筛查对于早期发现乳腺癌具有重要作用，可以显著降低整个女性人群的乳腺癌死亡率。不过，对于女性个体而言，目前的女性人群大规模乳腺癌筛查方案仅仅根据年龄段一刀切，造成大量不必要的浪费和伤害。越来越多的证据表明，通过针对风险而非一刀切的筛查方案，提供个体化的筛查起止年龄以及筛查间隔，可以减少不必要的浪费和伤害。家族史和基因致病变异已被用于指导特定高风险女性的风险监测，多基因风险评分也被证实可以通过将常见遗传因素信息结合到一次检测而有效地对乳腺癌风险进行分层。可惜，这种针对风险的监测长期以来仅被用于特定亚组女性，例如BRCA1、PALB2等中高风险乳腺癌易感基因致病变异携带者以及早发乳腺癌家族成员，对于现实生活整个女性人群乳腺癌筛查的作用尚不明确。 2024年2月29日，美国临床肿瘤学会《临床肿瘤学杂志》在线发表芬兰赫尔辛基大学、赫尔辛基大学医院、芬兰癌症学会、芬兰癌症登记处、美国麻省理工学院与哈佛大学布罗德研究所的FinnGen研究报告，利用大数据回顾分析了多基因风险评分、家族史和基因致病变异对整个女性人群进行乳腺癌分层筛查的效用。 该大数据回顾分析首先将FinnGen研究11万7252例女性数据与芬兰乳腺癌大规模筛查登记数据库（1992～2019年全国范围每两年组织一次对50～69岁女性进行筛查）进行关联，随后比较乳腺癌多基因风险评分、乳腺癌家族史、中高风险易感基因（CHEK2、PALB2）致病变异对乳腺癌筛查的效用。 结果发现，对于筛查年龄段的女性，家族史、致病变异、多基因风险评分>90%的效益大小相似，对筛查开始时年龄变化的作用相似。- 筛查结果阳性更有可能被诊断为乳腺癌（阳性预测值：39.5%，95%置信区间：37.6～41.5）
- 结合各种风险因素可将阳性预测值提高至45%～50%
- 筛查间期乳腺癌风险较高（50岁、60岁时风险比分别为2.78、2.48，95%置信区间：2.00～3.86、1.67～3.70）
因此，该大数据回顾分析研究利用现实生活筛查数据证实，乳腺癌多基因风险评分单独或结合家族史和致病变异进行风险分层筛查有效，将来尝试个体化乳腺癌筛查类型和时间表的研究应该认真考虑将多基因风险评分结合其他风险因素，有必要开展进一步前瞻研究评价多基因风险评分对风险分层筛查计划的作用，尤其是成本效益如何。 对此，美国宾夕法尼亚大学佩雷尔曼医学院艾布拉姆森癌症中心、退伍军人事务部迈克尔·克雷森兹医疗中心发表同期评论：采用多基因风险评分加强或减少乳腺癌筛查。J Clin Oncol. 2024 Feb 29. IF: 45.3 Comprehensive Inherited Risk Estimation for Risk-Based Breast Cancer Screening in Women. OPEN ACCESS Mars N, Kerminen S, Tamlander M, Pirinen M, Jakkula E, Aaltonen K, Meretoja T, Heinavaara S, Widén E, Ripatti S; FinnGen. University of Helsinki, Helsinki, Finland; Broad Institute of MIT and Harvard, Cambridge, MA; Helsinki University Hospital, Helsinki, Finland; Finnish Cancer Registry, Cancer Society of Finland, Helsinki, Finland. PURPOSE: Family history (FH) and pathogenic variants (PVs) are used for guiding risk surveillance in selected high-risk women but little is known about their impact for breast cancer screening on population level. In addition, polygenic risk scores (PRSs) have been shown to efficiently stratify breast cancer risk through combining information about common genetic factors into one measure. METHODS: In longitudinal real-life data, we evaluate PRS, FH, and PVs for stratified screening. Using FinnGen (N = 117,252), linked to the Mass Screening Registry for breast cancer (1992-2019; nationwide organized biennial screening for age 50-69 years), we assessed the screening performance of a breast cancer PRS and compared its performance with FH of breast cancer and PVs in moderate- (CHEK2)- to high-risk (PALB2) susceptibility genes. RESULTS: Effect sizes for FH, PVs, and high PRS (>90th percentile) were comparable in screening-aged women, with similar implications for shifting age at screening onset. A high PRS identified women more likely to be diagnosed with breast cancer after a positive screening finding (positive predictive value [PPV], 39.5% [95% CI, 37.6 to 41.5]). Combinations of risk factors increased the PPVs up to 45% to 50%. A high PRS conferred an elevated risk of interval breast cancer (hazard ratio [HR], 2.78 [95% CI, 2.00 to 3.86] at age 50 years; HR, 2.48 [95% CI, 1.67 to 3.70] at age 60 years), and women with a low PRS (<10th percentile) had a low risk for both interval- and screen-detected breast cancers. CONCLUSION: Using real-life screening data, this study demonstrates the effectiveness of a breast cancer PRS for risk stratification, alone and combined with FH and PVs. Further research is required to evaluate their impact in a prospective risk-stratified screening program, including cost-effectiveness. KEY OBJECTIVE: The current approach to population breast cancer screening uses a one-size-fits-all regimen, yet studies on inherited risk factors, including polygenic risk scores (PRS) for breast cancer, family history, and pathogenic variants (PVs) in susceptibility genes, suggest the potential for personalized screening on the basis of individual risk profiles. How do such inherited risk factors, particularly the PRS, which is a more recently identified risk factor, perform in real-life screening data? KNOWLEDGE GENERATED: The breast cancer PRS served for risk stratification of breast cancer screening both alone and combined with FH and PVs. A high PRS correlated with a high positive predictive value for breast cancer screening and conferred an elevated risk for interval breast cancer. RELEVANCE: Future trials attempting to personalize type and schedule of breast cancer screening should strongly consider incorporation of a PRS along with other risk factors. PMID: 38422475 DOI: 10.1200/JCO.23.00295 NOTE: This article is available under the Creative Commons CC-BY-NC-ND license and permits non-commercial use of the work as published, without adaptation or alteration provided the work is fully attributed. J Clin Oncol. 2024 Feb 29. IF: 45.3 Toward Application of Polygenic Risk Scores to Both Enhance and Deintensify Breast Cancer Screening. Maxwell KN, Domchek SM. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA; Corporal Michael Crescenz Veterans Affairs Medical Center, Philadelphia, PA. PMID: 38422469 DOI: 10.1200/JCO.24.00029
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