Effect of Polygenic Risk Modification on breast cancer risk management and prevention: The PRiMo Trial

INTERVENTION: The intervention is a 'personalised' breast and ovarian cancer risk assessment that includes the modifying effects of common genomic variation (the Polygenic Risk Score (PRS)). The trial will be offered to unaffected women referred to a participating specialist service (Familial Cancer Clinic) in Australia for predictive testing for a pathogenic variant in a high or moderate risk breast (+/‐ ovarian) cancer‐associated gene (BRCA1, BRCA2, PALB2, CHEK2, ATM, RAD51C or RAD51D) previously detected in a genetic relative ('single gene' testing). A cohort of unaffected women who have previously tested positive for a moderate risk breast cancer gene (PALB2, CHEK2, ATM, RAD51C, or RAD51D) will also be recruited to the study. The trial will compare the current standard of care with a personalised assessment of the risk of breast and ovarian cancer that includes 'single gene' testing, family history, personal risk factors and research genomic testing (PRS). For participants assigned to the intervention arm an integrated risk assessment will be completed by the study team. The assessment will involve combining basic risk factor information provided by the participant (age, ethnicity, lifestyle risk factors and the family history of cancer) with the result of the predictive gene test from the clinical laboratory and a polygenic risk score calculated by the study team using the genotyping results from the research testing. The PRS will be calculated from an individual's genotyping results as the sum of the log odds associated with previously validated risk allele and a report generated using the 'Polygen' tool developed at the Parkville Familial Cancer Centre. All components will be combined to produce a highly personalised risk CONDITION: Breast Cancer Risk Assessment;Ovarian Cancer Risk Assessment; ; Breast Cancer Risk Assessment ; Ovarian Cancer Risk Assessment Cancer ‐ Breast Cancer ‐ Ovarian and primary peritoneal Human Genetics and Inherited Disorders ‐ Other human genetics and inherited disorders INCLUSION CRITERIA: Prospective Enrolment: (1) Undergoing a predictive test for a known familial mutation in a gene associated with increased risk of breast cancer ‐ BRCA1, BRCA2, PALB2, CHEK2, ATM, RAD51C, RAD51D at a participating Familial Cancer Clinic. Retrospective Enrolment: (1) Have previously completed predictive testing and been found to harbour a likely pathogenic (Class 4) or pathogenic (Class 5) variant in a breast/ovarian cancer associated ‘moderate risk’ gene: PALB2, CHEK2, ATM, RAD51C, RAD51D at a participating Familial Cancer Clinic. Prospective and Retrospective enrolment (2) Female, unaffected by invasive or in‐situ breast cancer or epithelial ovarian cancer (3) Aged 18 years or above (4) Have access to the internet and a computer, tablet or smart phone and a basic level of familiarity with digital platforms. PRIMARY OUTCOME: Changes in risk management behaviour ‐ a composite outcome including rates of screening episodes, risk management intentions, and uptake of risk reducing measures, collected using study‐specific questionnaires. [Pre‐result, post‐result, and annually post‐result disclosure for 3 years.; ] Prospective breast cancer incidence rates distributed across the risk categories (high, moderate, low) collected using study‐specific questionnaires and matched to state‐based cancer registries or medical records.[Annually post‐result disclosure for 3 years (intervention or standard care).] Prospective ovarian cancer incidence rates distributed across the risk categories (high, moderate, low) collected using study‐specific questionnaires and matched to state‐based cancer registries or medical records.[Annually post‐result disclosure for 3 years (intervention or standard care).] SECONDARY OUTCOME: Assess positive outcomes reported by people who have experienced traumatic events using validated instrument PGI‐SF (Posttraumatic Growth Index‐Short Form) [Post‐result, 6 months post‐result, annually post‐result disclosure for 3 years.] Cancer Risk Perception assessed using a validated numerical measure collected through study‐specific questionnaires and semi‐structured qualitative interviews (on a subset of participants).[Pre‐result, post‐result, 6 months post‐result, annually post‐result disclosure for 3 years.] Experience of receiving personalised risk information‐ including motivation for genetic testing, expectations of information arising from genetic testing and understanding of information arising from genetic testing, impact of their results and changes over time, dis/advantages of participation. Evaluation by semi‐structured qualitative interviews [4‐6 weeks post‐result, 12 months post‐result disclosure] Measure common threatening life experiences such as serious illness and financial issues using validated instrument LTE (List of Threatening Experiences)[Post‐result, 6 months post‐result, annually post‐result disclosure for 3 years.] Measure impact of genetic counselling services using validated GOS (Genetic Outcome Scale)[Pre‐result, post‐result disclosure] Measure psychological adaptation to genetic information across four domains:Non‐intrusiveness,support,self‐worth and self‐efficacy using validated instrument PAGIS (Psychological adaptation to genetic information scale)[Post‐result, 6 months post‐result, annually post‐result disclosure for 3 years.] Measure the psychosocial impact of returning genomic findings to participants in research and clinical practice using validated instrument FACToR (Feelings about genomic testing results)[Post‐result, 6 months post‐result, annually post‐result disclosure for 3 years.] Measure worry about risk of developing cancer and the impact of worry on daily functioning among individuals at risk for hereditary cancer using validated Cancer Worry Scale (CWS).[Pre‐result, post‐result, 6 months post‐result, annually post‐result disclosure for 3 years.] Quality of life assessed using validated AQoL 8D instrument.Longitudianl quality of life scores from AQoL 8D will be used in the cost effectiveness analysis of PRS Risk Modified assessments along with the cost of care and the primary study outcomes [Pre‐result; post‐result; 6 months post‐result, annually post‐result disclosure for 3 years.]