雌激素和孕激素与绝经后女性乳腺癌发病率和死亡率的研究

       背景： 妇女健康倡议（Women's Health Initiative）是一项雌激素和孕激素的随机、安慰剂对照研究，平均干预时间为5.6年（标准差 SD，1.3）（范围3.7-8.6年），平均随访7.9年（SD 1.4），结果发现接受联合激素治疗的女性乳腺癌发病率增加。试验参与者的乳腺癌死亡率尚未报告。

       目的： 确定截止2009年8月14日共计平均随访11.0年（SD 2.7年）雌激素加孕激素治疗对乳腺癌累积发病率和死亡率的影响。设计、地点和受试者：美国40个临床中心共16,608名50至79岁既往未行子宫切除术的绝经后妇女，随机服用马结合雌激素 0.625mg/d和甲羟孕酮 2.5mg/d或服用安慰剂。在初始研究结束后（2005年3月31日），就继续随访乳腺癌的发病率请求患者的知情同意，12,788（83％）存活者签署了知情同意。
      主要观察指标： 浸润性乳腺癌的发病率和乳腺癌的死亡率。
      结果： 意向性治疗分析纳入所有随机受试者并排除了不同意进行后续随访的女性，研究发现雌激素加孕激素与安慰剂相比，侵袭性乳腺癌的发生更多（385例 [每年0.42％] vs 293例[每年0.34％]；风险比[HR]为1.25; 95％可信区间[CI]为1.07-1.46，P=0.004）。雌激素加孕激素组乳腺癌的组织学和分级与安慰剂组乳腺癌相似，但淋巴结阳性率更高（分别为81 [23.7％] vs 43 [16.2％]；HR 1.78 ；95％CI 1.23-2.58，P=0.03）。服用雌激素加孕激素的女性与安慰剂组相比，乳腺癌直接归因死亡病例更多（25人死亡[每年0.03％] vs 12人死亡[每年0.01％]；HR，1.96；95％CI 1.00-4.04，P=0.049），乳腺癌诊断后的全因死亡率更高（51人死亡[每年0.05％] vs31人死亡[每年0.03％]；HR，1.57；95％CI 1.01-2.48，P=0.045）。

      结论：雌激素加孕激素与乳腺癌发病率更高相关，乳腺癌淋巴结阳性更为常见。雌激素和孕激素联合使用似乎增加乳腺癌死亡率。

 CONTEXT: In the Women's Health Initiative randomized, placebo-controlled trial of estrogen plus progestin, after a mean intervention time of 5.6 (SD, 1.3) years (range, 3.7-8.6 years) and a mean follow-up of 7.9 (SD, 1.4) years, breast cancer incidence was increased among women who received combined hormone therapy. Breast cancer mortality among participants in the trial has not been previously reported.

OBJECTIVE: To determine the effects of therapy with estrogen plus progestin on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 (SD, 2.7) years, through August 14, 2009.

DESIGN, SETTING, AND PARTICIPANTS: A total of 16,608 postmenopausal women aged 50 to 79 years with no prior hysterectomy from 40 US clinical centers were randomly assigned to receive combined conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo pill. After the original trial completion date (March 31, 2005), reconsent was required for continued follow-up for breast cancer incidence and was obtained from 12,788 (83%) of the surviving participants.

MAIN OUTCOME MEASURES: Invasive breast cancer incidence and breast cancer mortality.

RESULTS: In intention-to-treat analyses including all randomized participants and censoring those not consenting to additional follow-up on March 31, 2005, estrogen plus progestin was associated with more invasive breast cancers compared with placebo (385 cases [0.42% per year] vs 293 cases [0.34% per year]; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.07-1.46; P = .004). Breast cancers in the estrogen-plus-progestin group were similar in histology and grade to breast cancers in the placebo group but were more likely to be node-positive (81 [23.7%] vs 43 [16.2%], respectively; HR, 1.78; 95% CI, 1.23-2.58; P = .03). There were more deaths directly attributed to breast cancer (25 deaths [0.03% per year] vs 12 deaths [0.01% per year]; HR, 1.96; 95% CI, 1.00-4.04; P = .049) as well as more deaths from all causes occurring after a breast cancer diagnosis (51 deaths [0.05% per year] vs 31 deaths [0.03% per year]; HR, 1.57; 95% CI, 1.01-2.48; P = .045) among women who received estrogen plus progestin compared with women in the placebo group.

CONCLUSIONS: Estrogen plus progestin was associated with greater breast cancer incidence, and the cancers are more commonly node-positive. Breast cancer mortality also appears to be increased with combined use of estrogen plus progestin.

评论：
1，This study confirms the concern initiated by the Women's Health Initiative (WHI) {1}: estrogen and progestin combined increase the risk of breast cancer deaths in postmenopausal women. Although there are limitations to this publication, it is critical for all physicians and healthcare providers to prepare for questions regarding this study.

The WHI researchers provided data that confirmed that the risk of breast cancer is increased with the use of conjugated equine estrogen and medroxyprogesterone acetate as compared to placebo. The hazard ratio (HR) was 1.25 (confidence interval [CI]=1.07-1.46). New data that confirmed the serious nature of the disease demonstrated that more women were node positive (HR 1.78, CI=1.23-2.58) and mortality was higher (HR 1.96, CI=1.00-4.04) for women on estrogen and progestin. The study did not address the critical issue of the effect of estrogen alone on breast cancer risk. Indeed, the initial study demonstrated no increased risk without the progestin component. The extended data on these subjects assessed the effect of estrogen versus estrogen + progestin. This study will be seen by women as confirmation of the danger of hormone use. Although the risk is small, these data confirm the risk of this hormone combination. There is insufficient data to demonstrate that other progestins or lower doses of hormones are safer for women. They will need the information that hormones after menopause increase breast cancer risk. 
Evaluated by:Julia Johnson

References: 
{1} Rossouw et al. JAMA 2002, 288:321-33 [PMID:12117397].


2，This is the first randomized study to examine the influence of estrogen plus progestin postmenopausal hormone therapy use compared to placebo with breast cancer mortality. The authors also conducted another analysis of breast cancer incidence based on the extended follow-up period in the Women’s Health Initiative (WHI). These results suggest that estrogen plus progestin use is associated with increased breast cancer incidence and mortality.

Many previous observational studies have suggested that, although breast cancer incidence is increased following the use of combined postmenopausal hormone therapy, those breast cancers have more favorable outcomes, including lower mortality. Using data from the WHI, a large randomized trial of 16,608 postmenopausal women aged 50 to 79 years in the US, these researchers were able to examine the association between estrogen plus progestin compared to placebo for breast cancer incidence and mortality. Randomization began on November 15, 1993, and the study invention was stopped on July 7, 2002 (after combined hormone therapy use was found to be harmful). However, follow up for outcomes was maintained until March 31, 2005 (the original study end date), and an extension phase of follow up continued until August 14, 2009, for 12,788 women who re-consented to continue to be followed up. 

In contrast to most previous observational studies, the authors found that breast cancer mortality risk (HR=1.96, 95%CI 1.00-4.04) and overall mortality (HR=1.57, 95%CI 1.01-2.48) was higher in women with combined hormone therapy compared with placebo. As some studies have suggested that this risk may be modified when use of combined hormone therapy was started in relation to menopausal status, there was no statistically significant difference between those who started combined hormone therapy within 5 years of menopause and for those who started more than 5 years after menopause. There was a suggested increased risk for those women who had combined hormone use prior to the study (HR=1.85, 95% CI = 1.25-1.80) compared to those women with no prior combined hormone use (HR=1.16, 95% CI -0.98-1.37). No differences were seen by age, body mass index or Gail risk score. Clinicians should have a serious discussion with their post-menopausal patients of the harms and benefits of being on combined hormone therapy after menopause. Competing interests: No potential interests relevant to this article were reported.
Evaluated by:Anita Koushik

专家评价：

         1. 本研究证实了妇女健康倡议（WHI）{1}的忧虑：雌激素和孕激素联合使用增加了绝经后妇女乳腺癌死亡的危险。虽然此文具有局限性，但对于所有医生和健康护理人员而言，对本研究的问题认真思考是很重要的。 WHI研究人员提供的数据证实，使用马结合雌激素和醋酸甲羟孕酮与使用安慰剂相比增加患乳腺癌的风险。危险比（HR）为1.25（可信区间 [CI] = 1.07-1.46）。研究乳腺癌严重程度的新证据表明，马结合雌激素和醋酸甲羟孕酮组乳腺癌妇女淋巴结阳性比例更高（HR 1.78，CI  1.23-2.58），死亡率较高（HR 1.96，CI 1.00-4.04）。这项研究并没有分析单独使用雌激素对乳腺癌风险影响这一关键问题。事实上，最初的研究表明不含孕激素成分的替代治疗不会增加乳腺癌风险。对这些受试者的延长研究比较了单用雌激素与雌激素+孕激素的影响。这一研究结果将被女性视作对激素使用风险的确认。虽然风险小，但这些数据证实了激素联合治疗的风险。没有足够的数据证明妇女使用其他孕激素或减低剂量更安全。妇女需要的是绝经后激素疗法增加乳腺癌风险的这一信息。

试验注册：NCT00000611          

作者：Julia Johnson         

2，这是第一项对比绝经后使用雌激素加孕激素的激素疗法与安慰剂对女性乳腺癌死亡率影响的随机研究。作者在妇女健康倡议（WHI）的延长随访基础上，还进行了另一项乳腺癌发病率的分析。结果表明，雌激素和孕激素的使用增加乳腺癌发病率和死亡率。   许多先前的观察研究表明，虽然绝经后联合使用激素治疗增加了乳腺癌发病率，但乳腺癌预后较好，死亡率较低。WHI是以美国16608名 50~79岁绝经后妇女为研究对象的大型随机试验，研究人员对比了雌激素联合孕激素与使用安慰剂与乳腺癌发病率和死亡率的关联。1993年11月15日开始随机分组，研究干预终止于2002年7月7日（发现联合激素疗法有害之后）。然而，对结局的随访持续至2005年3月31日（初始研究结束日）；12788名妇女同意继续随访，研究者对这部分女性继续延长随访至2009年8月14日。

   与以往大多数的观察性研究不同，研究人员发现，联合激素疗法与安慰剂相比，乳腺癌死亡风险（HR = 1.96，95％CI 1.00-4.04）和总死亡率（HR = 1.57，95％CI 1.01-2.48）较高。一些研究指出，这种风险可能因女性使用联合激素治疗时的绝经状态而异，绝经后5年内或在绝经后5年之后接受联合激素治疗的女性之间风险没有显著差异。在进入本研究之前使用过激素联合治疗（HR = 1.85，95％CI为1.25-1.80）的女性与未接受过联合治疗的女性（HR 1.16，95％CI - 0.98-1.37）相比，风险增加。年龄、体重指数或Gail风险评分无差异。临床医生应该与绝经后女性就绝经后接受联合激素治疗的危害和获益进行认真讨论。  

竞争利益：未报告与本文相关的潜在利益。         

作者:Anita Koushik

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• JAMA. 2011 Feb 2;305(5):466; author reply 466-7.
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• J Midwifery Womens Health. 2011 Mar;56(2):177-8.
• JAMA. 2011 Feb 2;305(5):466; author reply 466-7.
• JAMA. 2010 Oct 20;304(15):1719-20.