Breast Cancer
Conditions
Keywords
breast cancer, risk stratification, polygenic risk score, CanRisk model, feasibility study, personalized prevention
Brief summary
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.
Detailed 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: 1. Uptake of CanRisk+PRS pathway 2. Risk understanding and emotional impact, assessed using a validated questionnaire (Woof et al.) 3. Risk reclassification rate, after PRS integration in the CanRisk model assessment 4. Changes in breast cancer preventive pathway, recommended following multidisciplinary evaluation after CanRisk+PRS-based risk reclassification 5. 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.
Interventions
GENETICClinical pathway for breast cancer prevention based on PRS-integrated CanRisk assessment
Standard genetic counseling followed by a blood draw (0.5 mL) for DNA extraction. The sample is processed using a high-throughput SNP genotyping platform, and the PRS, based on 313 SNPs, is calculated and integrated into the CanRisk model for refined breast cancer risk stratification. In conjunction with result disclosure, participants complete structured questionnaires to assess psychological impact and risk comprehension (questionnaire by Woof et al.). At the end of the study, both participants and healthcare professionals complete feasibility questionnaires to evaluate the implementation of the PRS-integrated clinical pathway (Care Process Self-Evaluation Tool, CPSET; Vanhaecht et al.).
Sponsors
Catholic University of the Sacred Heart
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 79 Years
Healthy volunteers
Yes
Inclusion criteria
* Ability to provide informed consent * Voluntary consent to participate * Estimated risk of carrying an inherited pathogenic variant (in BRCA1, BRCA2, PALB2, CHEK2, ATM, RAD51D, RAD51C, BARD1) \> 5%, (calculated on www.canrisk.org) * Healthy women with: 1. Known family history of breast cancer, or 2. Known familiarity with carriers of pathogenic variants for genes included in the CanRisk model (BRCA1, BRCA2, PALB2, CHEK2, ATM, RAD51D, RAD51C, BARD1), or 3. Known carriers of pathogenic variants for genes included in the CanRisk model (BRCA1, BRCA2, PALB2, CHEK2, ATM, RAD51D, RAD51C, BARD1) * Affected women with: 1. Diagnosis of unilateral breast cancer 2. Personal history of ovarian cancer
Exclusion criteria
* 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 * Carriers or relatives of carriers of pathogenic variants in genes not included in the CanRisk model (genes other than BRCA1, BRCA2, PALB2, CHEK2, ATM, RAD51D, RAD51C, BARD1) * Inability to provide informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Feasibility of implementing an integrated clinical pathway including PRS | At 12 months from enrollment | The primary outcome is the feasibility of integrating polygenic risk score (PRS) testing into the CanRisk breast cancer risk model within a structured clinical pathway. Feasibility will be assessed using the Care Process Self-Evaluation Tool (CPSET), that includes 27 items across 5 domains: patient-centeredness, coordination of care, communication, cooperation, and monitoring/follow-up. The questionnaire will be administered at the end of the study to both enrolled women and involved healthcare professionals. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Uptake of CanRisk+PRS integrated pathway | At the time of enrollment, when eligible participants are offered PRS testing | Proportion of women accepting PRS testing among those offered: (Number accepting PRS / Number offered PRS) × 100 |
| Proportion of women requesting their individual CanRisk+PRS result | At month 12. | The percentage of enrolled women who actively request to receive their individualized breast cancer risk estimate generated by the CanRisk model integrated with PRS. This outcome will measure the degree of patient interest in receiving personalized genomic risk information. |
| Percentage of women reclassified into different risk categories after PRS integration | At month 12 | The percentage of women whose risk category (low, moderate, or high) changes when PRS information is added to their baseline CanRisk estimate. This outcome will assess the clinical utility of PRS in refining breast cancer risk stratification and identifying women who may benefit from adjusted preventive strategies. |
| Proportion of women with modified prevention pathways after PRS-informed reclassification | At month 12. | The percentage of women whose preventive or follow-up pathway is modified following a multidisciplinary team review prompted by PRS-informed risk reclassification. This outcome will capture the practical impact of PRS integration on clinical decision-making and preventive care planning. |
| Perception of risk and psychological impact | At month 12 | Evaluation of women's understanding and perception of their personal breast cancer risk, as well as the emotional and psychological impact of risk communication, after receiving their CanRisk+PRS result. This will be assessed using the validated questionnaire by Woof et al., which specifically measures comprehension of risk estimates and associated emotional responses. |
| Global redistribution of risk categories after PRS integration | At month 12. | The overall distribution of women across predefined breast cancer risk categories (low, moderate, high) before and after incorporating PRS into CanRisk. This outcome will provide a population-level view of how PRS influences breast cancer risk stratification and the extent of shifts in the global risk profile of the cohort. |
Countries
Italy
Contacts
CONTACTSara Farina, MD
CONTACTFrancesco A Causio, MD
PRINCIPAL_INVESTIGATORStefania Boccia, Phd
Life Sciences and Public Health Department, Università Cattolica del Sacro Cuore, Rome, Italy
Outcome results
None listed