Overview
This single-arm interventional feasibility study will evaluate whether integrating polygenic risk scores (PRS) into the CanRisk model can improve breast cancer risk prediction and personalized prevention in women at risk of breast cancer. The study will assess the organizational feasibility, patient acceptance, emotional impact and satisfaction of an integrated pathway combining PRS testing with standard genetic counseling and other risk factors at Fondazione Policlinico Universitario Agostino Gemelli IRCCS.
Description
This study will test the feasibility of integrating polygenic risk scores (PRS) into the CanRisk breast cancer risk model in a real-world clinical setting at Fondazione Policlinico Universitario Agostino Gemelli IRCCS. By embedding PRS testing into routine genetic counseling and patient care, the study aims to examine organizational, logistical, and patient-centered aspects of incorporating genomic data into breast cancer risk assessment.
Eligible participants include women with a family history of breast cancer, carriers of pathogenic variants included in CanRisk (BRCA1, BRCA2, PALB2, CHEK2, ATM, RAD51D, RAD51C, BARD1), and women with unilateral breast cancer for controlateral risk assessment. Carriers of pathogenic variants not included in CanRisk (e.g., PTEN, TP53, CDH1) as well as women with bilateral breast cancer or ductal carcinoma in situ (DCIS), will be excluded, as CanRisk does not estimate risk for this condition.
All participants will provide a blood sample (9 mL in three K2EDTA tubes) for DNA extraction and SNP genotyping. PRS will be calculated using a 313-SNP array with ThermoFisher GeneTitan and the Axiom Precision Medicine Diversity Array, followed by standard quality control and genotype imputation. Results will be integrated into the CanRisk model previously calculated without PRS, to provide individualized risk estimates, in combination with clinical, anthropometric, and family history variables systematically collected for every participant.
Participants who request their CanRisk with PRS results will receive an email report approximately within one month of sample collection, summarizing their CanRisk estimates with and without PRS, and will be invited to complete a questionnaire on comprehension, perception, and emotional impact of the result. If the PRS leads to a change in risk classification, the case will be reviewed in a multidisciplinary discussion and the prevention plan may be modified accordingly. Participants who accept to be enrolled in the study but decline to receive their PRS results will be asked their reason, which will be documented verbatim.
Primary outcome:
Feasibility of CanRisk+PRS pathway assessment, measured by a 27-item Care Process Self-Evaluation Tool (CPSET) validated questionnaire, completed by both participants and healthcare staff at the end of the study.
Secondary outcomes:
- Uptake of CanRisk+PRS pathway
- Risk understanding and emotional impact, assessed using a validated questionnaire (Woof et al.)
- Risk reclassification rate, after PRS integration in the CanRisk model assessment
- Changes in breast cancer preventive pathway, recommended following multidisciplinary evaluation after CanRisk+PRS-based risk reclassification
- Impact on overall distribution across risk categories after PRS integration
This study will generate evidence on the clinical, technical, and organizational feasibility of integrating PRS into breast cancer risk assessment, informing the future implementation of personalized prevention programs.
Eligibility
Inclusion Criteria:
- Ability to provide informed consent
- Voluntary consent to participate
- CanRisk score (without PRS) \> 5% (calculated on www.canrisk.org)
- Healthy women with:
- Known family history of breast cancer, or
- Known family history of genetic conditions associated with increased breast cancer risk (BRCA1, BRCA2, PALB2, CHEK2, ATM, PTEN, TP53, CDH1), or
- Known carriers of pathogenic variants (BRCA1, BRCA2, PALB2, CHEK2, ATM, PTEN, TP53, CDH1)
- Affected women with:
- Diagnosis of unilateral breast cancer
- Personal history of ovarian cancer
Exclusion Criteria:
- CanRisk score (without PRS) \< 5% (calculated on www.canrisk.org)
- Diagnosis or history of bilateral breast cancer
- Diagnosis of ductal carcinoma in situ
- Previous bilateral mastectomy
- Life expectancy \< 12 months due to other medical conditions
- Participation in interventional clinical trials for breast cancer prevention in the last 12 months
- Inability to provide informed consent
