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Trial registered on ANZCTR


Registration number
ACTRN12625000065493
Ethics application status
Approved
Date submitted
10/12/2024
Date registered
22/01/2025
Date last updated
22/01/2025
Date data sharing statement initially provided
22/01/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
Implementation of Personalised Risk Assessment in Oncogenetics
Scientific title
Implementation and evaluation of the impact of a personalised risk assessment for breast, bowel, prostate and ovarian cancer that includes polygenic scores, on risk management and prevention in individuals undergoing assessment at a specialist Familial Cancer Clinic in Australia.
Secondary ID [1] 312996 0
Funding body: Australian Government Medical Research Futures Fund, Genomics Health Future Mission; Grant code: MRF2024994
Universal Trial Number (UTN)
U1111-1315-7846
Trial acronym
IMPRESSION
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Breast cancer risk assessment 335763 0
Ovarian cancer risk assessment 335764 0
Prostate cancer risk assessment 335765 0
Bowel cancer risk assessment 335766 0
Condition category
Condition code
Human Genetics and Inherited Disorders 332325 332325 0 0
Other human genetics and inherited disorders
Cancer 332326 332326 0 0
Breast
Cancer 332327 332327 0 0
Prostate
Cancer 332328 332328 0 0
Ovarian and primary peritoneal
Cancer 332329 332329 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Cancer 332330 332330 0 0
Bowel - Anal

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The intervention under study is the provision of a personalised risk assessment for a range of common cancers, that combines information on family history, personal risk factors, single gene test results and a polygenic score (PGS) into a single assessment that reports an individual’s cancer risk in the medium term (5- and 10-year risks) and long term (lifetime risk). The specific cancers included in the risk assessment are: For women – invasive breast carcinoma, non-mucinous epithelial ovarian cancer and colorectal adenocarcinoma; For men – prostate adenocarcinoma and colorectal adenocarcinoma.
Currently thousands of individuals attend Familial Cancer Clinics (FCC) across Australia to undergo genetic testing of rare high- and moderate-risk cancer susceptibility genes. The current model of care is to provide a risk assessment and risk management advice based on the results of this genetic testing, residual family history +/- personal risk factors. This research project will compare this current standard of care with a personalised assessment that includes their genomic testing results (PGS).
Participants of this study will be individuals that have been referred to a FCC for clinical genetic testing. The trial will be integrated with the FCC's usual genetic testing processes. Eligible patients will be invited to participate in the study either before, during or after their clinical appointment to discuss genetic testing, which may be via telehealth, in-person or phone, according to usual clinical practice. The decision to offer genetic testing will be made based on standard clinical criteria and the trial will not have a role in this process. Eligible patients will provide a sample (usually blood) for clinical genetic testing, which will be undertaken by an accredited laboratory according to usual clinical practice, with permission from participants for an aliquot of the clinical DNA sample to be provided to the study for genomic testing. FCCs will provide participants with their genetic test results and risk management advice (usually around 8 weeks after sample collection) following their usual format (e.g. in-person, telehealth, by phone or by letter). For participants in the intervention arm, their cancer genetics specialist will provide them with their personalised risk assessment including PGS and this will form the basis of the counselling and risk management advice they receive.
Participants will be asked to complete an online questionnaire before their results appointment, 1-month after their results appointment and 12-months after their results appointment. They will provide permission for the study to collect and update their health information for the duration of the study and may be asked to participate in an optional in-depth interview.
The study will enrol the standard care and intervention arms consecutively without randomisation. Participants assigned to standard care will be allowed to crossover after 1 year. For individuals who elect to receive this information, their personalised risk assessment (including PGS) will be provided to their FCC who will then organise to convey the information along with any updated risk management advice through the usual process of the clinic: i.e. an appointment, phone call or letter, depending on the clinical implications of the individual result. Participants that choose to crossover will be asked to complete an additional online questionnaire 1-month after they've received their intervention results.
During the first stage of the study, while the clinical and psychosocial outcomes of the current approach of gene panel testing is being quantified through recruitment of a standard care arm, a data set of genotypes from existing Australian cohort studies will be used to operationalise breast, bowel, ovarian, and prostate cancer PGS for the Australian population. This pre-clinical study will generate bioinformatic solutions to the issues of imputation, determine the optimal strategy for accounting for ancestry, and operationalise those solutions (e.g. through automated pipelines).
Intervention code [1] 329974 0
Early detection / Screening
Comparator / control treatment
The comparator is the current model of care which is for a genetics specialist team to provide a risk assessment and risk management advice based on the results of genetic testing of rare high- and moderate-risk cancer susceptibility genes and residual family history, in line with the national eviQ guidelines.
The study will not supply additional risk information but the managing genetics team will be free to use any other risk information (e.g, lifestyle risk factors) that they would normally incorporate into a risk assessment.
Participants in the 'standard care' group will have the option of crossing over to receive a PGS modified risk assessment at 1 year.
Control group
Active

Outcomes
Primary outcome [1] 339900 0
Changes in cancer risk management behaviour
Timepoint [1] 339900 0
Baseline (pre-test), 1-month- and 12-months post genetic test results.
Secondary outcome [1] 441863 0
Accuracy of the individual polygenic score
Timepoint [1] 441863 0
This outcome relates to a pre-clinical study that will be undertaken during the first phase of the trial, while participants are being recruited to the standard care arm of the clinical trial.
Secondary outcome [2] 441864 0
Participant experience of receiving genetic test results
Timepoint [2] 441864 0
1-month- and 12-months post genetic test results
Secondary outcome [3] 441865 0
Participant perception of cancer risk
Timepoint [3] 441865 0
Baseline (pre-test), 1-month- and 12-months post genetic test results.
Secondary outcome [4] 441866 0
Subjective experience of personalised risk assessment
Timepoint [4] 441866 0
Post genetic test results
Secondary outcome [5] 441867 0
Frequency of cancer events
Timepoint [5] 441867 0
12-months post genetic test results.
Secondary outcome [6] 441868 0
Cost to the health service of the addition of personalised cancer risk assessment to current standard care.
Timepoint [6] 441868 0
Baseline (pre-test), 1-month- and 12-months post genetic test results.
Secondary outcome [7] 441869 0
The effectiveness of potential implementation strategies for cancer PGS in the Australian health system.
Timepoint [7] 441869 0
Data related to this outcome will be collected continuously throughout the trial.

Eligibility
Key inclusion criteria
1) Attending a participating clinical service for an assessment of cancer risk based on a personal and/or family history of cancer.
2) Undertaking clinical genetic testing for genes associated with increased risk of colorectal cancer, breast cancer, prostate cancer or ovarian cancer based on standard clinical criteria, as determined by the local clinical service.
3) Have access to the internet and a computer, tablet or smart phone and have a basic level of familiarity with digital platforms.
Minimum age
18 Years
Maximum age
74 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1) Unable to read (or have read to them) and understand patient study information, including English language surveys and patient information and consent form.
2) No DNA sample at a participating diagnostic laboratory available.
3) Known at time of enrolment to have a significant cancer risk-factor that is not captured in the intervention risk assessment. For example, a clinical diagnosis of colorectal polyposis or past exposure to mantel radiotherapy.
4) Serious or life-limiting illness that means that cancer risk-management advice and/or activities are not clinically indicated.

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
The study will enrol the standard care and intervention arms consecutively without randomisation. Participants assigned to standard care will be allowed to crossover after 1 year.
On commencement of the intervention arm of the study, participants from the standard care arm will be invited to crossover and receive their personalised PGS-based risk assessment following completion of their 12 month follow-up survey.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
1. Demographic and other cohort features will be examined by descriptive statistics and include tests for heterogeneity between study sites and laboratories.
2. Analysis of outcomes:
i) Risk Management Intentions: The proportion of participants in either arm reporting the intention to engage with each risk management option will compared (chi squared test) overall and subdivided by gene and risk category status.
ii) Risk Management uptake and frequency of cancer events: Simple proportions will be examined as above. Rates (screening episodes, risk reducing measures, cancer events) will be analysed by Cox regression and associations between variables and outcomes analysed by regression modelling.
iii) Accuracy and Calibration of Risk assessment: Accuracy will be measured using the continuous risk measures (Lifetime and 5- or 10-year risk) and comparing the area under the receiver operating curve (AUROC) and the Matthews Correlation Coefficient (MCC). Calibration will be measured by dividing the risk into the clinical categories or intervals (e.g. the deciles) of the continuous risk measures and estimating the goodness of fit.
iv) MICRA and Psychosocial measures of patient experience: Internal consistency of the psychosocial tools will be measured by Cronbach’s alpha coefficient. The impact of variables, including the PGS, on psychosocial outcomes will be analysed in a linear mixed model incorporating data on other stressful life events and accounting for clustering as above. Mean values for the tools will be compared between intervention and control groups using the Kruskal-Wallis H test.
v) Subjective experience of personalised risk assessment: Narrative data from the structured interviews will be analysed using response frequencies and qualitative content analysis.
vi) The cost to the Health service: A Markov individual-level simulation model will be used to estimate the incremental lifetime costs and benefits associated with PGS-based risk assessment for common cancers relative to current standard diagnostic care from an Australian healthcare system perspective.
vii) The effectiveness of potential Implementation strategies for Cancer PGS in the Australian health system: A multi-method approach will be used to evaluate both service-level data and implementation outcomes, integrating qualitative and quantitative analyses to data from interviews, focus groups, and observational studies involving clinicians and health professionals who developed or delivered the clinical trial.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/02/2025
Actual
Date of last participant enrolment
Anticipated
31/12/2027
Actual
Date of last data collection
Anticipated
1/06/2029
Actual
Sample size
Target
2000
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,VIC
Recruitment hospital [1] 27329 0
Peter MacCallum Cancer Centre - Melbourne
Recruitment hospital [2] 27330 0
Royal Melbourne Hospital - City campus - Parkville
Recruitment hospital [3] 27331 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 43420 0
3000 - Melbourne
Recruitment postcode(s) [2] 43421 0
3050 - Parkville
Recruitment postcode(s) [3] 43422 0
4029 - Herston

Funding & Sponsors
Funding source category [1] 317435 0
Government body
Name [1] 317435 0
The Commonwealth of Australia - Medical Research Futures Fund, Genomics Health Future Mission
Country [1] 317435 0
Australia
Primary sponsor type
Hospital
Name
Peter MacCallum Cancer Centre
Address
Country
Australia
Secondary sponsor category [1] 320182 0
None
Name [1] 320182 0
Address [1] 320182 0
Country [1] 320182 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 316154 0
Peter MacCallum Cancer Centre Human Research Ethics Committee
Ethics committee address [1] 316154 0
Ethics committee country [1] 316154 0
Australia
Date submitted for ethics approval [1] 316154 0
14/10/2024
Approval date [1] 316154 0
22/11/2024
Ethics approval number [1] 316154 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 136958 0
Prof Paul James
Address 136958 0
Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne VIC 3000
Country 136958 0
Australia
Phone 136958 0
+61 3 8559 5322
Fax 136958 0
Email 136958 0
[email protected]
Contact person for public queries
Name 136959 0
Simone McInerny
Address 136959 0
Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, VIC 3000
Country 136959 0
Australia
Phone 136959 0
+61 3 8559 6190
Fax 136959 0
Email 136959 0
[email protected]
Contact person for scientific queries
Name 136960 0
Paul James
Address 136960 0
Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne VIC 3000
Country 136960 0
Australia
Phone 136960 0
+61 3 8559 5322
Fax 136960 0
Email 136960 0
[email protected]

Data sharing statement
Will there be any conditions when requesting access to individual participant data?
Yes
Data Eligibility and Access Conditions?
Who is eligible to request access to the individual participant data?
Other
Will be assessed on a case-by-case basis at the discretion of the sponsor

Would there be any conditions for requesting access to individual participant data?
Other
-

What individual participant data will be or are expected to be shared?
Other
Reports and/or a subset of anonymised patient-level data, excluding data collected from Services Australia. Anonymised genotype data will be deposited in recognised data repositories, as required for publication, and where consistent with institutional policies on data access. Study documents such as the protocol and PICF will also be made available on reasonable request.

What types of analyses could be conducted using the individual participant data?
Other
Any purpose

When might the individual participant data become available to request access, and for how long?
From:
Other
Study data will be available beginning 3 months following primary analysis and publication and ending with the retention period when study data is destroyed

To:
Other
-

Where can requests to access individual participant data be made, or data be obtained directly?
Other
Data access requests can be emailed to [email protected]

Are there additional conditions or steps involved in requesting or accessing individual participant data?
No
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Reports and/or a subset of anonymised patient-level data, excluding data collected from Services Australia.
Anonymised genotype data will be deposited in recognised data repositories, as required for publication, and where consistent with institutional policies on data access.
Study documents such as the protocol and PICF will also be made available on reasonable request.
When will data be available (start and end dates)?
Study data will be available beginning 3 months following primary analysis and publication and ending with the retention period when study data is destroyed.
Available to whom?
Will be assessed on a case-by-case basis at the discretion of the sponsor
Available for what types of analyses?
Any purpose
How or where can data be obtained?
Data access requests can be emailed to [email protected]


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.