研究提示他汀可使乳腺癌死亡率降低2/3

华盛顿——美国癌症研究协会(AACR)2013年会上公布的一项大型数据库研究显示，在乳腺癌诊断前后使用他汀类药物可使乳腺癌死亡风险降低66%。

Teemu J. Murtola博士

这项回顾性研究由约翰霍普金斯大学的流行病学家Teemu J. Murtola博士及其同事进行，目的是研究他汀类应用与乳腺癌死亡率之间的关系，研究对象是芬兰癌症注册处1995~2003年收录的被诊断为乳腺癌的31,114例女性。该数据库还收集了有关他汀类应用和其他健康指标的详细资料。他汀类相关资料包括每次处方购买时间、续药次数、剂量和每次续药数量。乳腺癌资料包括诊断时间、分期(局部、淋巴结阳性或转移性)、形态学、初治方案(手术、放射、化疗、激素治疗或其他)及死亡原因和时间。

随访从诊断时开始，直至死亡或2003年12月31日(取最先者)。中位随访时间为3年，范围为＜1年~9年。

他汀类使用者占队列的13%(4,169)；其余为未使用过他汀类的女性。与未使用者相比，他汀类使用者的年龄显著更大(64岁vs. 58岁)，接受手术的比例更高(96% vs. 92%)，接受放射的比例也更高(55% vs. 54%)，但接受化疗(15% vs. 24%)或激素治疗(20% vs. 25%)的比例显著较低。他汀类使用者的转移癌比例显著低于未使用者(4% vs. 7%)。这些差异可能反映出他汀类使用者的乳腺癌发现较早，这可能是因为他们就诊接受血脂监测的频率更高。

然而，多因素分析对所有这些差异(包括转移性和局部疾病)都进行了校正。研究者随后研究了诊断前后他汀类的应用对死亡率的影响。

乳腺癌诊断前开始用药的女性对治疗的依从性较高，有85%的女性持续用药至随访结束。与未使用者相比，使用他汀类药物490天的女性死于局部疾病的风险降低46%，死于转移性疾病的风险降低30%。在诊断前使用他汀类≥491天的女性死于局部疾病的风险降低66%，死于转移性疾病的风险降低40%。

在诊断后应用他汀类药物的女性中未观察到死亡风险与他汀类应用之间存在这样的明显剂量依赖性关系。但依从性低可能掩盖了治疗获益。在诊断后使用他汀类的女性中，仅14%持续用药至随访期结束。在仅对依从用药至随访结束的患者进行分析的情况下，研究者观察到了非常相似的剂量依赖性乳腺癌死亡风险降低模式。

随访期间，6,011例女性死亡；3,169例死亡由乳腺癌引起。他汀类使用者的死亡率显著低于未使用者(7.5% vs. 21%)。校正分析发现，使用他汀类的局部乳腺癌患者的死亡风险比未使用者低67%[危险比(HR)=0.33]，使用他汀类的转移癌患者的死亡风险比未使用者低48% (HR= 0.52)。

该研究队列使用的所有他汀类药物均与乳腺癌死亡风险显著降低相关，这些药物包括辛伐他汀(HR=0.47)、阿托伐他汀(HR=0.27)、氟伐他汀(HR=0.35)和普伐他汀(HR=0.50)。

体外研究表明，他汀类药物可直接作用于乳腺癌细胞及阻断参与生成胆固醇和对细胞代谢有重要作用的甲羟戊酸通路。乳腺癌细胞等代谢率异常高的细胞可能特别容易受到这种作用的影响。研究者表示有必要对他汀类药物降低乳腺癌死亡风险的作用进行进一步研究。

Murtola博士声明无经济利益冲突。

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By: MICHELE G. SULLIVAN, Cardiology News Digital Network

WASHINGTON – Statin use – both before and after a diagnosis of breast cancer – was associated with up to a 66% reduction in the risk of dying from that cancer, a large database study has concluded.

Investigators reported that the risk reduction was consistent even after controlling for age, tumor stage and morphology, and primary treatment choice, Dr. Teemu Murtola said during an interview at the annual meeting of the American Association for Cancer Research.

"We saw that there was clearly a dose-dependent reduction in the risk of breast cancer mortality among statin users," who comprised 13% of the more than 31,000 women in the study, said Dr. Murtola, an epidemiologist at Johns Hopkins University in Baltimore. "The association held for both localized and metastatic tumors. There really appears to be something going on here, and it’s certainly a reason for further study."

During the follow-up, 6,011 women died; 3,169 deaths were due to breast cancer. The death rate among users was significantly lower than it was among nonusers (7.5% vs. 21%). In the adjusted analysis, statin users were 67% less likely to die than were nonusers with localized disease (hazard ratio, 0.33). Among those with metastatic disease, statins conferred a 48% decreased risk of death (HR, 0.52).

All of the statins investigated in the study cohort were associated with a significantly decreased risk of breast cancer death, including simvastatin (HR, 0.47), atorvastatin (HR, 0.27), fluvastatin (HR, 0.35), and pravastatin (HR, 0.50).

The retrospective study looked at statin use and breast cancer mortality among 31,114 women with breast cancer who were diagnosed in Finland during 1995-2003. All of the patients were included in the Finnish Cancer Registry. The country’s national health database also contained detailed information on statin use and other health indicators. The data on statins included the date of each prescription purchase, the numbers of refills, the dosage, and the number of pills in each refill.

Breast cancer data included the date of diagnosis, stage (local, lymph-node positive or metastatic), morphology, primary treatment choice (surgery, radiation, chemotherapy, hormonal therapy, or other), and the date and cause of death.

Follow-up started at the time of diagnosis and continued until death or the common closing date of Dec. 31, 2003, whichever came first. Median follow-up was about 3 years, but ranged from less than 1 year to 9 years.

Statin users accounted for 13% of the cohort (4,169); the remainder never used the drugs. Women who took the medications were significantly older than nonusers (64 years vs. 58 years), and more likely to have had surgery as a treatment (96% vs. 92%). They were also more likely to have undergone radiation (55% vs. 54%), but significantly less likely to have had chemotherapy (15% vs. 24%) or hormonal therapy (20% vs. 25%). Metastatic cancer was significantly less common among statin users – 4% vs. 7%. These differences may reflect an early identification of breast cancer among users, perhaps because they were visiting a physician more frequently for lipid monitoring, Dr. Murtola said. However, the multivariate analysis controlled for all these differences, including metastatic and local disease.

Dr. Murtola then investigated the mortality effects of both pre- and postdiagnostic statin use.

Compliance was high among women who started the drugs before their breast cancer diagnosis, with 85% continuing until the end of follow-up. Compared with nonusers, women who used statins for up to 490 days were 46% less likely to die of local disease and 30% less likely to die from metastatic disease.

Those who took the drugs for 491 days or more before diagnosis were 66% less likely to die from local disease and 40% less likely to die from metastatic disease.

There was no such clear, dose-dependent relationship between mortality risk and statins taken after diagnosis, Dr. Murtola said. But, he added, low compliance could have masked any benefit. "Only 14% of those who started statins after diagnosis continued to take them until the end of the follow-up period," he said. "When we limited the analysis to those who were compliant until the end of their follow-up, we saw a very similar dose-dependent risk reduction in breast cancer mortality."

In vitro studies suggest that statins could have a direct effect on breast cancer cells, he said. They seem to block the mevalonate pathway – a process involved in the manufacture of cholesterol, and also key to cell metabolism. Cells with abnormally high metabolic rates – like breast cancer cells – could be particularly vulnerable to this action, he said.

"I think that because the drugs target this pathway their impact extends beyond cholesterol. It’s certainly worth further study."

Dr. Murtola had no financial disclosures.