The ROSELLA Trial: A trial to deliver DNA risk assessment to Australians aged 40-59 in general practice, for our four most common cancers - breast, colorectal, prostate cancer, and melanoma.

This trial is a hybrid effectiveness-implementation trial. We are testing the success of strategies to implement a genomic cancer risk assessment in general practice when delivered in a complex, real-world setting, as well as the effect of this risk assessment. We will randomise a key implementation strategy to invite individuals to complete a genomic cancer risk assessment through their general practice within the trial. Recruitment rates will be a proxy measure for the uptake of the genomic risk assessment under different invitation methods. Practices will write to their patients in the target age group; these patients will be randomised to a different form of invitation to complete the genomic cancer risk assessment. This mailout will be done by clinic staff from a list of patients at the clinic that are in the age range for the trial and will be checked for known ineligibility. This invitation letter will include: • Cover letter with a QR code and link to the trial REDCap that will be used to guide them through enrolling in the trial online (eligibility survey, information video, knowledge check, consent forms, and baseline survey) • Hard copy trial plain language statement (PLS) • +/- DNA collection kit depending on which strategy for invitation to participate in the intervention the potential participant has been randomised to. The first invitation method (Arm A) involves one-step participation, where a DNA kit is provided to all with the invitation letter. The uptake of the genomic cancer risk assessment will be monitored by measuring the proportion of those recruited via letter invitation over the number of potential participants sent an invitation letter and will be compared by arm. Opportunistic recruitment at their GP clinic may also occur, as another implementation strategy. Potential participants recruited through this method will be given the same materials as those invited via letter with no DNA collection kit. There are many ways a patient at clinics enrolled in the trial might be opportunistically recruited to the trial. For example, they might express interest in the trial to their GP during an appointment or to reception following seeing a trial poster at the clinic. Other implementation strategies to be trialled include an information video for participants on the trial and genomic cancer risk assessment designed specifically for the study. This video will be provided to all potential participants, but the content will vary slightly to align with when they receive the DNA kit. This video will be approximately 4minutes in length for both groups. GPs and clinic staff will be provided with education on PRS for cancer and the trial intervention through an online module and patient communication tools. This education will be provided in a one-hour session with a researcher following clinic enrolment in the study and before letters to patients are sent out (approximately 1 month before results return), with the content then being available online after. The online content will be self-guided and contain approximately 1.5hours of content. These education materials will be available in both physical copy and online, and be designed specifically for this trial. GPs will also be provided with clear guidance on the risk reports and how to action the screening recommended. Follow-up consultations with GPs and other health professionals to discuss the cancer risk results and action screening recommended will be funded by the trial. The genomic cancer risk assessment contains several components. The main component is a multi-cancer polygenic risk score (PRS), a genomic risk prediction test for melanoma, colorectal, breast or prostate cancer (depending on sex). Participants will have a post-test consultation with a general practitioner (GP) to discuss their personal risks of these cancers and recommended screening according to risk. This is facilitated by an associated cancer risk report for the participant and their GP. This consultation will occur within 2 weeks of the results delivery and take approximately 10-20minutes. Individual cancer risks are generated from a PRS for each cancer and the individual’s family history of cancer. Applying Australian age-sex incidence data, 10-year and remaining absolute risks of each cancer will also be reported. Screening recommendations will be generated to correspond to NHMRC-endorsed national guidelines for each cancer. No participant will be recommended less screening than the current NHMRC-endorsed national guidelines. The reports are designed to alter screening and referral behaviours, with details for how participants and their GPs can action their recommendations (e.g. contact details for BreastScreen Victoria to book a mammogram). Participants’ GPs will be sent the results of the PRS and invited to prompt the participant to make an appointment at their general practice if they deem clinically appropriate or instead send the participant a letter describing the results if no screening is due. One week following the results being sent to the participant’s general practice, a copy of the report will be sent to the participant. Reports provided to GPs and participants will be the same except GPs will be provided more information about referral pathways and the Australian guidelines for screening from the RACGP Guidelines for Preventive Activities in General Practice Version 10 (Red Book). The effect of the genomic cancer risk assessment will be monitored through completion of risk-appropriate screening by 6-months, obtained from participant self-report (in surveys at 1-, 2- and 6-months), GP record audit and administrative datasets (Services Australia, NBCSP, BreastScreen Victoria and VAED).