长期使用钙通道阻滞剂或增加乳腺癌风险

《美国医学会杂志-内科学》8月5日在线发表的一篇报告显示，长期使用钙通道阻滞剂(CCB)与浸润性乳腺导管癌和浸润性乳腺小叶癌风险均翻倍有关(JAMA Intern. Med. 2013 Aug. 5 [doi:10.1001/jamainternmed.2013.9071])。

主要研究者、西雅图Fred Hutchinson癌症研究中心的Christopher I. Li博士指出，由于这是首次得出CCB对乳腺癌风险具有强烈长期影响的数据，因此这项大型以人群为基础的病例对照研究的结果尚有待进一步证实。

研究者还发现，乳腺癌与任何其他常用降压药均无关联，即使服用较长时间。鉴于降压药是目前最常用的药物类别，上述研究结果对于公众健康具有重要意义。


Christopher Li博士

既往研究显示乳腺癌风险与降压药总体之间可能存在关联，但针对CCB的研究却未能得出一致结果。这些研究纳入的乳腺癌患者数量往往较少，多数没有评估长期用药的影响，而且没有充分评估较新的药物。

为此，Li博士及其同事招募了长期服用降压药的绝经后女性，涉及所有主要类别的降压药，样本量大到足以分析乳腺癌最常见的两种组织学亚型：浸润性导管癌(IDC)和浸润性小叶癌(ILC)。研究者从一个肿瘤注册数据库中找出了在2000年1月~2008年12月期间被诊断为原发性IDC或ILC、年龄55~74岁的1,960例女性患者，并纳入了891名年龄、居住地相匹配的无肿瘤女性作为对照。这两组女性具有相似的家庭年收入和高血压、心脏病、高脂血症病史。

分析结果显示，总体使用、正在使用、既往使用以及短期使用降压药，均与IDC或ILC风险无关。仅有长期使用CCB(≥10年)与乳腺癌风险增加有关，对于IDC的比值比(OR)为2.4，对于ILC的OR值为2.6。

在校正肿瘤的雌激素受体(ER)状态后，上述相关性仍保持鲁棒性：ER阳性IDC的OR值为2.3，ER阴性IDC的OR值为3.1，ER阳性ILC的OR值为2.6。

其他类型降压药与乳腺癌风险之间均无显著关联。“就利尿剂而言，我们也单独评估了与使用噻嗪类和非噻嗪类利尿剂相关的风险，结果发现二者均与乳腺癌风险无关。”

研究者还开展了一项仅针对患有高血压且正在使用降压药的女性的敏感性分析，得出了与上述相似的结果。这意味着疾病本身并不能解释CCB与乳腺癌的关联，因此用药指征带来的混淆效应已经得到了充分控制。

“有一些迹象提示，正在使用血管紧张素转换酶抑制剂(ACEI)且已使用达10年，与ICD(OR，0.7)和ILC(OR，0.6)风险降低有关，不过对于IDC风险的估计值仍在几率范围内。”Li博士及其同事补充道，必须谨慎解读这一发现，并在纳入大量长期使用ACEI的患者的研究中加以验证。

美国国立癌症研究所与美国国防部为本项研究提供了支持。研究者无相关利益冲突披露。

随刊述评：停用CCB？

波士顿大学Slone流行病学中心的Patricia F. Coogan博士在随刊述评中指出，不应该依据本项研究的结果停用CCB，因为这是一项观察性研究，不能证明因果关系，而且仅凭一项研究的结果并不足以改变临床实践(JAMA Intern. Med. 2013 Aug. 5 [doi:10.1001/jamainternmed.2013.9069])。


Patricia Coogan博士

不过，这并不表示我们可以忽略这一研究结果。“这些数据很有说服力，因为它是一流水平的研究，具有大样本量、高病例应答率(80%)，且很好地采集了受试者的用药情况。研究者进行了缜密分析以找出研究结果的可能解释，并排除了用药指征方面的混淆因素。”

CCB是2009年美国处方量第9大的药物类别。假如未来的研究能证实CCB长期使用者的乳腺癌风险增加1~2倍，那么CCB的使用将成为一个重要的可纠正的乳腺癌危险因素。

Coogan博士报告称无相关利益冲突。

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By: MARY ANN MOON, Cardiology News Digital Network

The long-term use of calcium-channel blockers is associated with a doubling of the risk of both invasive ductal carcinoma and invasive lobular carcinoma of the breast, according to a report published online Aug. 5 in JAMA Internal Medicine.

This and other findings from a large population-based case-control study require confirmation in future research, because this is the first report of such a strong adverse long-term impact of calcium-channel blockers (CCBs) on breast cancer risk, said Dr. Christopher I. Li of the division of public health sciences, Fred Hutchinson Cancer Research Center, Seattle, and his associates.

The investigators found no such association between breast cancer and any of the other commonly used antihypertensive agents, even if they were taken for long durations.

The study results are relevant to public health, given that antihypertensive drugs are the most commonly prescribed class of medication in the United States, the researchers noted.

Previous studies of a possible link between breast cancer risk on the one hand and antihypertensive agents in general, and CCBs in particular, on the other hand, have produced inconsistent results. Most have included relatively few cases of breast cancer, have not assessed longer durations of use, and have inadequately examined the more recently introduced forms of the drugs.

Dr. Li and his colleagues averted these drawbacks by assessing postmenopausal women who had taken all the major classes of antihypertensive drugs for long durations, in a large enough sample to include many cases of the two most common histologic subtypes of breast cancer: invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC).

They identified through a tumor registry 1,960 women aged 55-74 years who were diagnosed as having a primary IDC or ILC during January 2000 to December 2008 in the greater metropolitan Seattle area. These cases were matched for age and area of residence with 891 cancer-free women who served as controls. The two groups had similar annual household incomes and medical histories of hypertension, heart disease, and hypercholesterolemia.

Overall use, current use, former use, and short-term use of antihypertensive drugs were not associated with the risk of either IDC or ILC.

Only the long-term use of calcium-channel blockers (10 years or more) was related to increased risk of breast cancer, with an OR of 2.4 for IDC and an OR of 2.6 for ILC, the investigators said (JAMA Intern. Med. 2013 Aug. 5 [doi:10.1001/jamainternmed.2013.9071]).

This association remained robust when the data were analyzed according to the tumor’s estrogen-receptor status: The ORs were 2.3 for ER-positive IDC, 3.1 for ER-negative IDC, and 2.6 for ER-positive ILC.

No other drug categories showed significant associations with breast cancer risk. "With respect to diuretic use, risks associated with thiazide and nonthiazide diuretic use were also assessed separately, but neither was associated with breast cancer risk," they said.

A sensitivity analysis limited to women in both study groups who had hypertension and were currently using antihypertensive medications produced similar results. This indicates that the underlying condition itself does not explain the association with breast cancer, and thus confounding by indication was adequately controlled for.

"There was also some indication that current use of ACE inhibitors for 10 years or longer was associated with reduced risks of both IDC (OR, 0.7) and ILC (OR, 0.6), though the risk estimate for IDC was within the limits of chance," they said.

This finding must be interpreted with caution and requires confirmation in future research that includes a large number of long-term users of ACE inhibitors, Dr. Li and his associates added.

The U.S. National Cancer Institute and the U.S. Department of Defense supported the study. No relevant financial conflicts of interest were reported.

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Stop prescribing CCBs?

The use of CCBs should not be discontinued on the basis of this study because it is observational, it cannot prove causality, and its findings alone should not change clinical practice, said Patricia F. Coogan, Sc.D.

But neither should the findings be dismissed. "The data are persuasive because this was a first-rate study," with a large sample, a high case response rate (80%), and best-practice ascertainment of medication use among the participants. "The study particularly excels in the careful analytic efforts used to identify alternate explanations for the findings," and in ruling out confounding by indication.

If future research confirms the two- to threefold increase in breast cancer risk with long-term use of CCBs – the ninth most commonly prescribed class of drugs in the United States in 2009 – avoiding these medications will become one of the major modifiable risk factors for breast cancer, she said.

Dr. Coogan is at Slone Epidemiology Center at Boston University. She reported no financial conflicts of interest. These remarks were taken from her invited commentary accompanying Dr. Li’s report (JAMA Intern. Med. 2013 Aug. 5 [doi:10.1001/jamainternmed.2013.9069]).