Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York.
Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York.
Cancer Res Commun. 2023 Jun 22;3(6):1104-1112. doi: 10.1158/2767-9764.CRC-23-0047. eCollection 2023 Jun.
Previous studies suggest associations of metabolic syndromes with breast cancer prognosis, yet the evidence is mixed. In recent years, the maturation of genome-wide association study findings has led to the development of polygenic scores (PGS) for many common traits, making it feasible to use Mendelian randomization to examine associations between metabolic traits and breast cancer outcomes. In the Pathways Study of 3,902 patients and a median follow-up time of 10.5 years, we adapted a Mendelian randomization approach to calculate PGS for 55 metabolic traits and tested their associations with seven survival outcomes. Multivariable Cox proportional hazards models were used to derive HRs and 95% confidence intervals (CI) with adjustment for covariates. The highest tertile (T3) of PGS for cardiovascular disease was associated with shorter overall survival (HR = 1.34, 95% CI = 1.11-1.61) and second primary cancer-free survival (HR = 1.31, 95% CI = 1.12-1.53). PGS for hypertension (T3) was associated with shorter overall survival (HR = 1.20, 95% CI = 1.00-1.43), second primary cancer-free survival (HR = 1.24, 95% CI = 1.06-1.45), invasive disease-free survival (HR = 1.18, 95% CI = 1.01-1.38), and disease-free survival (HR = 1.21, 95% CI = 1.04-1.39). PGS for serum cystatin C levels (T3) was associated with longer disease-free survival (HR = 0.82, 95% CI = 0.71-0.95), breast event-free survival (HR = 0.74, 95% CI = 0.61-0.91), and breast cancer-specific survival (HR = 0.72, 95% CI = 0.54-0.95). The above associations were significant at a nominal < 0.05 level but not after correcting for multiple testing (Bonferroni < 0.0009). Our analyses revealed notable associations of PGS for cardiovascular disease, hypertension, and cystatin C levels with breast cancer survival outcomes. These findings implicate metabolic traits in breast cancer prognosis.
To our knowledge, this is the largest study of PGS for metabolic traits with breast cancer prognosis. The findings revealed significant associations of PGS for cardiovascular disease, hypertension, and cystatin C levels with several breast cancer survival outcomes. These findings implicate an underappreciated role of metabolic traits in breast cancer prognosis that would warrant further exploration.
目的： 先前的研究表明代谢综合征与乳腺癌预后相关，但证据不一。近年来，全基因组关联研究结果的成熟使得许多常见特征的多基因评分（PGS）得以开发，从而可以使用孟德尔随机化来检验代谢特征与乳腺癌结局之间的关联。在 3902 例患者的途径研究中，中位随访时间为 10.5 年，我们采用孟德尔随机化方法计算了 55 种代谢特征的 PGS，并检测了它们与 7 种生存结局的关联。多变量 Cox 比例风险模型用于得出调整协变量后的 HR 和 95%置信区间（CI）。心血管疾病 PGS 的最高三分位（T3）与总生存（HR = 1.34，95%CI = 1.11-1.61）和第二原发癌无复发生存（HR = 1.31，95%CI = 1.12-1.53）较短有关。高血压（T3）PGS 与总生存（HR = 1.20，95%CI = 1.00-1.43）、第二原发癌无复发生存（HR = 1.24，95%CI = 1.06-1.45）、浸润性疾病无复发生存（HR = 1.18，95%CI = 1.01-1.38）和无病生存（HR = 1.21，95%CI = 1.04-1.39）较短有关。血清胱抑素 C 水平 PGS（T3）与无病生存（HR = 0.82，95%CI = 0.71-0.95）、乳腺癌无事件生存（HR = 0.74，95%CI = 0.61-0.91）和乳腺癌特异性生存（HR = 0.72，95%CI = 0.54-0.95）较长有关。在名义水平<0.05时，上述关联具有统计学意义，但在多重检验校正后（Bonferroni <0.0009）则不具有统计学意义。我们的分析显示，心血管疾病、高血压和胱抑素 C 水平的 PGS 与乳腺癌生存结局之间存在显著关联。这些发现表明代谢特征与乳腺癌的预后有关。
意义： 据我们所知，这是最大规模的代谢特征 PGS 与乳腺癌预后相关性研究。研究结果显示，心血管疾病、高血压和胱抑素 C 水平的 PGS 与多种乳腺癌生存结局显著相关。这些发现提示代谢特征在乳腺癌预后中的作用被低估，值得进一步探索。
