Background and aim: The involvement of cholesterol in cancer development remains a topic of debate, and its association with breast cancer has yet to be consistently demonstrated. Considering that circulating cholesterol levels depend on several concomitant processes, we tested the liability of plasma levels of proprotein convertase subtilisin/kexin type 9 (PCSK9), one of the key regulators of cholesterol levels, as a prognostic biomarker in the context of breast neoplastic events. Methods: Within a prospective randomized breast cancer prevention trial we measured baseline plasma levels ofPCSK9. A total of 235 at-risk premenopausal women were randomized and followed up for 17 years. Participants enrolled in this placebo-controlled, phase II, double-blind trial were randomly assigned to receive either tamoxifen 5 mg/d or fenretinide 200 mg/d, both agents, or placebo for 2 years. The associations with breast cancer events were evaluated through competing risk and Cox regression survival models, adjusted for randomization strata (5-year Gail risk ≥ 1.3% vs. intraepithelial neoplasia or small invasive breast cancer of favorable prognosis), age, and treatment allocation.PCSK9associations with biomarkers linked to breast cancer risk were assessed on blood samples collected at baseline. Results: The plasmaticPCSK9median and interquartile range were 207 ng/mL and 170–252 ng/mL, respectively. Over a median follow-up period of 17 years and 89 breast neoplastic events, disease-free survival curves showed a hazard ratio of 1.002 (95% CI: 0.999–1.005,p= 0.22) for women withPCSK9plasma levels ≥ 207 ng/mL compared to women with levels below 207 ng/mL. No differences between randomization strata were observed. We found a negative correlation betweenPCSK9and estradiol (r = −0.305), maintained even after partial adjustment for BMI and age (r = −0.287). Cholesterol (r = 0.266), LDL-C (r = 0.207), non-HDL-C (r = 0.246), remnant cholesterol (r = 0.233), and triglycerides (r = 0.233) also correlated withPCSK9. Conclusions: In premenopausal women at risk of early-stage breast cancer,PCSK9did not appear to have a role as a prognostic biomarker of breast neoplastic events. Larger studies are warranted investigating patients in different settings.
背景与目的：胆固醇在癌症发展中的作用仍存争议，其与乳腺癌的关联尚未得到一致证实。考虑到循环胆固醇水平受多种并存过程调控，本研究以前瞻性随机乳腺癌预防试验为背景，检测了胆固醇关键调节因子——前蛋白转化酶枯草溶菌素9型（PCSK9）的血浆水平，探讨其作为乳腺肿瘤事件预后生物标志物的可行性。方法：在一项前瞻性随机乳腺癌预防试验中，我们测量了235名高危绝经前女性的基线血浆PCSK9水平，并进行为期17年的随访。这项安慰剂对照、双盲、II期试验的参与者被随机分配接受他莫昔芬5 mg/天、芬维A胺200 mg/天、两药联合或安慰剂治疗2年。通过竞争风险模型和Cox回归生存模型评估PCSK9与乳腺癌事件的关联性，模型根据随机分层（盖尔5年风险≥1.3% vs. 上皮内瘤变或预后良好的小型浸润性乳腺癌）、年龄和治疗分配进行调整。通过基线血样评估PCSK9与乳腺癌风险相关生物标志物的关联。结果：血浆PCSK9中位数和四分位距分别为207 ng/mL和170-252 ng/mL。在中位随访17年期间共发生89例乳腺肿瘤事件，无病生存曲线显示：与血浆PCSK9水平<207 ng/mL的女性相比，PCSK9≥207 ng/mL者的风险比为1.002（95% CI：0.999-1.005，p=0.22）。不同随机分层间未观察到显著差异。研究发现PCSK9与雌二醇呈负相关（r=-0.305），经BMI和年龄部分校正后相关性依然存在（r=-0.287）。胆固醇（r=0.266）、低密度脂蛋白胆固醇（r=0.207）、非高密度脂蛋白胆固醇（r=0.246）、残余胆固醇（r=0.233）和甘油三酯（r=0.233）均与PCSK9呈正相关。结论：在早期乳腺癌高危绝经前女性中，PCSK9似乎不能作为乳腺肿瘤事件的预后生物标志物。未来需要在不同临床背景下开展更大规模的研究加以验证。
肿瘤(癌症)患者之家