionals felt the registry could be utilised to inform healthcare services, such as healthcare economic analysis, health service planning, and policy development, as well as clinical consultations. The ability to link the registry to other national datasets, such as the Medicare Benefits Scheme, was also identified by most healthcare professionals as invaluable to ensure quality data are available for clinical care.

Need to obtain active consent from carriers

Most healthcare professionals expressed support for the above uses/applications provided carriers were well informed and active consent was obtained, as illustrated by one healthcare professional who said:

Yeah, so I think if, as long as there’s been informed consent and the patients know, or people know, you know that they, people give consent to be re-contacted for research, and they’re happy for their data to be shared with research groups, then that’s fine.

Some healthcare professionals suggested that an ‘opt-out’ approach would be more suitable. When asked who should consent participants, some healthcare professionals felt that, to ensure high participation, most healthcare professionals were appropriate, provided they were well informed about the registry. A few healthcare professionals suggested a designated registry staff member should consent, due to limited consultation time of healthcare professionals to do so.

Data privacy and security and limited funding as key barriers

Reiterating the theme expressed by carriers, the most common barrier identified by almost all healthcare professionals was data privacy and security. These healthcare professionals were not concerned about data privacy/security themselves, feeling confident that the data would be secure and not misused based on their experience with other registries but did identify it as being an important concern for a minority of carriers. For example, one healthcare professional said:

I think that all of the ones [patient concerns] that I have come across are related to confidentiality. And so, it’s about storage of information. It’s about who is able to access the information that is stored about them, and it is about the type of research that might be generated and genetics approved...my experience of research projects and the little bit of exposure that I have had with the registries in Australia, and the ones that I am aware of in New Zealand are well regulated and well thought out. So, I feel that I trust those.

Other barriers to establishing a registry were limited funding and resources to maintain the registry and the overlap between the registry and existing resources.

Interview with data custodians and registry developers from the field of familial cancer

Table 3 shows sociodemographic and professional characteristics of data custodians and registry developers.

Consenting carriers to a registry

Similar to carriers, data custodians and registry developers stated it should require active consent of carriers if the registry contains identifiers, as one participant said:

Or their privacy is really important, and they’re just wondering how they got there and ability to completely opt-off somehow or yes a lot of reassurance around the security and all that.

While they thought that most carriers would be willing to be in a registry, it was noted there would always be a small number of carriers who would not want their data included, which is a theme that was also voiced by carriers. This would be a potential issue with information about relatives if they are linked, as information about the decliner may be hard to avoid including, as illustrated by the following quote:

Well there’s always the – you know the 1% who… Don’t want to be there, and with the family history stuff that’s sort of hard to avoid, so yes you’ve got one person wanting to join and then…I guess it’s how much of the family history how you’re going to link people if you’ve got de-identified pedigrees, then you’ve got one person who joins but it’s important to know if they’re related to somebody else, but if you don’t know the middle people, how can you link them up that sort of yes linking families and having family histories on there, I guess yes you can’t just consent everybody.

The concept of retrospective active consent has potential barriers, as identifying and re-contacting carriers, and then needing to follow up carriers who have not responded would be resource intensive. Related to the need for retrospective consent, data custodians and registry developers raised concerns that a low response rate could potentially lead to less powerful data, as many carriers may not be included. As this registry would contain sensitive information on carriers, it was seen as important that there was an option for carriers to withdraw their consent from the registry at any time.

Collaborations with other existing networks and centres

All data custodians and registry developers noted the need for a national registry to collaborate with multiple agencies. Related to this need, it was noted that a national registry would require adaptability from all parties, such that data was managed consistently at all participating centres. All four data custodians and registry developers highlighted the need for compatibility of state-specific software and datasets and the necessity for collaboration at a federal level to achieve interoperability, as highlighted by one participant:

So at a couple of different levels, so on a state-based level we work closely with our other state-based colleagues to learn how to bring those datasets together, but then there’s also the Australian genomics model who are trying to learn that there.

The need to obtain data from many different centres and providers was seen as a potential barrier, as noted by one participant:

Well l’ve always found that networking is the way to go. You know I don’t know whether how jealously people guard their data that might be an issue. But for me you know we’re an open book, if we can help, we do.

The difficulty of linkage between registries was also noted, as despite the good will of centres to share information with a registry, differences in data collection and storage between clinics and databases meant linkage was not straightforward, as highlighted by one participant:

I think they have a national registry, I mean we’ve had – we used to have to transfer files to other state registers and it used to be hereditary cancer registries in every state and now I think there’s only us and [name of major Australian city]…yes it would make sense to have a national thing.

It was important to data custodians and registry developers that this was well thought through before data collection began, so that potential issues could be addressed with clear processes for data management and storage. Being able to easily export data as required was considered important and was an identified flaw of many clinical databases.

Registry committee as a gatekeeper

The idea of a committee to act as gatekeepers and determine who could access data and for what purposes was raised by data custodians and registry developers, as outlined by one participant:

The challenge is really understanding who should access that data over what circumstances, and how you sustain a level of having a data access committee that is the kind of gateway into that data service.

It was suggested that data used for clinical purposes should be easily accessible, while access to data should be more stringent for other purposes.

What data to include on a registry

Participants thought that in addition to genotype and phenotype information, screening/risk prevention procedures, interval cancer recordings, and an ability to link family members should be included, as exemplified by one participant:

I think what you guys are going to need is a whole lot of extra information which is not just phenotype but is going to be clinical background, as well as the responses to treatment and things like that you need outcome data as well.

Even if certain data were not available on the registry, a desirable option was an ability to link up registry members with other datasets such as pathology datasets.

Availability of funding to manage registry as a key denominator

Participants noted that sufficient staff to adequately manage the large number of pathogenic variant carriers nationally were required, if accurate and comprehensive data were going to be involved. Funding of appropriate staff if obtained in an ongoing fashion was an enabler for the registry, while limited funding for staff may lead to shortfalls of the registry’s capabilities. In addition to funding being required for staffing, it would also be required for the database and its storage capacity. One participant explained:

The biggest enabler of any of this is ongoing secure funding. So, it’s just we get these little bits of project funding, and it allows you to get something up and running for a few years and then it tends to be fully funded ongoing, and you lose the ability to actually do anything with the data…An income stream that would continue to fund these things would be the biggest enabler but it’s not something that we have at the minute.

Interviews with heads of molecular pathology laboratories

Sociodemographic and professional characteristics of heads of laboratories are shown in Table 3.

Registry datasets

It was unanimously agreed that individuals with a class 3 variant (variant of uncertain significance) should be included in the registry, as it is these variants that require further curation. One head of laboratory said:

I think it would be beneficial probably…if you were capturing the VUSs, the variant of unknown significance, because I think that’s the group of variants that really needs to be investigated further.

All five heads of laboratories stated that rare and new suspicious class 3 variants are often unable to be ruled as pathogenic due to the limited amount of information included across currently available platforms and that the information held within the proposed registry, such as cancer diagnosis and pedigree data, could address these limitations, as one head of laboratory pointed out:

I think that they [unclassified variants] would be another group that would probably benefit from this given that some people might want to do some research on reanalysis of these variants of unknown significance sometime down the track…We need some automated approaches on how to monitor these variants for how they change over time.

Some indicated the registry could assist with arriving at the correct classification. Some heads of laboratories stated that an additional benefit would be the ability to track and identify a cohort of specific variants to support further investigations and research, when current data are insufficient to determine pathogenicity. Heads of laboratories indicated that the inclusion of carriers with a known pathogenic variant would be helpful in facilitating greater access to clinical trials or interventions that could reduce cancer risk and poor outcomes for patients, particularly for patients who undergo genetic testing outside of a familial cancer centre or genetics service where the treating clinician may not have established connections with clinical trials and other research.

All heads of laboratories agreed that in addition to variant data, cancer diagnosis and segregation data should be included in the proposed registry. One head of laboratory said:

I think the types of cancer. Some way of coding a pedigree, like how many first-degree relatives are affected, that sort of thing. Build a really good family history.

Due to the multiethnic nature of the Australian population, one head of laboratory suggested that the inclusion of ethnicity would also be valuable in determining ethnospecific polymorphisms in the registry cohort, given that every variant detected could assist with determining if the lower class variants are more likely polymorphisms or haplotypes, which are associating with more pathogenic variants.

Responsibility for uploading/entering data

A combined approach for data sourcing was supported by interviewees. There was a range of opinions on how variant data should be sourced, with heads of laboratories believing testing laboratories should do so, while others thought the treating clinician would provide a better source of this information. The importance of data curation was echoed by some interviewees.

Access to registry data

The question of who should have access to data within the registry was discussed by all interviewees. The general consensus was that testing laboratories and treating clinicians should have full access to data held within the registry for a carrier to assist with variant curation and clinical management. One head of laboratory expressed the view:

…yes, clinicians should have access to that. Laboratories for variants and things like that, so I think that all that part is good.

Regarding the provision of datasets to research groups, cancer councils, and drug companies for trials, it was agreed that data should be made available to these groups, as noted by one head of laboratory:

…the most useful people to have access to [data within the registry] are my reporting scientists because then if they can clear all that and come to an intelligent classification based on the data that’s available then that makes my review of their reports so much easier…

However, several interviewees indicated that this should be limited via an application process or tiered-access approach, with only relevant data after personal details have been removed provided for research purposes. Opinions on whether carriers should have access to their own information were varied. One interviewee felt very strongly that carriers should not have access, as they may misinterpret information, which in turn may affect their management. Others proposed that carriers could have limited access or that the registry could be set up in a way that all engagement with the carrier occurred outwardly through distribution of information either directly or through their treating clinician. Another head of laboratory believed that access by carriers was important to maintain engagement.

Patient privacy

The general agreement amongst interviewees was that if carriers know what they are consenting to, are made aware of the risks involved, the data are held securely, and access to the data held within the registry is limited, and then there was no significant issue regarding privacy of carriers. One head of laboratory commented on the importance of carefully governing clinical information of family members to minimise the risk of inadvertent disclosure of information to family members. During the interviews, it was highlighted that any information released from the registry would have all personal details removed to protect the privacy of carriers, as highlighted by one head of laboratory:

…I think privacy is a big issue. It should never be disclosed, the patient’s identity… it doesn’t matter how much detail one gives, but it can [released data], it should be anonymised.

Funding

Several heads of laboratories indicated that the registry should be publicly funded through Australian state and/or federal governments. The potential for other groups, such as pharmaceutical companies and testing laboratories, to contribute financially by paying to access data through single payments or registration fees was proposed by several interviewees, as proposed by one of head of laboratory:

I don’t know whether you can get grant to set it up, and then you’ve got ongoing maintenance of it… I think it would probably come down to something like the labs that want to – that see the benefit of using the data – have a registration fee or something like that.

However, one of the interviewees proposing one-off payments or registration fees raised the potential ethical issue with private groups, such as pharmaceutical companies, providing money for accessing data.

Discussion

Registries enable the organization of surveillance programmes and assist with the coordination of multidisciplinary care (Barrow et al. 2013b) through an identified list of people, who can be tracked through the medical systems and contacted by registry staff as needed. Registries also aid the systematic tracing of at-risk relatives and provide many other research benefits (Barrow et al. 2013b). Given these benefits of registries, the enthusiasm expressed by carriers and healthcare professionals is perhaps not surprising. This study shows that all carriers and healthcare professionals were enthusiastic about the research applications of the registry, in particular through providing investigators and clinical services access to a national cohort and providing more carriers with the opportunity to participate in research. This enthusiasm amongst carriers about a registry is consistent with other studies demonstrating that carriers typically have positive attitudes towards genetic research because of their beliefs that such research will benefit society (Forrest et al. 2018; Kerath et al. 2013).

Carriers described altruistic motivations that provided the foundation of their support of the potential registry. Altruistic motivations, i.e. the desire to benefit humanity in some way without the expectation of a direct benefit in return (Quinn et al. 2013) and helping others rather than undertaking actions for personal gain (De Angelis et al. 2005), have been described in relation to participation in genetic studies (Hallowell et al. 2010), underscoring the findings of the current study. Altruistic factors such as benefiting other family members, adding to the advancement of research to benefit future generations, and contributing to a greater understanding of familial cancer conditions have been described by many studies in the context of BRCA1/2 testing, e.g. (d'Agincourt-Canning 2006; Geller et al. 1999; Hallowell et al. 2010; Phillips et al. 2000), as well as for Lynch syndrome (Esplen et al. 2001). These altruistic motivations suggest that altruistic motivations may play a key role in carriers’ decision to participate in the potential registry and to commit to long-term involvement due to the desire that their contribution will benefit their families and others in the future.

This study found a diversity of views on the issue of consent amongst potential registry participants; some carriers felt comfortable with a broad consent (consenting once, prospectively, to have their data included in a registry and then the registry can be used for multiple research purposes), while others preferred a narrow consent approach, which involves contacting carriers each time their de-identified data is accessed. These findings are consistent with studies undertaken in the US, involving veterans (Kaufman et al. 2012) and the general population (Ewing et al. 2015; Platt et al. 2014), which fail to show a consensus regarding consent approaches (Ewing et al. 2015; Platt et al. 2014; Kaufman et al. 2012). These studies show an even split of participants preferring broad versus narrow consent, e.g. 52% versus 48%, respectively (Platt et al. 2014). In the study by Platt et al., participants with concerns about research and those who reported that they would feel respected if asked for permission for each data use preferred a narrow consent (Platt et al. 2014). Preference for broad consent was associated with the desire not to be approached multiple times and the view that research could lead to improved treatments and lives saved. The findings from these US studies are not consistent with a meta-analysis of preferences for consent regarding biological samples that were previously collected and not originally selected for a specific research purpose, which shows that most people prefer an opportunity to make an active decision to participate (Wendler 2006). The choice of a consent model has important implications for registries, and the results of the current study indicate preferences for both broad and narrow consent amongst carriers. One solution may be to ask carriers when consenting them to the registry whether they prefer broad or narrow consent, and then approach them accordingly, with only those opting for narrow consent being asked each time the data are used to consent. Innovative online platforms are available to achieve informed consent that enables ongoing engagement and communication to increase participant choice and autonomy in decision-making (Haas et al. 2021).

In the current study, some carriers raised concerns about the potential for personal information to be misused and/or leaked, and that this could lead to employment or insurance discrimination, underscoring findings from studies on public expectations and attitudes about genetics research (Etchegary et al. 2013, 2015). Patients also expressed reluctance to link family members without appropriate consent. In addition, data custodians and registry developers highlighted similar concerns that when relatives are linked, it would be difficult to avoid including information about decliners. These concerns about non-consent need to be balanced against the common good provided by linkage. Also, given these concerns about non-consent of relatives, a pathway back to the responsible clinician to approach appropriate carriers for consent for specific research or indeed direct approaches to registrants if such research is available may be needed. While healthcare professionals were not concerned about data privacy and security, they identified such concerns as an important issue for a minority of carriers. These findings point to areas of concern that must be addressed to promote trust amongst carriers, high consent rates, and good retention in a registry.

Heads of laboratories suggested that the registry be used to hold data about rare and suspicious class 3 variants. They proposed that information included in the registry might address limitations of currently available variant curation platforms. Accordingly, the proposed registry may assist with both national and international efforts on variant curation, and thus inclusion of class 3 variants should be considered. As such it would be important to avoid redundancy given this function overlaps with other national and international programs to consolidate variant and curation data held in clinical laboratories. The proposed registry could add to the international centralization of data, and national and international registries and databases could then assist collectively in determining pathogenicity of variants through sharing information, for example, of segregation information done in one jurisdiction not otherwise available elsewhere or for definitive pathogenicity assessment. Importantly the focus of the proposed registry would be different to most variant databases, in that it would be collecting the personal cancer history and familial segregation data that contribute to variant classification but which testing laboratories do not routinely have access to. As such, some data may be shared nationally (e.g. segregation data in the clinical setting), while only summary information (e.g. Bayesian scores or meiosis counts) may be shared internationally.

A major risk of developing a registry from the ICCon database is losing the comprehensive nature of the current ICCon database, thereby reducing its utility to inform appropriate clinical service development and research. The requirement for active consent may mean that a large proportion of potential participants will not be included in the registry if they (a) cannot be contacted, (b) do not reply to the invitation to participate, or (c) actively choose not to participate. One potential solution might be a two-tiered model, where the current ICCon database existed alongside a future registry, which would only house data for those ICCon participants who have actively consented to be included in the registry as well.

The limitations of this study should be mentioned before discussing its implications. Findings are only relevant to hereditary cancer pathogenic variant carriers, and generalisations to the broader population of pathogenic variant carriers cannot be assumed. As with all qualitative studies, data are not generalisable, and quantitative studies involving probabilistic sampling are required to obtain generalisable data. The response rate was relatively low. Also, relatively few data custodians and registry developers as well as heads of laboratories were included in the study.

Conclusions

Through the documentation of stakeholder views, this study aimed to prevent potential unforeseen problems when developing a registry. The current study informs the design of the planned registry to facilitate its eventual implementation and uptake. To the best of our knowledge, the establishment of the proposed registry would be the first national-level registry of germline pathogenic variants in cancer-related genes intended to facilitate research nationally and internationally with carriers. Participants’ enthusiasm and support for such a registry heralds a productive and responsive clinical and research partnership once the registry has been established. A national registry for carriers of pathogenic variants in cancer susceptibility genes is a key enabler to realise the benefits of the new genomics knowledge being generated and to serve as an efficient means of identifying at-risk relatives for predictive testing. A well-constructed registry would overcome the often fragmented nature of clinical care by bridging the various public and private healthcare pathways, which often function as silos of information. If working correctly, a national registry will effectively target carriers of pathogenic variants to translate existing research findings into optimised clinical care as well as creating a population resource for further clinical research and therapy discovery.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contribution

BM and RK led the design and conduct of this study. PJ, ABS, HD, FM, NT, CS, and NP contributed to the study concept and design. RK coordinated this multicentre study. MM, RA, CN, EC, and LS were responsible for data acquisition and/or qualitative analyses of interviews. BM wrote the manuscript. All authors contributed to the critical revision of the manuscript for intellectual content. BM and RK are guarantors.

Funding

This study was funded by a Strategic Research Partnership Grant (CSR 18–01) from the Cancer Council of New South Wales. Bettina Meiser was supported by a National Health and Medical Research Council (NHMRC) Senior Research Fellowship Level B (ID 1078523). Amanda Spurdle was supported by an NHMRC Investigator Fellowship (APP177524).

Availability of data and materials

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Code availability

Not applicable.

Declarations

Ethics approval

The study was approved by the Peter MacCallum Cancer Centre and King Edward Memorial Hospital Human Research Ethics Committees.

Consent to participate

All interviewees gave their consent to participate in interviews.

Consent for publication

Not applicable.

Conflict of interest

The authors declare no competing interests.