What question did this study set out to answer?

The study aims to evaluate how integrating polygenic risk scores impacts breast cancer risk assessment and clinical decisions in carriers of specific pathogenic variants.

February 19, 2026

Abstract PD4-04: Impact of Polygenic Risk Scores on Breast Cancer Risk Assessment and Clinical Decision Making in Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2: Results from the Prospective Multisite GENRE-2 Clinical Trial

Key Result

PRS integration changed breast cancer risk categories in 29.2% of ATM and 16.7% of CHEK2 carriers but <5% of BRCA1/BRCA2 carriers, aiding risk stratification in moderate-risk genes.

Key Points

The study aims to evaluate how integrating polygenic risk scores impacts breast cancer risk assessment and clinical decisions in carriers of specific pathogenic variants.
Conducted a prospective single-arm multisite clinical trial involving 933 women with germline pathogenic variants in breast cancer-related genes.
Utilized pre- and post-PRS risk estimates and surveys to evaluate risk changes and decisions on screening and preventive actions.
Categorized women into lifetime risk levels (average, moderate, high) based on PRS integrated CanRisk estimates.
29.2% of ATM pathogenic variant carriers and 16.7% of CHEK2 carriers experienced shifts in breast cancer risk categories after PRS integration.
BRCA1 and BRCA2 carriers showed limited category shifts after PRS integration, with <5% changing.
High-risk carriers showed higher intent for preventive actions compared to average-risk carriers, indicating more proactive decision-making.

Structured PICO

Does the integration of Polygenic Risk Scores (PRS) refine breast cancer risk estimates and influence clinical decision-making in women with germline pathogenic variants?

Population

633 women enrolled in the GENRE-2 trial who received Polygenic Risk Score (PRS) results and completed a survey, including 214 (33.8%) carriers of germline pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, or PALB2.

Intervention

Incorporation of 313-Polygenic Risk Scores (PRS) into standard CanRisk-based breast cancer risk assessment models.

Comparator

Pre-PRS standard CanRisk-based breast cancer risk estimates.

Outcome

Changes in categories of lifetime breast cancer risk estimates (average <20%, moderate 20-40%, high >40%) and impact on patient decisions to undertake screening or preventive action.surrogate

Integrating Polygenic Risk Scores into breast cancer risk assessment provides clinically meaningful risk restratification for carriers of moderate-risk genes (ATM, CHEK2) but has limited utility for high-risk genes (BRCA1, BRCA2).

Main Result

Absolute Event Rate: 0% vs 0%

Abstract

Abstract Background: Incorporation of Polygenic Risk Scores (PRS) can refine traditional breast cancer (BC) risk assessment models to provide precise estimates of BC risk. However, the impact of such an integrated model on BC risk estimates and clinical decision-making related to BC screening and preventive strategies in germline pathogenic variant (PV) carriers is not fully understood. Methods: The GENRE-2 is a prospective single-arm multisite clinical trial (NCT04474834) incorporating 313-PRS into standard BC risk assessment models to determine the impact of PRS on risk estimates and clinical decisions on prevention and screening. All women received pre- and post-PRS BC risk estimates and completed surveys on their screening and cancer prevention decisions before and after integrating PRS estimates. Herein, we report on the impact of integrating PRS into CanRisk-based BC risk estimates among women enrolled in GENRE-2 due to PVs in ATM, BRCA1, BRCA2, CHEK2, or PALB2. Women were categorized into average risk (20%), moderate risk (20-40%), or high risk (40%) for BC based on clinically relevant lifetime risk thresholds for supplemental MRI screening and risk-reducing bilateral mastectomies. Changes in categories of lifetime BC risk estimates were then evaluated before and after integration of PRS. Impact of PRS on patient decisions to undertake screening or preventive action (medication or prophylactic mastectomy) was evaluated based on pre- and post-PRS surveys. Results: Between 2020 and 2025, 933 women were enrolled, 633 received PRS results and completed a survey to date. Of those who received PRS results, 214 (33.8%) were PV carriers (ATM: 24, BRCA1: 54, BRCA2: 73, CHEK2: 54 and PALB2: 9). Among PV carriers, the CanRisk-based median 10-year and lifetime pre-PRS risk estimates were 6.0% and 23.9% for ATM, 22.5% and 77.5% for BRCA1, 17.9% and 77.6% for BRCA2, 7.1% and 26.6% for CHEK2, and 16.6% and 42.4% for PALB2, respectively. A total of 7 (29.2%) ATM PV carriers had a shift in lifetime BC risk categories after integration of PRS, with 1 (4.2%) shifting from average to moderate-risk, 3 (12.5%) shifting from moderate to average-risk category, and 3 (12.5%) shifting from moderate to high-risk category. Among CHEK2 PV carriers, 9 (16.7%) had a shift in lifetime risk categories, with 4 (7.4%) shifting from moderate to average-risk, 2 (3.7%) shifting from moderate to high-risk, and 3 (5.6%) shifting from high to moderate-risk. None of the BRCA1 and 4.1% of BRCA2 PV carriers had a shift in lifetime risk categories after PRS integration. Only 1 (11.1%) PALB2 PV carrier had a change in lifetime risk category after integration of PRS, although this was limited by a small sample. A significantly higher proportion of PV carriers with a high lifetime risk intended to take preventative action compared to the PV carriers with average lifetime risk (41.4% vs. 20.0%, p=0.007). Conclusions: Integration of PRS into BC lifetime risk estimates led to a clinically meaningful change in risk categories in 29.2% of ATM PV carriers and 16.7% of CHEK2 PV carriers, but in 5% of BRCA1 or BRCA2 PV carriers. These findings suggest that PRS may be helpful for BC risk stratification in moderate-risk genes such as ATM and CHEK2 but may have limited clinical utility in high-risk genes such as BRCA1 or BRCA2. Citation Format: S. Yadav, C. Klassen, D. Stan, J. Fraker, S. Sahni, S. A. Khan, L. Khatri, C. Vachon, D. Schaid, J. P. Sinnwell, E. Carlson, L. Hasadsri, F. J. Couch, S. Pruthi. Impact of Polygenic Risk Scores on Breast Cancer Risk Assessment and Clinical Decision Making in Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2: Results from the Prospective Multisite GENRE-2 Clinical Trial abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD4-04.

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