Myriad Genetics, Inc., Salt Lake City, UT.
Myriad Genetics, Inc., Salt Lake City, UT.
Genet Med. 2024 Jul;26(7):101128. doi: 10.1016/j.gim.2024.101128. Epub 2024 Jun 3.
We previously described a combined risk score (CRS) that integrates a multiple-ancestry polygenic risk score (MA-PRS) with the Tyrer-Cuzick (TC) model to assess breast cancer (BC) risk. Here, we present a longitudinal validation of CRS in a real-world cohort.
This study included 130,058 patients referred for hereditary cancer genetic testing and negative for germline pathogenic variants in BC-associated genes. Data were obtained by linking genetic test results to medical claims (median follow-up 12.1 months). CRS calibration was evaluated by the ratio of observed to expected BCs.
Three hundred forty BCs were observed over 148,349 patient-years. CRS was well-calibrated and demonstrated superior calibration compared with TC in high-risk deciles. MA-PRS alone had greater discriminatory accuracy than TC, and CRS had approximately 2-fold greater discriminatory accuracy than MA-PRS or TC. Among those classified as high risk by TC, 32.6% were low risk by CRS, and of those classified as low risk by TC, 4.3% were high risk by CRS. In cases where CRS and TC classifications disagreed, CRS was more accurate in predicting incident BC.
CRS was well-calibrated and significantly improved BC risk stratification. Short-term follow-up suggests that clinical implementation of CRS should improve outcomes for patients of all ancestries through personalized risk-based screening and prevention.
我们之前描述了一种综合风险评分（CRS），该评分将多血统多基因风险评分（MA-PRS）与 Tyrer-Cuzick（TC）模型相结合，以评估乳腺癌（BC）风险。在这里，我们在真实队列中对 CRS 进行了纵向验证。
本研究纳入了 130058 名因遗传性癌症基因检测且 BC 相关基因种系致病性变异阴性而就诊的患者。通过将基因检测结果与医疗索赔相关联（中位随访 12.1 个月）获得数据。通过观察到的 BC 与预期 BC 的比例评估 CRS 的校准情况。
在 148349 患者年中观察到 340 例 BC。CRS 校准良好，在高危十分位数中显示出优于 TC 的校准。MA-PRS 单独具有比 TC 更高的判别准确性，而 CRS 的判别准确性比 MA-PRS 或 TC 大约高 2 倍。在 TC 分类为高危的患者中，有 32.6%的患者为 CRS 低风险，而在 TC 分类为低风险的患者中，有 4.3%的患者为 CRS 高风险。在 CRS 和 TC 分类不一致的情况下，CRS 更能准确预测 BC 的发生。
CRS 校准良好，显著改善了 BC 风险分层。短期随访表明，CRS 的临床应用应通过个性化基于风险的筛查和预防，改善所有种族患者的结局。
