Integrating breast cancer polygenic risk scores at scale in the WISDOM Study: a national randomized personalized screening trial.

IF 10.4 1区生物学 Q1 GENETICS & HEREDITY

Genome Medicine Pub Date : 2025-08-28 DOI:10.1186/s13073-025-01524-7

Kirkpatrick B Fergus, Rachel S Heise, Lisa Madlensky, Allison Fiscalini, Leah Sabacan, Sarah Theiner, Shreya Kapoor, Irene A Soto, Amie Blanco, Katherine Ross, Deborah Goodman-Gruen, Maren Scheuner, Donglei Hu, Diane Heditsian, Susie Brain, Vignesh A Arasu, Andrea Kaster, Lisa Chapa, Olufunmilayo I Olopade, Martin Eklund, Jeffrey A Tice, Elad Ziv, Laura van 't Veer, Laura J Esserman, Yiwey Shieh

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引用次数: 0

Abstract

Background: The Women Informed to Screen Depending On Measures of risk (WISDOM) Study is the first prospective, population-wide application of personalized breast cancer screening. We aim to demonstrate the feasibility of the study's novel use of polygenic risk scores (PRSs) to tailor screening, evaluate our strategy for adapting PRSs to diverse populations, and quantify the impact of incorporating PRS on the study's screening recommendations.

Methods: WISDOM is a randomized, preference-tolerant screening trial in the USA testing the safety and morbidity of risk-based versus annual screening in women aged 40-74 without a prior history of breast cancer. This early report includes participants in the risk-based arm only and compares screening recommendations generated by the Breast Cancer Surveillance Consortium (BCSC) clinical risk model alone versus the BCSC model modified by a PRS (BCSC-PRS). The main outcome of interest is the proportion of participants with a change in screening recommendation after integrating PRS for risk stratification.

Results: In the risk-based arm, 21,631 participants received a PRS. Small but statistically significant differences in the PRS were seen between major racial and ethnic groups (p < 0.001), and higher PRS was associated with greater extent of family history (p < 0.001) and denser breasts (p < 0.001). BCSC-PRS risk estimates changed the screening recommendations for 14% of women aged 40-49 compared to BCSC alone and for 10% of women aged 50-74. Projected net screening encounters at the population level were similar for both age groups.

Conclusions: In a first-in-kind application of PRS to inform breast cancer screening approaches, we demonstrate feasibility for scaled implementation, moderate changes to individual screening recommendations, and minimal projected downstream burden on the healthcare system.

Trial registration: Prospectively registered on ClinicalTrials.gov as NCT02620852 on 12/2/2015.

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在WISDOM研究中整合乳腺癌多基因风险评分：一项全国性随机个性化筛查试验。

背景：根据风险措施接受筛查的妇女（WISDOM）研究是第一个前瞻性的、全民范围的个性化乳腺癌筛查应用。我们的目标是证明该研究新使用多基因风险评分（PRS）来定制筛查的可行性，评估我们使PRS适应不同人群的策略，并量化纳入PRS对研究筛选建议的影响。方法：WISDOM是一项在美国进行的随机、偏好耐受筛查试验，在40-74岁无乳腺癌病史的女性中测试基于风险的筛查与年度筛查的安全性和发病率。该早期报告仅包括基于风险组的参与者，并比较了乳腺癌监测联盟（BCSC）单独临床风险模型与经过PRS修改的BCSC模型（BCSC-PRS）产生的筛查建议。主要关注的结果是在整合PRS进行风险分层后，筛查建议发生改变的参与者比例。结果：在基于风险的组中，21,631名参与者接受了PRS。在主要种族和族裔群体之间，PRS的差异很小，但在统计学上具有显著意义(p结论：在首次将PRS应用于乳腺癌筛查方法中，我们证明了大规模实施的可行性，对个人筛查建议的适度改变，以及对医疗保健系统的预期下游负担最小。试验注册：于2015年2月12日在ClinicalTrials.gov上前瞻性注册，注册号为NCT02620852。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Genome Medicine GENETICS & HEREDITY-

CiteScore

20.80

自引率

0.80%

发文量

128

审稿时长

6-12 weeks

期刊介绍： Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.