Implementation of Personalised Risk Assessment in Oncogenetics

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).