Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women's Health Initiative Randomized Clinical Trials
Association of Menopausal Hormone Therapy With Breast Cancer Incidence and Mortality During Long-term Follow-up of the Women's Health Initiative Randomized Clinical Trials
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DOI：
10.1001/jama.2020.9482
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发表时间：
2020-07-28
影响因子：
120.7
通讯作者：
Prentice, Ross L.
中科院分区：
文献类型：
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作者：
Chlebowski, Rowan T.;Anderson, Garnet L.;Prentice, Ross L.
重要性绝经期激素治疗对乳腺癌的影响仍然不稳定，观察性研究和随机临床试验的结果不一致。目的评估妇女健康倡议临床试验中既往随机使用雌激素加炔雌醇或既往随机使用雌激素与乳腺癌发病率和死亡率的关系。长期随访2项安慰剂对照随机临床试验，纳入27347名绝经后妇女，年龄50 - 79岁，既往无乳腺癌，基线筛查乳腺X线检查阴性。从1993年至1998年，美国40个中心的妇女参加了这项研究，随访至2017年12月31日。干预在这项涉及16608名子宫妇女的试验中，8506名妇女随机接受0.625 mg/d的结合马雌激素（CEE）加2.5 mg/d的醋酸甲羟孕酮（MPA）治疗，8102名妇女接受安慰剂治疗。在涉及10739名既往子宫切除术的女性的试验中，5310名随机接受0.625 mg/d的CEE单独治疗，5429名接受安慰剂治疗。CEE + MPA试验在中位干预持续时间为5.6年后于2002年停止，在中位干预持续时间为7.2年后，仅CEE试验于2004年停止。主要结局和指标主要结局为乳腺癌发病率（方案预先规定的伤害主要监测结局）次要结局是乳腺癌死亡和乳腺癌后死亡。结果在两项试验中随机分配的27347名绝经后妇女中，（基线平均[SD]年龄，63.4岁[7.2岁]），在超过20年的中位累积随访后，死亡率信息超过98%。在10739例既往行子宫切除术的妇女中，与安慰剂相比，CEE单独治疗与238例乳腺癌发病率统计学显著降低相关（年发生率，0.30%）vs 296例病例（年发生率，0.37%;风险比[HR]，0.78; 95% CI，0.65-0.93; P = 0.005），并与统计学上显著降低的乳腺癌死亡率（30例死亡）相关（年死亡率，0.031%）vs 46例死亡（年死亡率，0.046%; HR，0.60; 95% CI，0.37-0.97; P = 0.04）。相比之下，在16608名有子宫妇女中，CEE + MPA与安慰剂相比，乳腺癌发病率在统计学上显著升高，分别为584例（年发病率为0.45%）和447例（年发病率为0.36%; HR为1.28; 95%CI为1.13-1.45; P
IMPORTANCE The influence of menopausal hormone therapy on breast cancer remains unsettled with discordant findings from observational studies and randomized clinical trials.OBJECTIVE To assess the association of prior randomized use of estrogen plus progestin or prior randomized use of estrogen alone with breast cancer incidence and mortality in the Women's Health Initiative clinical trials.DESIGN, SETTING, AND PARTICIPANTS Long-term follow-up of 2 placebo-controlled randomized clinical trials that involved 27347 postmenopausal women aged 50 through 79 years with no prior breast cancer and negative baseline screening mammogram. Women were enrolled at 40 US centers from 1993 to 1998 with follow-up through December 31, 2017.INTERVENTIONS In the trial involving 16 608 women with a uterus, 8506 were randomized to receive 0.625 mg/d of conjugated equine estrogen (CEE) plus 2.5 mg/d of medroxyprogesterone acetate (MPA) and 8102, placebo. In the trial involving 10 739 women with prior hysterectomy, 5310 were randomized to receive 0.625 mg/d of CEE alone and 5429, placebo. The CEE-plus-MPA trial was stopped in 2002 after 5.6 years' median intervention duration, and the CEE-only trial was stopped in 2004 after 7.2 years' median intervention duration.MAIN OUTCOMES AND MEASURES The primary outcome was breast cancer incidence (protocol prespecified primary monitoring outcome for harm) and secondary outcomes were deaths from breast cancer and deaths after breast cancer.RESULTS Among 27 347 postmenopausal women who were randomized in both trials (baseline mean [SD] age, 63.4 years [7.2 years]), after more than 20 years of median cumulative follow-up, mortality information was available for more than 98%. CEE alone compared with placebo among 10 739 women with a prior hysterectomy was associated with statistically significantly lower breast cancer incidence with 238 cases (annualized rate, 0.30%) vs 296 cases (annualized rate, 0.37%; hazard ratio [HR], 0.78; 95% CI, 0.65-0.93; P =.005) and was associated with statistically significantly lower breast cancer mortality w th 30 deaths (annualized mortality rate, 0.031%) vs 46 deaths (annualized mortality rate, 0.046%; HR, 0.60; 95% CI, 0.37-0.97; P =.04). In contrast, CEE plus MPA compared with placebo among 16 608 women with a uterus was associated with statistically significantly higher breast cancer incidence with 584 cases (annualized rate, 0.45%) vs 447 cases (annualized rate, 0.36%; HR, 1.28; 95% CI, 1.13-1.45; P