Direct Information to At-risk Relatives (DIRECT)

Direct Letters to Relatives at Risk of Hereditary Cancer- a Multi-centre Randomised Controlled Trial of Healthcare-assisted Versus Family-mediated Risk Disclosure at Swedish Cancer Genetics Clinics (DIRECT-study)

This study evaluates if uptake of genetic counselling in high-risk families is increased when patients at cancer genetics clinics are being offered healthcare-assisted disclosure to at-risk relatives compared to current standard care (with family-mediated disclosure). Patients/families who have undergone a cancer genetic investigation will be invited to participate in the study. All participants will receive standard care. Half of them will in addition be offered a healthcare-assisted disclosure with the service of direct letters to identified at-risk relatives distributed by the healthcare provider. After a year we will compare the proportion of at-risk relatives who have contacted a cancer genetic clinics in each study arm.

(When the formal study protocol is published, this section will instead refer to the published study protocol). This study is a multi-centre open label, prospective, randomized controlled superiority trial comparing an intervention of healthcare-assisted disclosure with standard care of family-mediated disclosure of hereditary cancer risk information in high-risk families in Sweden. SUBJECTS AND METHODS Patients/families will be enrolled and allocated in parallel to intervention or standard care. All participants receive standard genetic counseling and information summarizing the results of their family investigation. They are informed about preventive measures when applicable, and are encouraged to inform their at-risk relatives (t=0 months). The intervention component is the addition of a healthcare-assisted disclosure procedure. Participants in the intervention arm will be offered the service of sending letters directly to their at-risk relatives. If the participant approves the offer, letters will be sent to eligible at-risk relatives deemed to be recommended genetic counseling within a year. The direct letter will inform the at-risk relative that a cancer genetic investigation has been conducted in the family and the implications for him or her, and their blood relatives. To facilitate access to further information, contact details to the closest cancer genetics unit are included in the letter. The letters are sent with registered mail in neutral envelopes which means that recipients will have to show proof of identity to retrieve the letter from their local delivery service provider. METHODS FOR ASSESSMENT OF STUDY OUTCOMES For participants in both study arms, contact details of the at-risk relatives are identified in collaboration between health care provider and the participant. The health care provider records the name, approximate or exact year of birth and postal address of each at-risk relative for follow-up. At the time of follow-up (t=12 months) the research nurse will check whether the relatives, listed one year before, have contacted a Swedish cancer genetic unit. Primary outcome data is retrieved from the patient data registries at each clinic. The research nurse will also record additional data points from CRFs, enabling analysis of the other pre-specified outcome measures in the intervention arm. The outcome data are reported back to the national study secretariat as plain numbers without any personal details of the at-risk relatives. SAMPLE SIZE AND STATISTICAL METHODS For sample size calculation and statistical methods, see attached documents. INTERNAL PILOT, AUDIT and PROGRESS CRITERIA As this protocol has never been tested in Swedish clinical practice an internal pilot phase is included in the outline of the project. Progress criteria at each study site are evaluated at internal pilot point and thereafter at formal audit at least yearly. Internal pilot point is set to the time when 20 individuals in total (across the 3 pilot study sites) have been included and treated according to protocol. Continuation of the full-powered study at the specific study site will be determined by considering the criteria filled, the potentially necessary amendments, and the degree of which the amendments deviate from the original piloted study protocol. The outcomes and process criteria are found in the attached document.

Familial Breast Cancer, Familial Colorectal Cancer, Hereditary Breast and Ovarian Cancer Syndrome, Hereditary Breast Cancer, Lynch Syndrome

hereditary cancer risk, prevention, family-mediated disclosure, healthcare-assisted disclosure, information disclosure, risk information, genetic risk

Multi-centre, parallel assignment, balanced ratio, investigator-blinded, randomised, controlled superiority trail in Sweden.

Since the intervention in this trial is an offer of sending physical direct letters to at-risk relatives, neither the health care providers nor the study participant can be blinded to the allocation. However, the final data analysis will be performed by a statistician blinded to the study arm allocations and subgroups.

Genetic counseling according to current clinical practice with the addition of an offer from health care provider to mail letters directly to eligible at-risk relatives.

At counseling, eligible at-risk relatives (who may benefit from disclosure of risk information) are listed on a specified protocol in collaboration between health care provider and the participant.

The participant is offered that the health care provider at the cancer genetic unit mail a direct letter with personalized family risk information to all at-risk relatives that participant approve contact with.

Number of potential at-risk relatives who have contacted a Swedish cancer genetic unit out of the total number of potential at-risk relatives for each patient.

One year (12 months) following the first counselling session when implications of the cancer genetic investigation for the patient´s at-risk relatives is discussed, hence 12 months after t=0.

Comparing intervention and control group with respect to proportion of first-degree ARRs who have contacted a Swedish cancer genetics clinic within 12 months of the proband receiving post-test genetic counselling because the proband is a carrier of a pathogenic variant in BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2.

One year (12 months) following the first counselling session when implications of the cancer genetic investigation for the patient´s at-risk relatives is discussed, hence 12 months after t=0.

Comparing intervention and control group with respect to proportion of second-degree, third-degree or more distant ARRs who have contacted a Swedish cancer genetics clinic within 12 months of the proband receiving post-test genetic counselling because the proband is a carrier of a pathogenic variant in BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2.

One year (12 months) following the first counselling session when implications of the cancer genetic investigation for the patient´s at-risk relatives is discussed, hence 12 months after t=0.

Number of potential at-risk relatives that proband allowed contact with, compared to total number of potential at-risk relatives for that specific patient. [proportion]

One year (12 months) following the first counselling session when implications of the cancer genetic investigation for the patient´s at-risk relatives is discussed, hence 12 months after t=0.

Number of at-risk relatives that proband allowed contact with and where contact data allowed distribution of direct letter, compared to total number of potential at-risk relatives for that specific patient. [proportion]

One year (12 months) following the first counselling session when implications of the cancer genetic investigation for the patient´s at-risk relatives is discussed, hence 12 months after t=0.

Number of at-risk relatives that proband allowed contact with, contact data was sufficient and the registered letter was collected from the post-office within 12 months, compared to total number of potential at-risk relatives for that specific patient. [proportion]

One year (12 months) following the first counselling session when implications of the cancer genetic investigation for the patient´s at-risk relatives is discussed, hence 12 months after t=0.

Inclusion criteria Patient being offered a cancer genetic investigation for hereditary breast, ovarian or colorectal cancer. Written consent to participate the study, Belonging to a family with; a) familial breast cancer, b) familial colorectal cancer, c) pathogenic variant in PALB2, BRCA1/2 (Hereditary breast cancer, hereditary breast and ovarian cancer), MLH1, MSH2, MSH6, PMS2 (Lynch syndrome) and Having at least one eligible at-risk relative (family member deemed to be an ARR recommended genetic counseling within a year). Exclusion Criteria: Cannot convey personal opinions and preferences by themselves. No eligible at-risk relatives living in Sweden.