Background/Objectives:The implementation of polygenic scores (PGSs) and multifactorial risk assessments (MFRAs) has the potential to enhance breast cancer risk stratification, particularly in carriers of moderate-penetrance pathogenic variants (PVs), whose risk profiles often remain unclear if testing is limited to monogenic risk factors.Methods:To enhance breast cancer risk stratification, we included the BCAC313 polygenic score, together with MFRA, for carriers of moderate-penetrance pathogenic variants (PVs) during routine diagnostics and assessed its effect on the classification of patients’ risk categories in a real-world cohort at our center in its first year of implementation. Seventeen carriers with PVs in moderate-risk breast cancer genes were included in this study. Thirteen of them qualified for analysis for a full MFRA, including PGS, according to ancestry estimation and clinical criteria. The MFRA was performed using the CanRisk tool, which incorporates clinical, lifestyle, familial, and genetic data, including the BCAC313 score.Results:PGS z-scores were significantly higher in breast cancer patients compared to the unaffected control cohort (p= 0.016). The MFRA, including PGS, increased risk estimates for contralateral breast cancer in seven of eight patients with breast cancer and for primary breast cancer in three of five healthy carriers, compared to the risk conferred by the MFRA and moderate-penetrance pathogenic variant alone. Risk estimates varied widely, demonstrating the value of MFRA in personalized care. In five cases, one with aCHEK2-PV and four with anATM-PV, the modified risk assessment contributed to the surgical decision for a prophylactic mastectomy.Conclusions:The MFRA, including PGS, provides the clinically meaningful refinement of breast cancer risk estimates in individuals with moderate-risk PVs. Personalized risk predictions can inform clinical management and support decision-making, which highlights the utility of this approach in clinical practice.
背景/目的：多基因评分（PGS）与多因素风险评估（MFRA）的应用有望提升乳腺癌风险分层能力，尤其对于中穿透性致病性变异（PV）携带者——若检测仅限于单基因风险因素，这类人群的风险特征常不明确。方法：为优化乳腺癌风险分层，我们在常规诊断中对中穿透性PV携带者纳入BCAC313多基因评分及MFRA，并在实施首年评估其对本中心真实世界队列患者风险分类的影响。本研究纳入17例中风险乳腺癌基因PV携带者，其中13例符合祖源评估与临床标准，可进行包含PGS的完整MFRA分析。MFRA通过CanRisk工具实施，该工具整合临床、生活方式、家族史及遗传数据（含BCAC313评分）。结果：乳腺癌患者的PGS z评分显著高于未患病对照组（p=0.016）。相较于仅基于MFRA和中穿透性PV的风险评估，纳入PGS的MFRA使8例乳腺癌患者中的7例对侧乳腺癌风险预估升高，5例健康携带者中的3例原发性乳腺癌风险预估升高。风险评估结果差异显著，体现了MFRA在个体化诊疗中的价值。在5例病例（1例CHEK2-PV，4例ATM-PV）中，修正后的风险评估为预防性乳房切除术的决策提供了依据。结论：包含PGS的MFRA能为中风险PV携带者提供具有临床意义的乳腺癌风险精细化评估。个体化风险预测可指导临床管理并支持决策制定，凸显了该方法在临床实践中的应用价值。
肿瘤(癌症)患者之家