Breast Cancer Res:如何预测乳腺癌幸存者冠心病风险?看多基因风险评分啊!

2021-10-06 MedSci原创 MedSci原创

心血管疾病是乳腺癌幸存患者中的长期风险因素,且随着乳腺癌疗法而增加。

2018年全球新增女性乳腺癌病例约210万例,占女性癌症病例的25%。过去30年来,随着癌症治疗的进展,妇女的长期生存状况有所改善,由此其他原因导致的死亡率变得更加重要。血管疾病 (CVD) 是乳腺癌幸存老年患者的主要死因。细胞毒性化疗和放射治疗的影响,也与心血管发病率和死亡率的增加有关。本文将重点研究最常见的CVD类型——冠状动脉疾病(CAD)。多种生活方式和环境风险因素与CAD息息相关,包括吸烟、体重指数(BMI)、总胆固醇、1型和2型糖尿病以及高血压。而遗传因素也被证明会影响CAD风险:全基因组关联研究 (GWAS) 已识别出许多与 CAD 相关的常见遗传变异,多基因风险评分 (PRS) 已被证明可有效识别 CAD 风险。

鉴于目前对生存益处和未来心毒性伤害的平衡导致乳腺癌幸存者的心血管疾病负担增加,而风险分层可能有助于解决这一临床困境。本研究首次评估了冠状动脉疾病特异性多基因风险评分与女性乳腺癌幸存者冠状动脉事件之间的关系。

本研究组覆盖12413名参与者。确诊时平均年龄为54.6岁,从诊断到进入研究的中位数时间为1.8年,中位随访时间为10.3年,随访期间共750人经历了CAD事件。9496人(77%)接受了内分泌治疗,8773人(71%)接受了放射治疗,4735人(38%)接受了辅助化疗。表1为随访期间观察到的CAD患者的基因分型特征。

以年龄校正后,研究每个变量与事件 CAD 存活率的关联(表2)。PRS与乳腺癌生存率无相关性(HR 1.02;95%CI 0.96 - -1.08)。

多变量模型的样本量为8946个,共432个事件(图1)。仅根据诊断时的年龄、基因型排列和8个遗传pc调整后,每高1SD PRS的冠心病发生率的HR为1.36 (95% CI 1.23-1.51)。调整吸烟状态和BMI等传统危险因素后,仅有一点减少(表3,HRmodel2=1.34;95% CI 1.21 -1.49)。调整其他社会人口学、生活方式和医疗变量后,PRS的HR并没有显著变化(HRmodel5=1.33;95%可信区间1.20-1.47)。在本研究中,没有证据表明,在纳入或PRS和其他中介变量的情况下,化疗、放疗或内分泌治疗与冠心病发生相关。

将PRS与心血管疾病危险因素、log(BMI)和吸烟之间的相互作用添加到一个包含基因型数组、8个遗传pc、log(BMI)、吸烟、教育水平、饮酒、胎次、激素替代疗法的模型中(表4)。联合危险比见表5。

PRS与肿瘤治疗的相互作用:在包含基因型序列、8个基因PCs、log(BMI)、遗传因子的模型中,PRS与放疗、PRS与化疗、PRS与抗激素治疗交互项的HR分别为1.15(0.92,1.43)、0.93(0.74,1.16)、1.15(0.90,1.46)。

PRS对乳腺癌幸存者冠心病风险分层的能力:风险最低五分之一的妇女在15.1岁时累积发病率达到5%,而风险最高五分之一的妇女累积发病率为8.9年。

仅通过c指数测量的PRS的判别略低于BMI和吸烟合并模型(0.73 vs. 0.74, P=0.048)(图3)。添加PRS对包括基因型序列、8个遗传pc、BMI、吸烟状况、教育水平、饮酒、IMD、初潮期年龄、胎次、激素替代治疗和甲状腺疾病在内的模型几乎没有实际改善(0.757 vs. 0.764, P=0.052)。经筛选的CAD和非CAD病例的总比例分别为22%和11%。

这项基于大量英国乳腺癌女性的队列研究结果,表明针对一般人群制定的CAD多基因风险评分可推广到乳腺癌患者,估计每增加1个SD的PRS, CAD风险就会增加33% (HR=1.33, 95% CI 1.20, 1.47)。这独立于已确定的心血管危险因素(年龄,吸烟,BMI),肿瘤治疗和其他与心血管危险相关的变量(教育水平)。PRS可以改善乳腺癌幸存者的风险识别,例如,我们在比较风险评分分布的顶部和底部1 / 5的个体时发现,冠心病的HR超过两倍。此外,当考虑乳腺癌诊断后10年发生冠心病的风险时,我们发现在基线模型中添加PRS后,5.6%没有记录冠心病事件的低风险参与者被重新分类为高风险组。

综上,心血管疾病是乳腺癌幸存患者中的重要长期风险,而这种风险因一些乳腺癌疗法而增加。心血管疾病的综合风险模型有可能帮助临床管理这种风险,并可能改善这些妇女的长期结果。

原文来源:

Liou et al. Genomic risk prediction of coronary artery disease in women with breast cancer:a prospective cohort study.Breast Cancer Res (2021) 23:94
https://doi.org/10.1186/s13058-021-01465-0

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    2022-01-11 syscxl
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    2021-10-08 zhaojie88
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    2021-10-07 ms5000000518166734

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    2021-10-07 老龙一点

    学习

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